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Depression

FitSugar — Wed, 08 Oct 2008 17:34:57 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Complications of Depression...
Diagnosis
Treatment
Antidepressants and Drug Tr...
Psychotherapy
Other Treatments
Lifestyle Changes
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In 2007, the Food and Drug Administration (FDA) approved the atypical antipsychotic drug aripiprazole (Abilify) for treatment of major depression in adults. Aripiprazole is used for treatment of schizophrenia and bipolar disorder. For depression, it is used in combination with antidepressant drug therapy. Researchers are also investigating other atypical antipsychotics for major depression treatment.

Antidepressants and Suicide Risk

In 2007, the FDA proposed adding new information to antidepressant warning labels concerning the increased risk for suicidal thinking and behavior among young adults ages 18 - 24 during the initial months of drug therapy.
The benefits of antidepressants for children and adolescents outweigh their potential risks, suggests a 2007 study in the Journal of the American Medical Association.

Antidepressants During Pregnancy

Most selective serotonin reuptake inhibitors (SSRIs) do not significantly increase the risk for birth defects when taken during early pregnancy, indicate several 2007 studies in the New England Journal of Medicine. However, some SSRIs -- such as paroxetine (Paxil) -- carry a higher risk than others. Researchers are still studying the overall safety of SSRIs during pregnancy. Women with depression should discuss with their doctors all potential risks and benefits.

Introduction

Everyone experiences some unhappiness, often as a result of a change, either in the form of a setback or a loss, or simply, as Freud said, "everyday misery." The painful feelings that accompany these events are usually appropriate, necessary, and transitory, and can even present an opportunity for personal growth. However, when depression persists and impairs daily life, it may be an indication of a depressive disorder. Severity, duration, and the presence of other symptoms are the factors that distinguish normal sadness from a depressive disorder.

Depression has been alluded to by a variety of names in both medical and popular literature for thousands of years. Early English texts refer to "melancholia," which was for centuries the generic term for all emotional disorders.

Depression is now referred to as a mood disorder, and the primary subtypes are major depression, dysthymia (chronic and usually milder depression), and atypical depression. Other important forms of depression are premenstrual dysphoric disorder (PDD or PMDD) and seasonal affective disorder (SAD).

Depression is defined as a mood disorder, and there are several subtypes. Bipolar disorder, also known as manic-depressive illness, is considered in a separate category.

The other major mood disorder is bipolar disorder, or manic-depressive illness, which is characterized by periods of depression alternating with episodes of excessive energy and activity. Bipolar disorder is not discussed in this report. [For more information, see In-Depth Report #66: Bipolar disorder.]

In major, or acute, depression, at least five of the symptoms listed below must occur for a period of at least 2 weeks, and they must represent a change from previous behavior or mood. Depressed mood or loss of interest must be present. Symptoms include:

1. Depressed mood on most days for most of each day -- irritability may be prominent in children and adolescents

2. Total or very noticeable loss of pleasure most of the time

3. Significant increases or decreases in appetite, weight, or both

4. Sleep disorders, either insomnia or excessive sleepiness, nearly every day

5. Feelings of agitation or a sense of intense slowness

6. Loss of energy and a daily sense of tiredness

7. Sense of guilt or worthlessness nearly all the time

8. Inability to concentrate occurring nearly every day

9. Recurrent thoughts of death or suicide

In addition, other criteria must be met:

The symptoms listed above do not follow or accompany manic episodes (such as in bipolar disorder or other disorders).
They impair important normal functions (such as work or personal relationships).
They are not caused by drugs, alcohol, or other substances.
They are not caused by normal grief.

A long-term study found that episodes of major depression usually last about 20 weeks. Between 30 - 40% of depressed patients experience sudden attacks of anger that they describe as uncharacteristic and inappropriate.

Click the icon to see an image of childhood depression.

Dysthymia, or chronic depression, afflicts 3 - 6% of the general population and is characterized by many of the same symptoms that occur in major depression. Symptoms of dysthymia are less intense and last much longer, at least 2 years. The symptoms of dysthymia have been described as a "veil of sadness" that covers most activities. Possibly because of the duration of the symptoms, patients who suffer from chronic minor depression do not exhibit marked changes in mood or in daily functioning, although they have low energy, a general negativity, and a sense of dissatisfaction and hopelessness.

Double Depression. Often, symptoms become more severe over time. In one long-term study, nearly all patients with dysthymia suffered at least one episode of major depression superimposed over chronic depression (sometimes called double depression) at some time in their life. Some experts believe that such double depression should be considered as part of the natural course of dysthymic disorder. Women may be more susceptible to double depression. In one study, more than one-third of those who recovered from dysthymia relapsed within 5 years.

About a third of patients with depression have atypical depression. Symptoms include overeating and oversleeping. Such patients tend to have a feeling of being weighed down and react strongly to rejection. It tends to occur more in women, unmarried people, and those with other emotional disorders, such as anxiety or substance abuse. It also may impair functioning more severely than ordinary depression does.

Seasonal affective disorder (SAD) is characterized by annual episodes of depression during fall or winter that remit in the spring or summer. Other SAD symptoms include fatigue and a tendency to overeat (particularly carbohydrates) and oversleep in winter. A minority of individuals with SAD has the more common depressive symptoms of undereating and being sleepless. SAD tends to last about 5 months in those who live in the northern part of the U.S.

Seasonal changes affect many people's moods, regardless of gender and whether or not they have SAD. Simply being mildly depressed during the winter does not mean that one has SAD. Living in a northern country with long winter nights does not guarantee a higher risk for depression. Changes in light may not be the only contributor to SAD.

Causes

The causes of depression are not fully known. Most likely a combination of genetic, biologic, and environmental factors are at work.

Because depression runs in families, and has a strong genetic component, compelling evidence suggests that depression is a biologic phenomenon. Data from family, twin, adoption, and genetic studies have confirmed this. Studies have found that first-degree relatives of patients with depression are two to six times more likely to develop the problem than individuals without a family history.

Evidence supports the theory that depression has a biologic basis. The basic biologic causes of depression are strongly linked to abnormalities in the delivery of certain key neurotransmitters (chemical messengers in the brain). These neurotransmitters regulate mood and associated behaviors. Scientists hope that by identifying the gene mutations that code the regulation of these neurotransmitters, they may eventually be able to predict which patients are most likely to respond to specific antidepressant drugs.

Serotonin. Perhaps the most important neurotransmitter in depression is serotonin. Among other functions, it is important for feelings of well-being. Imbalances in the brain’s serotonin levels can trigger depression and other mood disorders.
Other Neurotransmitters. Other neurotransmitters possibly involved in depression include acetylcholine and catecholamines, a group of neurotransmitters that consists of dopamine, norepinephrine, and epinephrine (also called adrenaline). Corticotropin-releasing factor (CRF), which is believed to be a stress hormone and a neurotransmitter, is thought to be involved in depression and anxiety. Increased CRF concentrations appear to interact with serotonin and have been detected in patients with either depression or anxiety.

Endocrine glands release hormones into the bloodstream that are transported to various organs and tissues throughout the body. For instance, the pancreas secretes insulin, which allows the body to regulate levels of sugar in the blood. The thyroid gets instructions from the pituitary gland to secrete hormones that determine the pace of chemical activity in the body. The more hormone in the bloodstream, the faster the chemical activity; the less hormone, the slower the activity.

The degree to which these chemical messengers are disturbed is determined by other factors, such as light, structural abnormalities in the brain, sleep disorders, or genetic susceptibility. For example, researchers have identified a defect in the gene known as SERT, which regulates serotonin and has been linked to depression.

Reproductive Hormones. In women, the female hormones estrogen and progesterone most likely play a role in depression.

Women, regardless of nationality or socioeconomic level, have significantly higher rates of depression than men. The causes of such higher rates appear to be a mix of biologic and cultural factors.

Social and Economic Factors. The role that work, marriage, and children play in a woman's depression is complex. Many women feel that they must be everything to everyone and at the same time feel as if they are no one at all. Such a self-image is common and should be strongly considered as a major contributor to depression in many women, particularly those who work and have small children.

Hormonal Fluctuations and Life Stages. Extreme hormonal shifts can trigger emotional swings in all women. The role of hormones in depression is not clear, however, and is mostly based on observations of depression during specific stages in female development. Female hormones undoubtedly play some role in premenstrual dysphoria, postpartum depression, and SAD. These forms of depression recede or stop after menopause.

Early Puberty. Girls who go through puberty early (reaching the midpoint at 11 years or younger) are more likely to experience depression during adolescence than girls who mature later.

Premenopause. Premenopausal women ages 20 - 45 are most susceptible to depression, with 22% of this age group reporting symptoms of major depression. Specifically, premenstrual dysphoric disorder (severe depression before a period) affects an estimated 3 - 8% of women during their reproductive years. [For more information, see In-Depth Report # 79: Premenstrual syndrome.]

Perimenopause. Depression often occurs around menopause (the perimenopausal period), when, in addition to hormonal changes, other factors such as cultural pressures favoring young women, sudden recognition of aging, and sleeplessness are involved.

Postmenopause. Once women pass into the postmenopausal period, studies suggest that average depression scores are nearly as low as those in premenopausal women. In fact, many women report that after menopause, previous bouts of depression, particularly when caused by seasonal changes or premenopausal syndrome, recede or stop completely.

Premenstrual Dysphoric Disorder. The syndrome of severe depression, irritability, and tension before menstruation is known as premenstrual dysphoric disorder (PDD or PMDD), also called late-luteal dysphoric disorder. It affects an estimated 3 - 8% of women in their reproductive years. A diagnosis of PDD depends on having five or more standard symptoms of major depression that occur during most menstrual cycles, with symptoms worsening a week or so before the menstrual period and resolving afterward. PMDD has features of both anxiety and depression disorders, although experts increasingly believe it is a distinct disorder with specific biochemical abnormalities. [For more information, see In-Depth Report #79: Premenstrual disorder.]

Depression During Pregnancy. Pregnancy is certainly an occasion of great celebration for most women most of the time. However, emotions during that time are not always straightforward, and depression is a common (although most often a temporary) companion. Prenatal depression can affect a mother's sleep, physical activity, adherence to care, and appetite.

Miscarriage. Miscarriage poses a very high risk for depression, particularly in the first month after the loss. Older women with no previous successful pregnancies and those with a history of depression are at particular risk during this time. (Despite some concern that depression increases the risk for miscarriage in the first place, there is no evidence to support this.)

Postpartum Depression. Most new mothers experience weeping, irritability, and confusion for a few days following childbirth. Such symptoms, known as the "baby blues," are not considered signs of postpartum depression unless they persist in severe form nearly every day for more than 1 - 2 weeks.

Women are most likely to develop postpartum depression and other mental disorders in the first 3 months following delivery. (The risk is highest for first-time mothers, especially in the 10 - 19 days after delivery.) Other studies have reported that 8 - 20% of women have diagnosable postpartum depression within that 3-month period. In one study, 5% of these women had suicidal thoughts.

Studies have not found any association between a higher risk for postpartum depression in women and the following:

Educational level
Gender of the child
Whether or not the woman breast-feeds
Whether or not the pregnancy was planned
Whether the delivery was vaginal or cesarean

The rapid decline of reproductive hormones that accompany childbirth is likely to play the major role in postpartum depression in susceptible women. Fluctuating thyroid hormones can also contribute to depression. Studies suggest that women who are more sensitive to hormone fluctuations are at greater risk for postpartum depression if they have one or more of the following conditions:

A history of prior depressive episodes
A family history of mood disorders
Stressful life events (such as being a new mother and having an infant with medical problems)
Lack of social support or feeling as if it is lacking

Depressed children often suffer in silence, and depression may be evident only from reports of problems in school. It is also often difficult for adults to believe that children can be chronically depressed. Symptoms for depression in children often differ from those in adults and may include the following:

An inability to enjoy favorite activities
Persistent sadness
Increased irritability
Complaints of physical problems, such as headaches and stomachaches
Poor performance in school
Persistent boredom
Low energy
Poor concentration
Changes in eating and/or sleeping patterns
A greater tendency to bully others -- anxious children are more often bullied.

Risk Factors for Depression in Children and Adolescents. Depression can occur in children of all ages, including preschoolers, although adolescents have the highest risk (about 20%). Risk factors for depression in young people include having parents, particularly mothers with depression. Early negative experiences and exposure to stress, neglect, or abuse also pose a risk for depression. Sometimes depression develops after a physical illness. In adolescents, feeling alienated from parents is a strong predictor for depression.

Outlook for Future Emotional Problems. Adolescents who have depression are at significantly higher risk for substance abuse, recurring depression, and other emotional problems (such as bipolar disorder) in adulthood.

Risk for Suicide in Adolescents. Suicide is the third most common cause of death among adolescents, and is one of the most devastating events than can happen to a family. Suicide is most commonly associated with depression in young people but it is also linked with anxiety, psychosis, substance abuse, or impulsivity. More girls attempt suicide but more boys succeed, most often because they choose guns or violent methods while girls tend to overdose, which is more treatable. Nevertheless, attempts are major risk factors for a later suicide. Any expression of suicidal intent should be treated very seriously.

The following are danger signs in young people:

Withdrawal from friends
Sudden decrease in school performance
Loss of interest in activities that were previously pleasurable
Unusual irritability
Unusual changes in sleep or eating habits

Risk factors for suicide include a history of neglect or abuse, history of deliberate self-harm, a family member who committed suicide (nearly always one who shared a common mood disorder), access to firearms, and living in communities where there have been recent outbreaks of suicide in young people. A romantic break-up is often the trigger for a suicidal attempt in teenagers. Feeling connected with parents and family protected young people with depression in one study, regardless of gender or ethnicity.

Adolescents may fail to seek help for suicidal thoughts for the following reasons:

They believe nothing would help
They are reluctant to tell anyone they had problems
They think it is a sign of weakness to seek help
They do not know where to go

Parents should not hesitate to seek professional help for their children if they suspect they are thinking about killing themselves. This is a medical emergency and requires immediate treatment.

Behavioral therapies and antidepressants are promising treatments for preventing suicide but need study. There has been a decline in adolescent suicides over the past decade, which some experts attribute to the increased use of antidepressants in this population. However, recent evidence has indicated that antidepressants can also raise the risk for suicidality (suicidal thoughts and behavior) in some people. Children, adolescents, and young adults who are prescribed antidepressant medication should be carefully monitored by both their parents and doctor, especially during the first few months of treatment, for any worsening of depression symptoms or changes in behavior. [See Suicide Risk and Antidepressant Medications in Medication section.]

Although depression in the elderly is very common, the aging process itself is unlikely to be the cause in most cases. An Italian study, for example, indicated that the very old (people who lived beyond 90 years of age) were no more likely to be depressed than younger adults. (The rate was 10% in both groups.) Studies on the cause or extent of depression in the elderly are not clear.

The severity of depression in elderly patients is strongly associated with poor health and less ability to function. In one study of older adults undergoing rehabilitation, half of whom were depressed, as their function improved so did their mood.

Anyone who experiences cumulative negative life events, physical illness, the death of a loved one, impaired functioning, or loss of independence can become deeply depressed. The elderly are at highest risk for such events.

Diagnosing Depression in the Elderly. Because of the complex relationship between depression, drug interactions, and serious physical illness in the elderly, an accurate diagnosis in this group is important but not always straightforward. The characteristic symptoms of depression are not always present or readily apparent in older people:

Some older people may be aware of their depression but believe that nothing can be done about it.
Many elderly people who are depressed may report only physical symptoms (aches and pains) or other mood states (confusion, agitation, anxiety, and irritability) related to depression rather than depression itself.
Often they are unable or unwilling to express their feelings or are even unaware that they are depressed.
Their symptoms are often ignored or confused with other ailments common in the elderly, including Parkinson's or Alzheimer's disease, dementia, thyroid disorders, arthritis, stroke, cancer, heart disease, and other chronic conditions.
Depression is also a side effect of many drugs that are commonly prescribed for the elderly. It is often very difficult, then, to determine if the patient's depression is a psychologic reaction to the illness, caused by the disease itself, or completely independent from the medical condition. Both physical and emotional conditions should be considered in making a diagnosis in older people.

Many studies suggest strong associations between even mild depression and poorer quality of life as well as a shorter lifespan.

Risk for Suicide in the Elderly. Suicide in the elderly is the third-leading cause of death related to injury. Men account for 81% of these suicides, with divorced or widowed men at highest risk.

Effects of Depression on the Ability to Function. Even mild depressive symptoms in people aged 65 and above are associated with a higher risk of becoming disabled and having a lower chance of recovery.

Heart Disease and Heart Attacks. Depression increases the severity of a heart attack and may even impair a patient's response to medication for heart disease. Although people with heart disease may certainly become depressed, this does not explain entirely the link between the two problems. Data suggest that depression itself may be a true risk factor for heart disease as well as its increased severity. A number of studies indicate that depression has biologic effects on the heart, including a higher risk for blood clotting, changes in heart rate, and impaired blood flow to the heart (particularly in response to mental stress). The more severe the depression, the more dangerous to the health, although even mild depression, including feelings of hopelessness, experienced over many years, may harm the heart, even in people with no early signs of heart disease.

Mental Decline. Depression in the elderly is associated with a decline in mental functioning, regardless of the presence of dementia. Depression may be a predictor or even a cause of Alzheimer's disease. Brain scans in the elderly, for example, have reported greater atrophy in the brains of depressed individuals than in those of nondepressed ones.

Risk Factors

According to a major surveys, more than 13% of Americans have major depression disorder over the course of their lifetimes. Furthermore, an estimated 18 million Americans experience major depression each year. Depression is second only to high blood pressure as a chronic condition encountered by primary care doctors. Depression is an illness that can afflict anyone, regardless of age, race, class, or gender. A third of all depressed people consider suicide, and 9% attempt it.

Depression in Women. At any given time, 5 - 9% of women are depressed, compared to 1 - 3% of men. In one study, nearly half of all women surveyed had experienced depression at some point in their lives and over half of those who suffered from it had sought treatment. Women are also more apt to have multiple types of depression (dysthymia and major depression). [For more information, see Depression in Women.]

Depression in Men. Depression is not rare in men. In fact, prepubescent boys are more likely than girls of the same age to be depressed. Older men are also at much higher risk for suicide and, as with women, they are at risk for health complications of depression. Some evidence suggests that men are more apt than women to mask their depression by using alcohol, which may result in a lower reported (but not actual) incidence of depression in men. Some experts suggest that men with depression might be identified with the following indicators:

Low tolerance to stress
Behaviors such as "acting out" and being impulsive
A history of alcohol or substance abuse
A family history of depression, alcohol abuse, or suicide

Depression is less reported in the male population, but this may be caused by male tendency to mask emotional disorders with behavior such as alcohol abuse.

Depression in Children and Adolescents. Children ages 12 - 16 are at high risk for depression. Studies suggest that 3 – 5% of children and adolescents suffer from depression, and 10 – 15% have some depressive symptoms. Depression before puberty is more likely to occur in boys and after puberty in girls.

Depression in Adults. Surveys indicate that depression usually begins around the age of 30, although people do not generally seek treatment until they are about 33 years old. Statistics also suggest that depression is becoming more common among middle-aged people ages 45 - 64. According to a 2005 survey, middle-aged adults have the highest lifetime risk for depression.

Depression in the Elderly. Studies suggest that 5 – 14% of the elderly population suffer from some form of depression. In addition, the elderly are highly vulnerable to suicide. Elderly people comprise 13% of the U.S. population but account for 18% of all suicide deaths.

The role of society and economics has specific implications for women. [See Depression in Women.] Being in a low socioeconomic group is a major risk factor for depression in anyone. Money, of course, allows greater access to good medical care, but this factor does not fully explain the higher rates of depression in impoverished people. People at any income level are likely to be depressed if they have poor health and are socially isolated. Some studies suggest that Western cultural attitudes that link income to social status may play a significant role in the connection between poverty and depression:

In one British study, actual poverty or unemployment increased the duration of any existing depression, but it did not appear to play any important causal role. Feelings of financial insecurity, however, both caused and prolonged depression.
Another study reported that Mexican adults who immigrated to America had half the psychiatric illnesses as did Mexican-Americans born in the U.S., regardless of their income. But the longer the immigrants lived in the U.S., the greater their risk for psychiatric problems. Traditional influences of Mexican culture and social ties appeared to protect newly arrived immigrants from mental illness, even when they were poor. Eventually, however, the consequences of Americanization added to poverty and led to feelings of alienation and inferiority.

Depression in family members increases the risk for depression in other family members. Studies report that depression for even 1 - 2 months in a mother increases the risk for depression in her children. The more severe the maternal depression, the higher the risk for depression in the children. In a perpetuating cycle, being depressed as a child increases the risk for depression during adulthood. In such cases, genetic or environmental factors or both may be responsible. Spouses of partners with depression are themselves at higher risk for depression.

Patients who have had serious bouts of depression usually cite a stressful life event as the precipitating factor for their illness. Adverse events during childhood pose a higher risk for depression in adulthood. In one study, parental divorce, physical abuse, and frightening experiences were particularly associated with onset of depression in adulthood. Only divorce was associated with recurrence, however.

Adverse events in adulthood also trigger depression. Losing a spouse through divorce or death is a major risk factor for depression in anyone. In fact, recent loss of a loved one is the most frequently reported precipitant of acute depression. All major (and even minor) losses, however, cause grief reactions. People who develop acute or chronic depression after a loss may have predisposing factors, including genetic or biologic ones, which make them more vulnerable. The existence or absence of a strong social network of family, friends, or both also has a major positive or negative effect, respectively, on recovery. Most people are able to cope with the emotional pain and eventually move beyond it without becoming chronically depressed. [See Ruling out Grief and Loneliness in the diagnosis section of this report.]

Traumatic events such as abuse or even natural disasters can cause severe immediate or delayed depression from which recovery takes a long time.

Severe or Chronic Medical Conditions. Any chronic or serious illness that is life-threatening or out of a person's control can lead to depression.

Thyroid Disease. Hypothyroidism (a condition caused when the thyroid gland does not produce enough hormone) can cause depression. However, hypothyroidism may also be misdiagnosed as depression and go undetected.

Chronic Pain Conditions. Studies have reported a strong association between depression and headaches, including chronic tension-type and migraine. Some experts believe that a syndrome of migraine headaches (and also possibly tension-type), anxiety, and depression is caused by common factors, such as abnormalities in chemical messengers, particularly dopamine or serotonin. Fibromyalgia and other chronic pain syndromes are also associated with depression.

Stroke and Other Neurological Conditions. Having a stroke increases the risk of developing depression. Also, patients with Parkinson's disease, spinal cord injuries, and other similar problems that impair movement or thinking are associated with depression.

Heart Failure. Patients with heart failure or patients who have suffered a heart attack may also suffer from depression.

A number of drugs taken for chronic problems cause depression. Among them are pain relievers for arthritis, cholesterol-lowering drugs, medications for high blood pressure and heart problems, and bronchodilators used for asthma and other lung disorders.

There is a significant association between cigarette smoking and a susceptibility to depression. People who are prone to depression face a 25% chance of becoming depressed when they quit smoking, and this increased risk persists for at least 6 months. What's more, depressed smokers are unlikely to stop smoking. Only about 6% remain smoke-free after a year. Smokers with a history of depression are not encouraged to continue smoking, but rather to keep a close watch on recurrence of depressive symptoms if they do stop smoking. The antidepressant bupropion (Wellbutrin), which is approved for helping people quit smoking (marketed under the name Zyban), is proving to be very useful in helping smokers to quit.

Chronic depression is a frequent companion to anxiety disorders. In one study, up to 96% of patients with depressive disorders experienced concurrent anxiety. More than two-thirds of people with obsessive-compulsive disorder, a common anxiety disorder, also suffer from depression.

Some evidence suggests that certain personality styles, which include an intense need for close relationships and concern for disapproval or need for control, pose a high risk for depression, particularly after an adverse life event. In line with these findings, the following specific personality disorders have been associated not only to a first episode of depression, but also to relapses:

A person with borderline personality disorder acts impulsively and has a poor self-image and unstable relationships. In one study, patients with borderline personality disorder and major depression were more likely than those with either condition alone to plan and attempt suicide.
An individual with an avoidant personality avoids strangers and unfamiliar situations.

(Personality disorders, as opposed to emotional disorders, are those with abnormal behavioral patterns rather than abnormal emotions.)

Sleep abnormalities are an integral part of depressive disorders, with more than 90% of depressed patients experiencing insomnia. Although stress and depression are major causes of insomnia, insomnia may also increase the activity of the hormones and pathways in the brain that can produce emotional problems. Even modest alterations in waking and sleeping patterns can have significant effects on a person's mood. Persistent insomnia may even predict the future development of emotional disorders. Some experts think that some psychiatric disorders can be prevented by early recognition and treatment of insomnia.

Seasonal affective disorder (SAD) affects about one in 20 adults. About 80% of people who suffer from SAD are women. People who live in the north are more apt to experience SAD than people who live in southern latitudes.

Complications of Depression

Depression is often chronic, with episodes of recurrence and improvement. About one-third of patients with a single episode of major depression will have another episode within 1 year after discontinuing treatment, and more than 50% will have a recurrence at some point in their lives. Depression is more likely to recur if the first episode was severe or prolonged, or if there have been recurrences. To date, even newer antidepressants have failed to achieve permanent remission in most patients with major depression, although the standard medications are very effective in treating and preventing acute episodes.

About 90% of suicides are due to treatable disorders, most commonly depression or substance abuse. People with depression have up to a 15% risk for suicide, with the highest risk in patients who are hospitalized for depression. Some studies indicate that atypical depression poses a higher risk for suicide than typical depression and that dysthymia may pose a higher risk than episodic major depressive disorder. Depressed men are more likely to commit suicide than depressed women. Around the world, suicide is most common in men older than 60. Suicidal preoccupation or threats of suicide should always be treated seriously in anyone, however. [See Depression in the Elderly or Depression in Children in this report.]

Major depression in the elderly or in people with serious illness seems to reduce their survival rates, even independently of any accompanying illness. Decreased physical activity and social involvement certainly play a role in the association between depression and illness severity.

Effect on Heart Disease and Other Age-Related Problems. Many studies report strong associations between depression and a worse and even shorter old age. Depression is also associated with mental decline in older people.

Studies are now showing that depression may contribute to poor outcomes for patients with heart disease.

Obesity. Both obesity and depression are increasing in Americans. Adolescents who are depressed have a high risk for obesity. Conversely, obese people are about 25% more likely than non-obese people to develop depression or other mood disorders. The conditions may have common risk factors. For example, being in a lower social and economic group increases the risk for both obesity and depression. Low physical activity may also be a common factor.

Increasing Sensations of Pain. Depression coincides with increased pain in people with conditions such as those arthritis or fibromyalgia.

Cancer. The relationship between depression and cancer has been explored for years with only a few clear-cut associations. Certainly depression and anxiety can have a profound impact on quality of life in cancer patients.

Effects of Parental Depression on Children. Depression in parents can have profound effects on their children and may increase the risk for childhood depression.

Effects on Marriage. In one survey, nearly half of people who suffered from psychiatric disorders before or during their first marriage were divorced, compared to a divorce rate of 36% in those who never suffered from emotional disorders. Spouses of partners with depression are themselves at higher risk for depression.

Effect on Work. Depression is well-known to adversely affect a person's work life. It significantly increases the risk for unemployment and lower income. Nearly half of the nation's excess lost productive time (in most cases because of reduced performance at work) may be a result of depression. Workers with depression also lose significantly more time due to ill health than non-depressed workers. Such lost time is estimated to cost the country billions of dollars each year.

Alcohol and Drug Abuse. About 14% of people with major depression also have an alcohol use disorder and 5% have drug abuse problems. Studies on the connections between alcohol dependence and depression have still not resolved whether one causes the other or if they both share some common biologic cause.

Smoking. Depression is a well-known risk factor for smoking, and 26% of people with major depression are nicotine dependent. Nicotine may stimulate receptors in the brain that improve mood in certain people with genetically induced depression.

Diagnosis

Most people who are depressed do not seek psychiatric help and must rely on their family doctor. Unfortunately, it is often difficult for a primary care doctor to recognize the problem if the patient does not bring it up directly.

Patients themselves may be unable to sense or admit their own depression. In one study, although 21% of patients who visited their family doctors were depressed, only 1% described their problem as depression.

Depression can also be confused with other medical illnesses. Weight loss and fatigue, for example, accompany many conditions, some serious, but they can also occur with depression.

Although not all patients who visit their doctor should be screened for depression, individuals who have certain factors might ask their doctor if they should be screened for depression. For example, the following people may be at higher risk and therefore warrant a screening test:

People with a family or personal history of depression
Patients with multiple medical problems
Patients with physical symptoms that have no clear medical cause
Patients with chronic pain
Individuals who visit their doctor more frequently than expected

A mental health specialist, such as a psychiatrist, social worker, or psychologist, is the best source for a diagnosis of depression. Such health professionals may administer a screening test such as the Beck Depression Inventory or the Hamilton Rating Scale, both of which consist of about 20 questions that assess the individual for depression. Studies are finding that even computerized phone interviews are valuable as screening tools for depression. However, most mental health professionals generally diagnose depression based on symptoms and other criteria.

Specific ethnic groups may present different symptoms of depression. People from non-Western countries are more apt to report physical symptoms (such as headache, constipation, weakness, or back pain) related to the depression, rather than mood-related symptoms.

Grief. The symptoms of grief (bereavement) and depression have much in common; indeed, it may be difficult to separate the two. Grief, however, is considered to be a healthy and important emotional response for dealing with loss, and it generally follows a characteristic path:

Grief normally has a limited duration. In people without any co-existing emotional disorder, bereavement usually lasts between 3 - 6 months.
The grieving person typically endures a succession of emotions that include shock and denial, loneliness, despair, social alienation, and anger.
The recovery period following this process, during which the individual becomes re-involved with life, takes about the same amount of time as the bereavement cycle.

If the grief is still severe after this period, however, it may affect a person's health or increase the risk for on-going depression. Some experts suggest that such a severe persistent grieving state be categorized as a separate psychologic diagnosis, termed complicated grief disorder, which would be related to post-traumatic stress syndrome and require special treatment.

Loneliness. Like grief, loneliness is a condition that may often be mistaken for depression. In fact, while loneliness and depression often go hand in hand, some researchers believe that some people with loneliness may be effectively treated for depression. Of course, every person feels loneliness now and then. Debilitating loneliness, however, is often characterized by misery, a feeling of hollowness, unrealistic expectations for one's life, and feeling removed from others. Shy people may be more prone to loneliness. Psychotherapy of various kinds may help people address and allay loneliness.

Treatment

Depression is a treatable illness, with many therapeutic options available. Increasingly, professionals are viewing major depression as a chronic illness (the condition nearly always returns when treatment is stopped). Therefore, medical intervention and help must be ongoing.

Patients with chronic depression have a number of options, including psychotherapy, antidepressants, or both. In general, the treatment choice depends on the degree and type of depression and other accompanying conditions. It also may depend on age, pregnancy status, or other individual factors.

Unfortunately, many Americans with major depression receive either inadequate treatment or no treatment at all. Reasons may include treatment by providers who may not have sufficient information or training on dosages or specific drugs that would be best suited for individual cases, lack of recognition of depression symptoms by providers, poor access to health care services, lack of health insurance, and poor compliance with medications.

Patients with Major Depression. Numerous studies support a combination of cognitive behavioral therapy (CBT) plus antidepressants, typically a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI). Although some people may feel better after taking antidepressants for a few weeks, most people need to take medication for at least 6 - 12 months to ensure a full response. Research indicates that patients respond better to medications when drug therapy is combined with CBT. Exercise is also important in helping relieve depressive symptoms.

For patients who are not helped by SSRIs or SNRIs, other types of antidepressants are available. Sometimes an atypical antipsychotic drug may be given in combination with an antidepressant for patients with severe major depressive disorder.

Brain stimulation techniques, such as electroconvulsive therapy (ECT) and vagus nerve stimulation, are also options. In recent years, experimental procedures, such as repetitive transcranial magnetic stimulation, have also been found to help in some cases of treatment-resistant depression. Researchers are also investigating new types of drugs (such as ketamine), which may provide a rapid, if temporary, improvement for these patients. In general, the more treatment strategies that patients need, the less likely they are to recover completely from depression.

Patients with Minor Depression. Patients with minor depression (fewer than five symptoms that persist for fewer than 2 years) may respond well to watchful waiting to see if antidepressants are necessary. Some studies indicate that antidepressants do not work that well for mild depression. Counseling or cognitive behavioral therapy may be helpful, as is regular exercise.

Patients with Depression and Other Psychiatric Problems. Other psychiatric problems often coexist with depression. If patients also suffer from anxiety, treating the depression first often relieves both problems. More severe psychiatric problems, such as bipolar disorder or schizophrenia, require specialized treatments.

Patients with Depression and Medical Conditions. Depression can worsen many medical conditions and may even increase mortality rates from some disorders, such as heart attack and stroke. Depression, then, should be aggressively treated in anyone with a serious medical problem.

Patients with Depression and Substance Abuse Problems. Treating depression in patients who abuse alcohol or drugs is important and can sometimes help patients quit. However, absence from substance abuse is considered essential for adequate treatment of depression.

Most people with depression can be treated in an office setting by a psychiatrist or other therapist. Infrequently, the level of dysfunction may be serious enough to warrant hospitalization to provide protection from further deterioration or self-harm.

Health professionals who can prescribe antidepressants include:

Doctors, including psychiatrists
Some nurse clinicians

Although other mental health professionals cannot prescribe drugs, most therapists have arrangements with a psychiatrist for providing medications to their patients. In general, mental health professionals are categorized by their training:

Psychoanalysts tend to have a degree in psychiatry, psychology, or social work as well as several years of training at a psychoanalytic institute.
Psychologists have received a Ph.D, including an internship in a mental healthcare facility.
A clinical social worker has a master's degree and 2 years of supervised experience in mental health and human services.
Advanced-practice psychiatric nurses have a master's degree and can provide therapeutic services.

Tips for Selecting a Therapist:

Patients can locate a mental health professional in their area by asking their doctor for a referral or by contacting a mental health organization. [See Resources.]
The patient should describe problems briefly but specifically over the phone to any prospective therapist to get a sense of whether he or she will suit the patient's needs.
An advanced degree does not necessarily guarantee quality therapy. The patient's belief in their health care provider may be the most important component in recovery.
Patients should not be shy about considering a change in their therapist if they lack confidence in their current one.

Although a mother's depression during and after pregnancy can have serious effects on her child, researchers are still trying to determine the best methods for preventing and treating pregnancy-related depression.

The use of antidepressants during pregnancy is controversial, especially for women with major depression who regularly take antidepressant medication. Most doctors advise women to avoid, if possible, any medications during pregnancy and nursing. But, women with depression who stop taking antidepressants during pregnancy may be likely to have a relapse of depression. Women who are pregnant or thinking about becoming pregnant should not stop taking antidepressants without first talking to their doctors.

Some research suggests that certain serotonin reuptake inhibitors (SSRIs) may increase risks for the fetus. The strongest evidence concerns the SSRI paroxetine (Paxil), which can cause major birth defects -- including heart abnormalities -- if taken during the first trimester of pregnancy. In 2006, the American College of Obstetricians and Gynecologists recommended that doctors should not prescribe paroxetine to women who are pregnant or planning on becoming pregnant.

Other research indicates that first-trimester use of SSRIs may increase the risk for rare skull and neural tube defects. Venlafaxine (Effexor), a dual inhibitor antidepressant, has been associated with birth complications when taken during the last trimester. In addition, some studies have shown that babies may experience withdrawal symptoms if their mothers take SSRIs late in pregnancy. However, the overall evidence indicates that there is a very low overall risk for antidepressant-associated birth defects and problems. Still, women should discuss all potential risks with their doctors.

In terms of non-drug treatment of postpartum depression, a review of 15 clinical trials suggested that postpartum depression is best treated by intensive and individualized psychotherapy within a month after a woman gives birth. The researchers found that women are too busy in the weeks before birth to attend prenatal classes that focus on preventing postpartum depression.

Some experts recommend only psychotherapy or attention intervention for elderly patients with mild depression. In many older patients, a regular exercise program may be sufficient to improve mood. Ideally, elderly people with more serious depression should be treated with a combination of psychotherapy and antidepressants on an ongoing basis, even after their depressive symptoms are relieved.

The use of antidepressants in the elderly is problematic:

Tricyclics are as effective as, and less expensive than, SSRIs, but they have more side effects. Specifically, they pose a higher risk for adverse effects on the heart and possibly the lungs. (The older tricyclics, such as amitriptyline and imipramine, have other severe side effects in older adults.)
SSRIs have fewer side effects than tricyclics. However, SSRIs may not pose any lower risk for falls than the older tricyclic antidepressants. In addition, researchers are investigating whether SSRIs are associated with an increased rate of osteoporosis (“thin bones”) and fractures in older adults.

About 2% of American primary school-age children and 4 - 8% of adolescents suffer from depression. Studies suggest that when children or adolescents are treated, up to 80% recover. Still, 25 - 50% of these young people have a recurrence of depression within 2 years of their first episode of depression.

It is important to recognize that childhood depression differs from adult depression and that children may respond differently than adults to antidepressant medication. These variances are due to childhood brain development processes as well as age-related differences in drug metabolism. Children may experience medication side effects not seen in adults, and some antidepressants that are effective for adults may not work for children.

Mild-to-Moderate Depression. The pediatrician may want to monitor a child with mild depression for 6 - 8 weeks before deciding whether to prescribe psychotherapy, antidepressant medication, or a referral to a mental health professional. Once medication has been started, the doctor will decide if the dosage needs to be increased after another 6 - 8 weeks. Medication may need to be continued for 1 year after the symptoms have resolved, and the doctor should continue to monitor the child on a monthly basis for 6 months after full remission of depression. For psychotherapy, cognitive therapy may be the best approach for children and adolescents with depression. Some studies suggest that other types of psychotherapy, such as family therapy and supportive therapy, can also be very effective.

Severe Depression. The American Academy of Child and Adolescent Psychiatry recommends an SSRI antidepressant for children and adolescents with very severe depression that does not respond to psychotherapy. Tricyclic antidepressants do not tend to help adolescents and children and these drugs have many side effects. MAOIs are also not commonly prescribed.

Many SSRIs appear to be safe and effective, but at this time fluoxetine (Prozac) is the only one approved for children over age 7 and for adolescents. The FDA strongly advises against the use of specific SSRIs, such as paroxetine (Paxil), due to concerns about an increased risk for suicidal behavior as well as the lack of any evidence supporting the drug's efficacy in pediatric patients. On an encouraging note, a 2007 review in the Journal of the American Medical Association indicated that the overall benefits of antidepressants for children and adolescents appear to be much greater than the risks for suicidal behavior. Still, the study found that antidepressants have only modest benefits for major depressive disorder, which underlines the importance of adjunctive psychotherapy.

For optimal results, SSRIs should be combined with either cognitive-behavioral or interpersonal psychotherapies. A study of adolescents with depression reported that combination treatment with fluoxetine and cognitive behavioral therapy was more effective than either treatment alone.

Due to potential suicide risks, children and adolescents should be monitored regularly during the initial months of antidepressant treatment. [For more detailed information, see Suicide Risk and Antidepressant Medications.]

Antidepressants and Drug Treatment Guidelines

Major classes of antidepressants include:

Selective serotonin-reuptake inhibitors (SSRIs). These have become the standard antidepressants. They target the brain chemical (neurotransmitter) serotonin. They are effective and have very moderate side effects. Some may be beneficial in treating anxiety and certain subtypes of depressive disorders unresponsive to previous drugs, including premenstrual dysphoric disorder and seasonal affective disorder, atypical depression, and recurrent brief depression.
Other neurotransmitter inhibitors. These drugs target neurotransmitters other than or in addition to serotonin, such as norepinephrine. Many are proving to be effective in patients who do not respond to standard antidepressants or in specific patients, such as smokers who want to quit or patients with chronic pain.
Tricyclic antidepressants (TCAs). These drugs are effective but can have severe adverse effects, particularly in older people.
Monoamine oxidase inhibitors (MAOIs). These drugs include newer selective MAOIs. MAOIs are the most effective antidepressants for atypical depression, but have some severe side effects and require restrictive dietary rules.
St. John's wort and other herbal remedies are included in the Lifestyle section of this report.

Approach and Duration of Initial Treatment. The guidelines for the duration of an initial antidepressant regimen is as follows:

Patients should start at a low dose, which is increased over a period of 5 - 10 days.
Patients should see their doctor every 1- 2 weeks until substantial improvement occurs. It may take 4 - 8 weeks before a patient experiences the effects of any antidepressant.
Side effects usually diminish within 1 - 4 weeks. (Exceptions may be weight gain and sexual dysfunction.)
If no improvement occurs, an alternative drug may be tried. More than 80% of patients respond to some antidepressant, although specific drugs are helpful for only about half of patients. This suggests that if one medication fails, another has a good chance of being helpful. In general, the fewer drug treatment strategies required, the better a patient’s chances of recovering completely from depression. Patients who become symptom-free have the best chance for complete recovery compared to patients whose symptoms merely improve.
In general, patients should continue taking antidepressants for at least 6 months after symptom relief to help prevent relapse. (Patients who improve within 2 weeks of taking medications may not require lengthy treatment.)

Treating Recurrence. Recurrence of depression is very common. About a third of patients will relapse after a first episode within a year of ending treatment, and more than half will experience a recurring bout of depression at some point during their lives. Among those at highest risk for early relapse and who may require ongoing antidepressants are:

Patients with at least two episodes of major depression or major depression that lasts for 2 years or longer before initial treatment.
Patients who continue to have low-level depression for 7 months after starting antidepressant treatments.

Patients may need maintenance therapy. Experts disagree, however, on the optimal length or the appropriate dosage of maintenance therapy. Some patients may need to stay on antidepressants for 1 - 2 years -- or even indefinitely. Some experts recommend withdrawing from medication after a year. (This should be done gradually, over 2 - 3 months.) If depression recurs, the patient should go back on the antidepressants.

There is no risk for addiction with current antidepressants, and many of the common antidepressants, including most standard SSRIs, have been proven safe when taken for a number of years.

Common Side Effects of Most Antidepressants. No matter how well a drug treats depression, the ability of the patient to tolerate its side effects strongly influences their compliance with therapy. Lack of compliance is probably the major barrier to success. Side effects can be avoided or moderated if any regimen is started at low doses and built up over time. Although specific side effects are discussed under individual drugs, there are a few that are common to many of them:

Sexual dysfunction is a common side effect of many of the standard antidepressants and some of the newer drugs. These side effects can be particularly distressing for patients on maintenance treatment who otherwise feel well. Some of the newer antidepressants, such as bupropion, may be effective alternatives without as high a risk for this problem. Sildenafil (Viagra), used for erectile dysfunction in men, may help reverse sexual dysfunction from antidepressants. It does not heighten sexual interest, however.
An increased risk of oral health problems caused by dry mouth is associated with long-term use of most antidepressants. Patients can increase salivation by chewing gum, taking vitamin C tablets, using saliva substitutes, and rinsing the mouth frequently.
Virtually all antidepressants have complicated interactions with other drugs; some are very important. Patients should inform the doctor of any drugs they are taking, including over-the-counter medications and herbal remedies.
Nearly all antidepressants are metabolized in the liver, so anyone with liver abnormalities should use them with caution.
Abrupt withdrawal from many antidepressants can produce severe side effects; no antidepressant should be stopped abruptly without consultation with a doctor.

In recent years, there has been concern that SSRI antidepressants may increase the risk for suicidal behavior. Of particular concern is a greater risk for suicide in young people taking these medications. While depression is itself the major risk factor for suicide, and antidepressant medication may revitalize suicidal attempts in patients who were too despondent before treatment to make the effort, evidence suggests that in some cases the medication itself can cause suicidal behavior. One specific SSRI, paroxetine (Paxil), has been definitely linked with suicidal behavioral risk in adults ages 18 - 30. In May 2006, the drug’s manufacturer warned doctors that all patients, and particularly young adults, should be carefully monitored during paroxetine therapy.

The U.S. Food and Drug Administration (FDA) has been conducting in-depth research on suicide risk and antidepressant medications. In October 2004, after careful review of scientific evidence, the FDA issued a public health advisory instructing drug manufacturers to include a "black box" warning explaining the association between antidepressant use and increased risk for suicidality (suicidal thoughts and behavior) in children and adolescents. In May 2007, the FDA proposed that the labels of antidepressant medications should include additional warnings about the risk of suicidal thoughts and behavior in young adults (ages 18 - 24) during the first 1 - 2 months of treatment. The FDA also notes there is a decreased risk of suicidality for adults age 65 years and older taking antidepressants.

The FDA based its recommendations for children and adolescents on a review of 24 clinical trials of nine antidepressant drugs. These trials enrolled over 4,400 pediatric patients and tested the safety and efficacy of SSRIs as well as other classes of antidepressants. The data suggested a greater risk for suicidality within the first few months of treatment. The average risk was minimal. Children and adolescents treated with these drugs had a 4% risk for suicidality compared with 2% for patients who received placebo. No patients in these studies actually committed suicide.

Based on these findings, the FDA recommends that caregivers monitor children being treated with antidepressants for sudden behavioral changes, and immediately notify their doctor if such changes occur. These behavioral signs include:

Agitation
Irritability
Anxiety
Panic attacks
Insomnia
Aggressiveness
Impulsivity
Hyperactivity in actions and speech
Worsening of depression
Increased thoughts of suicide

The FDA’s guidelines for medication usage recommend that patients see their doctor regularly after initiating drug treatment. The recommended schedule is:

Once per week for 4 weeks (1st month)
Every 2 weeks for the next month (2nd month)
At the end of week 12 following the start of drug treatment (3rd month)
More frequently if changes in mood or behavior occur
Patients should also be closely monitored if their drug dosage is changed.

Patients should immediately contact their doctor if depression symptoms worsen or if suicidal thoughts or behavior increase.

Selective serotonin-reuptake inhibitors (SSRIs) are now the first-line treatment of major depression. They work by increasing levels of serotonin in the brain. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro). There are no significant differences among SSRI brands in effectiveness for treating major depressive disorder, although individual drugs may have different side effects or benefits for specific patients. At this time, fluoxetine is the only one of these drugs to be approved for children over age 7 and adolescents.

Because they act specifically on serotonin, SSRIs have fewer side effects than older antidepressants, which have more widespread effects in the body.

Candidates for SSRIs. SSRIs appear to help people with the following conditions:

Mild to moderately severe major depression
Seasonal affective disorder
Dysthymia
Severe premenstrual syndrome and premenstrual dysphoric disorder (PMDD) -- a repackaged form of fluoxetine (Sarafem) is the first SSRI specifically FDA-approved for PMDD. Other SSRIs and newer antidepressants are also proving to be effective
Anxiety disorders
Bulimia
Impulsive and aggressive behaviors in psychiatric patients and in people with no mental health problems

Duration of Effectiveness and Use. SSRIs take, on average, 2 - 4 weeks to be effective in most adults. They may take even longer, up to 12 weeks, in the elderly and in those with dysthymia. By 14 weeks, depression should be in remission in everyone who responds to the drugs. Unfortunately, recurrence is common once the drugs are stopped. Studies indicate that the standard SSRIs are generally safe, although it is still unclear which patients would most benefit from on-going medication. Some doctors recommend withdrawing from medication after a year. If depression recurs, then the patient should go back on the antidepressant.

Side Effects of SSRIs. Side effects may include:

Nausea and gastrointestinal (GI) symptoms usually wear off over time.
Agitation, insomnia, mild tremor, and impulsivity occur in 10 - 20% of people who take SSRIs. These symptoms may be particularly problematic in patients who also suffer from anxiety, sleeplessness, or both.
Drowsiness affects about 20% of SSRI-treated patients. Newer SSRIs, such as escitalopram (Lexapro), may have fewer of these adverse effects.
Dry mouth is a common side effect.
Patients may lack motivation, feel tired, be confused, and experience mental dullness, but this side effect is fairly rare.
Headache and flu-like symptoms may occur.
Heart palpitations and chest pain may occur.
Weight gain varies depending on the SSRI. For example, in one study patients who took paroxetine (Paxil) experienced five times the weight gain as those who took citalopram (Celexa). Patients should be encouraged to maintain a low-calorie diet and to exercise. They should be aware that some of the weight-loss medications, notably sibutramine (Meridia), can have serious interactions with SSRIs.
Sexual side effects include delayed or loss of orgasm and low sexual drive. They are a well-known side effect of SSRIs. Taking a supervised drug "holiday" on the weekend may improve sexual function during that time. Some of the newer SSRIs or other antidepressants may cause less severe impairment of sexual function.
Paroxetine (Paxil) may cause birth defects if taken during the first 3 months of pregnancy. Most reported defects have been heart-related. The most common heart abnormalities are ventricular septal defects, which are holes in the muscular wall that separate the main pumping chambers of the heart. Venlafaxine (Effexor) has also been associated with birth defects. Still, recent research suggests that most types of SSRI-associated birth defects are rare and the overall risks are low. Pregnant women who are being treated for major depression should not stop taking antidepressants without first talking to their doctors. [For more information on antidepressant treatment guidelines during pregnancy, see Treating Depression During and After Pregnancy in Treatment section.]

Drug Interactions. SSRIs can interact with other antidepressants such as tricyclics and, in particular, monoamine oxidase inhibitors (MAOIs). SSRIs should never be taken in combination with an MAOI or within 2 weeks after discontinuing MAOI treatment. Other serious interactions have occurred with meperidine (Demerol) and illegal substances (such as LSD, cocaine, or ecstasy). People who take SSRIs may drink alcohol in moderation, although the combination may compound any drowsiness experienced with SSRIs, and some SSRIs increase the effects of alcohol.

Withdrawal Symptoms. Cognitive problems, sleep disturbances, increase in depressive symptoms, and electric shock-like symptoms have been known to occur with sudden discontinuation of SSRIs. The symptoms are more likely to occur with antidepressants with shorter half-lives as compared with fluoxetine, which has a long half-life. The dose of the antidepressant should be slowly reduced before stopping.

These newer antidepressants target other neurotransmitters, such as norepinephrine or dopamine, alone or in addition to serotonin. In general, the advantages of the new designer antidepressants are:

They may be better tolerated than the older tricyclic compounds and even some SSRIs, although long-term side effects are not fully known in this group.
Most of these drugs have fewer adverse effects than SSRIs on sexual function.
They may be more effective than SSRIs for severely depressed patients.
Some of these drugs are helpful for additional problems -- such as insomnia, fibromyalgia and similar chronic pain syndromes, or smoking -- that may affect people with depression.

They do share some side effects with other antidepressants, including dizziness and dry mouth.

Dual Inhibitors. Dual inhibitors act directly on two neurotransmitters -- norepinephrine and serotonin. These drugs are also known as serotonin norepinephrine reuptake inhibitors (SNRIs). The following SNRIs are approved for treatment of major depression in adults:

Venlafaxine (Effexor) is similar to Prozac in effectiveness and tolerability for most patients. As with SSRIs, venlafaxine may impair sexual function. The drug can increase blood pressure and heart rate and should be used with caution in patients with high blood pressure or heart disease. It can also cause uterine and vaginal bleeding unrelated to menstruation. Venlafaxine should not be taken during the last trimester of pregnancy as it can cause complications in newborn infants. Some patients report severe withdrawal symptoms, including dizziness and nausea. In 2006, the drug’s manufacturer warned of an increased overdose risk and advised doctors to prescribe their patients only small amounts of venlafaxine pills.
Duloxetine (Cymbalta) also acts on both serotonin and norepinephrine. Side effects are generally mild and include dry mouth, nausea, and sleepiness. Patients with narrow-angle glaucoma or patients with liver or kidney diseases should not take duloxetine. Because duloxetine can cause liver damage, patients who drink large quantities of alcoholic beverages should not take it. Signs of liver damage include itching, dark urine, yellowing of skin and eyes (jaundice), and fatigue. Patients should immediately contact their doctor if they experience these symptoms.
Mirtazapine (Remeron) can cause sleepiness, increased appetite, weight gain, and dizziness.

Other Antidepressants with Effects on Multiple Neurotransmitters. Bupropion (Wellbutrin, Zyban) affects the reuptake of serotonin, norepinephrine, and dopamine -- a third important neurotransmitter. In addition to depression, bupropion is also approved for smoking cessation and for treating seasonal affective disorder (SAD). Bupropion causes less sexual dysfunction than SSRIs. About 25% of patients experience initial weight loss. Side effects include restlessness, agitation, sleeplessness, headache, and stomach problems. Bupropion has a risk for seizures, which increases with higher doses. High doses may also cause dangerous heart arrhythmias.

Before the introduction of SSRIs, tricyclics were the standard treatment for depression.

Tricyclics are sometimes grouped into two categories:

Tertiary amines include amitriptyline (Elavil, Endep) and imipramine (Tofranil).
Secondary amines include desipramine (Norpramin) and nortriptyline (Pamelor, Aventyl). Secondary amines may have fewer side effects, including drowsiness, than tertiary amines, but they are as toxic in high amounts.

Less commonly used tricyclics include doxepin (Sinequan), amoxapine (Asendin), maprotiline (Ludiomill), protriptyline (Vivactil), trimipramine (Surmontil), mianserin (Bolvidon), and dothiepin (Prothiaden).

Tricyclics are as effective for treating depression but they have many side effects. They may offer benefits for many people with dysthymia, who generally do not respond to SSRIs. They may also be prescribed in lower dosages to be taken at night to help with insomnia.

Side Effects of Tricyclics. Side effects are common with these medications. In fact, in an analysis of studies, more tricyclic users discontinued their drugs due to side effects than did SSRI or MAOI users. Those most often reported include:

Dry mouth
Constipation
Blurred vision
Sexual dysfunction
Weight gain
Difficulty urinating
Drowsiness
Dizziness -- blood pressure may drop suddenly when sitting up or standing.

Tricyclics can have serious, although rare, side effects:

They tend to cause disturbances in heart rhythm, which can pose a danger for some patients with certain heart diseases. Care should be taken when these medications are prescribed to the elderly and to those at risk of overdose.
Also of concern are reports that tricyclics, particularly imipramine as well as mianserin and dothiepin, may increase the risk for a lung disease called idiopathic pulmonary fibrosis (IPF), which can cause lung inflammation and scarring. Initial symptoms are breathlessness and dry cough.
Tricyclics can be fatal with an overdose.
Protriptyline can cause sun sensitivity. People who take this drug should take precautions against sunlight when they go outdoors.

Monoamine oxidase inhibitors (MAOIs) block monoamine oxidase, an enzyme which has negative effects on many of the neurotransmitters that are important for well-being. MAOIs include phenelzine (Nardil), isocarboxazid (Marplan), and tranylcypromine (Parnate). Because these drugs can have very severe side effects, they are usually prescribed only when other types of antidepressants do not help. Research indicates that MAOIs are an effective option for atypical and treatment-resistant depression.

Newer MAOIs, such as selegiline (Eldepryl, Movergan), target only one form of the MAOI enzyme. They may cause fewer side effects than older MAOIs. In 2006, a skin patch form of selegiline (Emsam) was approved for treatment of major depressive disorder in adults.

Candidates for MAOIs. MAOIs may be effective for the following conditions:

Atypical depression
Eating disorders
Post-traumatic stress disorder
Borderline personality

Side Effects. MAOIs commonly cause the following side effects:

Orthostatic hypotension (a sudden drop in blood pressure upon standing)
Drowsiness or insomnia
Dizziness
Sexual dysfunction
The most serious side effect is severe hypertension (high blood pressure), which can be brought on by eating certain foods having high tyramine content. Such foods include aged cheeses, most red wines, sauerkraut, vermouth, chicken livers, dried meats and fish, canned figs, fava beans, and concentrated yeast products.
MAOIs can cause birth defects and should not be taken by pregnant women.

Very dangerous side effects, such as serotonin syndrome, can occur from interactions with other antidepressants, including SSRIs. Serotonin syndrome is a potentially fatal condition that is caused by the interaction of serotonergic drugs. Symptoms include confusion, agitation, sweating and shivering, and muscle spasms. There should be at least a 2-week break between taking MAOIs and other antidepressants. MAOIs can have serious interactions with other drugs as well, including some common over-the-counter cough medications. In such cases, severe high blood pressure or dangerous reactions can occur. It is important that patients discuss with their doctors any other medications they are taking.

If patients fail to respond to antidepressants, doctors may try adding on a different type of drug. (This combination strategy is called “augmentation” or “adjunctive treatment”.) Atypical antipsychotics are drugs that are usually prescribed for schizophrenia or bipolar disorder, but they can also play a role in the treatment of severe depression. In 2007, aripiprazole (Abilify) was approved in combination with antidepressant therapy for treatment of adults with major depressive disorder. Investigators are also studying whether combination treatment with the atypical antipsychotic risperidone (Risperdal) can help patients with major depression achieve remission.

Ketamine. Ketamine, an anesthetic drug, may be helpful for patients with severe treatment-resistant depression. In a small preliminary study, a single intravenous dose of ketamine helped patients quickly recover from depression within 2 hours, and some patients sustained benefits for up to a week. (Standard antidepressant drugs usually take about 8 weeks to have an effect.) Ketamine blocks the NMDA brain protein receptor, which is involved in glutamate regulation. Glutamate is a brain chemical that is thought to be involved in depression.

Psychotherapy

Among the various psychotherapies, cognitive-behavioral therapy appears to be the most effective approach. If psychotherapy is used alone without medications, benefits should be evident within 8 weeks and symptoms should be fully resolved by 12 weeks. If these conditions are not met, then the patient should strongly consider antidepressant drugs.

In a major analysis of four randomized comparative studies, cognitive behavior therapy worked as well as antidepressants in treating severe depression for many patients. Much of the success of psychologic therapy depends on the skill of the therapist. Many studies suggest that combining cognitive therapy with antidepressants offer the greatest benefits for many patients, particularly for dysthymia (chronic depression).

Medical evidence also has found that the benefits of cognitive therapy persist after treatment has ended. Cognitive behavioral therapy has been shown to help prevent future suicide attempts in patients with a history of suicidal behavior.

Best Candidates. Cognitive therapy may be particularly helpful for the following patients:

Patients with atypical depression
Adolescents with mild symptoms of major depression
Women with non-psychotic postpartum depression
Children of parents with the disorder -- in this case, therapy should involve the whole family.
Cognitive therapy does not appear to be as beneficial as antidepressants for most patients with dysthymia.

Approach. This approach focuses on identification of distorted perceptions that patients may have of the world and themselves, on changing these perceptions, and on discovering new patterns of actions and behavior. These perceptions, known as schemas, are negative assumptions developed in childhood that can precipitate and prolong depression. Cognitive therapy works on the principle that these schemas can be recognized and altered, thereby changing the response and eliminating the depression.

First, the patient must learn to recognize depressive reactions and thoughts as they occur, usually by keeping a journal of feelings about, and reactions to, daily events.
The patient is often given "homework" that tests old negative assumptions against reality and demands different responses.
Then, the patient and therapist examine and challenge these entrenched and automatic reactions and thoughts.
As the patient begins to understand the underlying falseness of the assumptions that cause depression, they can begin substituting new ways of coping.

Over time, such exercises help build confidence and eventually alter behavior. Patients may take group or individual cognitive therapy. Cognitive therapy is a time-limited treatment, typically lasting 12 - 14 weeks. Extending this period, however, may help prevent relapse. In one study, therapy was continued for 10 sessions over an additional 8 months. This extended treatment significantly reduced the risk of recurrence. In fact, some experts believe that short-term therapy is not effective for patients with chronic or relapsing psychiatric disorders.

Based in part on psychodynamic theory, interpersonal therapy acknowledges the childhood roots of depression, but focuses on symptoms and current issues that may be causing problems. IPT is not as specific as cognitive or behavioral therapy, and all work is done during the sessions. The therapist seeks to redirect the patient's attention, which has been distorted by depression, toward the daily details of social and family interaction. The goals of this treatment method are improved communication skills and increased self-esteem within a short period (3 - 4 months of weekly appointments) of time. Among the forms of depression best served by IPT are those caused by distorted or delayed mourning, unexpressed conflicts with people in close relationships, major life changes, and isolation.

The intent of supportive psychotherapy or attention intervention is to provide the patient with a nonjudgmental environment by offering advice, attention, and sympathy. Supportive therapy appears to be particularly helpful for improving compliance with medications by giving reassurance, especially when setbacks and frustration occur.

Other Treatments

Electroconvulsive therapy (ECT) is commonly called shock treatment. It has received bad press, in part for its potential memory-depleting effect. Since its introduction in the 1930s, ECT has been significantly refined, and is now considered an effective and safe treatment for severe depression in the appropriate situation. It is especially effective for patients with severe depression who experience delusions and hallucinations. Maintenance ECT may also help prevent relapse.

Candidates for ECT. ECT may be helpful for the following patients with severe depression:

Patients who cannot, for any reason, take antidepressant drugs
Suicidal patients
Elderly patients who are psychotic and depressed
Pregnant women with severe depression
Patients with certain heart problems
Young patients who fit the adult criteria for ECT

The Procedure. In general, hospitalization is not necessary. ECT involves the following steps:

The patient receives a muscle relaxant and short-acting anesthetic.
A small amount of electric current is sent to the brain, causing a generalized seizure that lasts for about 40 seconds.
Most patients receive 6 treatments, spaced every 2 - 5 days. Others receive up to 15 treatments, followed by 6 - 12 additional treatments spaced every other week or longer for another 2 - 4 months.

Side Effects. Side effects of ECT may include temporary confusion, memory lapses, headache, nausea, muscle soreness, and heart disturbances. Concerns about permanent memory loss appear to be unfounded.

Transcranial magnetic stimulation (TMS) uses high frequency magnetic pulses that target affected areas of the brain. This investigational treatment is similar to electroconvulsive therapy (ECT) but, unlike ECT, it is more precise. However, it is not yet clear whether it as effective as ECT. Researchers are continuing to refine rTMS techniques to improve treatment outcomes.

Vagus nerve stimulation (VNS) is a procedure that is effective for certain patients with epilepsy, and is now showing some success in patients with treatment-resistant depression

VNS involves implanting a battery-powered device under the skin in the upper left of the chest. The neurologist programs the device to deliver mild electrical stimulation to the vagus nerve. The two vagus nerves are the longest nerves in the body. They run along each side of the neck, then down the esophagus to the gastrointestinal tract. The vagus nerve travels to areas of the brain that control functions such as sleep and mood.

Studies report response rates of 35 - 46% in appropriate candidates with treatment-resistant depression. VNS is approved by the FDA for long-term treatment of chronic depression in adults who have not responded to typical treatments for their major depressive episode. Patients who use VNS may continue to show improvement in both their depression symptoms and quality of life.

Vagal stimulation can cause shortness of breath, hoarseness, sore throat, coughing, ear and throat pain, or nausea and vomiting. These side effects can be reduced or eliminated by reducing the intensity of stimulation. Long-term studies on patients with epilepsy have reported no serious adverse side effects, although the treatment may cause lung function deterioration in some people with existing lung disease.

The vagus nerves branch off the brain on either side of the head and travel down the neck, along the esophagus to the intestinal tract. They are the longest nerves in the body, and affect swallowing and speech. The vagus nerves also connect to parts of the brain involved in seizures. In many seizures disorders, electrical stimulation of the vagus nerves may help relieve symptoms.

Phototherapy is recommended as treatment for seasonal affective disorder (SAD), particularly for patients who do not wish to try antidepressants.

The Procedure. The procedure is noninvasive and simple. It is best performed immediately after waking in the morning. The patient sits a few feet away from a box-like device that emits very bright fluorescent light (10,000 lux) for about 30 minutes every day.

Some people report mood improvement as early as 2 days after treatment. In others, depression may not lift for 3 - 4 weeks. If no improvement is experienced after that, depressive symptoms will be unlikely to respond to phototherapy. Phototherapy may work best when combined with cognitive behavioral therapy.

Side Effects. Side effects include headache, eye strain, and irritability, although these symptoms tend to disappear within a week. Patients taking light-sensitive drugs (such as those used for psoriasis), certain antibiotics, or antipsychotic drugs should not use light therapy. Patients should be examined by an ophthalmologist before undergoing this treatment.

A surgical technique called cingulotomy interrupts the cingulate gyrus, a bundle of nerve fibers in the front of the brain, by applying heat or cold. A variation of this procedure using MRI scans to guide the surgeon produced long-term improvement in 53 - 78% of patients with severe intractable depression. The procedure is generally safe with few serious complications. It does not affect intellect or memory.

Some small studies have suggested that acupuncture may help in relieving depression. Larger studies are required to confirm its benefits.

Lifestyle Changes

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

St. John's wort (Hypericum perforatum) is an herbal remedy that may help some patients with mild-to-moderate depression. It does not appear to help patients with moderate or severe depression.

The herb St. John's wort is believed to be helpful in relieving mild-to-moderate depression, but should only be taken under a doctor's supervision. Manufacturers of herbal supplements do not need FDA approval to sell the products.

This herbal substance is not regulated, and there is no guarantee of quality in any brands currently available. In fact, in a 2003 study, only 2 of 54 St. John's products bought in Canada and the U.S. contained concentrations of the active ingredients that fell within 10% of the claims on the labels.

The following guidelines are recommended:

People with depression should not use St. John's wort without consulting a doctor. Children and pregnant or nursing women should not take this substance.
People should purchase brands only from well-established manufacturers.
Although no specific dose levels have been established, evidence suggests taking 900 mg daily (300 mg taken 3 times a day or 450 mg taken twice a day).
It takes between 2 - 3 weeks for the herb to have an effect.
St. John's wort should not be combined with other antidepressants. This herb may also interact with other types of medications and increase or decrease their potency. St. John's wort can increase the risk for bleeding when used with blood-thinning drugs. It can also reduce the strength of certain drugs including cancer and HIV treatments.

Side Effects. Side effects are uncommon but may include nausea, dry mouth, allergic reactions, and fatigue. This herb may increase sensitivity to light (photosensitivity). Some people have reported temporary nerve damage after sun exposure, specifically pain and tingling on sun-exposed areas.

Carbohydrates and Tryptophan. Some people report relief from depression by eating foods or diet supplements that boost levels of tryptophan, an amino acid involved in the production of serotonin. There are high-carbohydrate drinks available over the counter that increase tryptophan levels and may alleviate depression associated with premenstrual syndrome for about 3 hours. Simply eating a high amount of carbohydrates, however, is not a solution for depression.

Impurities found in diet supplements containing L-tryptophan itself have caused cases of eosinophilia-myalgia syndrome, a condition that elevates certain white blood cells and can be fatal. Supplements containing L-tryptophan are currently banned in the U.S. by the FDA.

Fish Oil. Some evidence suggests that an imbalance in the ratio of specific fatty acids (omega-6 to omega-3) may increase the risk for depression. Both are polyunsaturated fats, but omega-6 fatty acids are mostly found in corn, safflower, soybean, and sunflower oil whereas omega-3 fatty acids are found in fish oil, canola oil, soybeans, flaxseed, and certain nuts and seeds.

The bottom line may be to increase intake of omega-3 rich foods, such as fish, nuts, and canola oil, and reduce consumption of foods containing omega-6 fatty acids, such as corn and sunflower oils. Such a dietary approach is healthy in any case. Researchers are studying whether eating fish or taking fish oil supplements can reduce depression. Small preliminary studies suggest that these dietary approaches may be helpful for some patients. Scientists are also investigating which type of fish oil compound -- eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) -- provides the greatest benefit.

Omega-3 fatty acids, found in oily fish and flaxseed and canola oils, may be beneficial to people with depression.

Vitamins and Other Supplements. Certain B vitamins have been associated with some protection against depression.

Vitamin B-3 (niacin) is important in the production of tryptophan and is produced from processing vitamin B3 (niacin). Dietary sources of niacin include oily fish (such as salmon or mackerel), pork, chicken, dried peas and beans, whole grains, seeds, and dried fortified cereals.
Vitamin B-12 and calcium supplements may help reduce depression that occurs before menstruation. One study also suggested that calcium might help prevent postpartum depression.
Low levels of folate, a B vitamin, may be associated with depression. Researchers are studying whether folate supplements may help enhance the effectiveness of SSRIs and other antidepressants.

Increasingly studies are reporting major benefits from exercise for people with depression.

Aerobics. Either brief periods of intense training or prolonged aerobic workouts can raise chemicals in the brain, such as endorphins, adrenaline, serotonin, and dopamine that produce the so-called runner's high. And, of course, weight loss and increased muscle tone can boost self-esteem.

Yoga. Yoga practice, which involves rhythmic stretching movements and breathing, may help improve and stabilize mood.

Click the icon to see an image depicting the practice of yoga.

A strong network of social support is important for both prevention and recovery from depression. Support from family and friends must be healthy and positive. One study of depressed women showed, however, that overprotective as well as very distant parenting was associated with a slow recovery from depression. Studies indicate that people with strong spiritual faiths have a lower risk for depression. Such faith does not require an organized religion. People with depression might find solace from less structured sources, such as those that teach meditation or other methods for obtaining spiritual self-fulfillment.

Resources

www.nimh.nih.gov -- National Institute of Mental Health
www.dbsalliance.org -- Depression and Bipolar Support Association
www.fda.gov/cder/drug/antidepressants -- FDA Antidepressant Use in Children, Adolescents, and Adults
www.parentsmedguide.org -- American Psychiatric Association-sponsored information on pediatric antidepressants
www.nami.org -- National Alliance on Mental Illness
www.nmha.org -- Mental Health America
www.aabt.org -- Association for Behavioral and Cognitive Therapies
www.psych.org -- American Psychiatric Association
www.apa.org -- American Psychological Association
www.aacap.org -- American Academy of Child and Adolescent Psychiatry
www.postpartum.net -- Postpartum Support International
www.mentalhealth.samhsa.gov -- National Mental Health Information Center
www.mentalhealth.samhsa.gov/suicideprevention/concerned.asp -- National Strategy for Suicide Prevention (if contemplating suicide, call 1-800-273-TALK)
www.suicidology.org -- American Association of Suicidology

References

Allen JJ, Schnyer RN, Chambers AS, Hitt SK, Moreno FA, Manber R. Acupuncture for depression: a randomized controlled trial. J Clin Psychiatry. 2006 Nov;67(11):1665-73.

Alwan S, Reefhuis J, Rasmussen SA, Olney RS, Friedman JM; National Birth Defects Prevention Study. Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects. N Engl J Med. 2007 Jun 28;356(26):2684-92.

Bridge JA, Iyengar S, Salary CB, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials. JAMA. 2007 Apr 18;297(15):1683-96.

Cheung AH, Zuckerbrot RA, Jensen PS, Ghalib K, Laraque D, Stein RE; GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): II. Treatment and ongoing management. Pediatrics. 2007 Nov;120(5):e1313-26.

Diem SJ, Blackwell TL, Stone KL, et al. Use of antidepressants and rates of hip bone loss in older women: the study of osteoporotic fractures. Arch Intern Med. 2007 Jun 25;167(12):1240-5.

Eranti S, Mogg A, Pluck G, et al. A randomized, controlled trial with 6-month follow-up of repetitive transcranial magnetic stimulation and electroconvulsive therapy for severe depression. Am J Psychiatry. 2007 Jan;164(1):73-81.

Frederikse M, Petrides G, Kellner C. Continuation and maintenance electroconvulsive therapy for the treatment of depressive illness: a response to the National Institute for Clinical Excellence report. J ECT. 2006 Mar;22(1):13-7.

George MS, Nahas Z, Borckardt JJ, et al. Brain stimulation for the treatment of psychiatric disorders. Curr Opin Psychiatry. 2007 May;20(3):250-4; discussion 247-9.

Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial magnetic stimulation (rTMS) treatment for depression improved? A systematic review and meta-analysis comparing the recent vs. the earlier rTMS studies. Acta Psychiatr Scand. 2007 Sep;116(3):165-73.

Hetrick S, Merry S, McKenzie J, Sindahl P, Proctor M. Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2007 Jul 18;(3):CD004851.

Institute for Clinical Systems Improvement. Health Care Guideline: Major Depression in Adults in Primary Care. Tenth addition. May 2007.

Jarema M. Atypical antipsychotics in the treatment of mood disorders. Curr Opin Psychiatry. 2007 Jan;20(1):23-9.

Kasper S, Anghelescu IG, Szegedi A, Dienel A, Kieser M. Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial. BMC Med. 2006 Jun 23;4:14.

Kellner CH, Knapp RG, Petrides G, et al. Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry. 2006 Dec;63(12):1337-44.

Krishnan KR. Revisiting monoamine oxidase inhibitors. J Clin Psychiatry. 2007;68 Suppl 8:35-41.

Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007 Jul;68(7):1056-61.

Louik C, Lin AE, Werler MM, Hernández-Díaz S, Mitchell AA. First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects. N Engl J Med. 2007 Jun 28;356(26):2675-83.

Mahmoud RA, Pandina GJ, Turkoz I, et al. Risperidone for treatment-refractory major depressive disorder: a randomized trial. Ann Intern Med. 2007 Nov 6;147(9):593-602.

Papakostas GI, Shelton RC, Smith J, Fava M. Augmentation of antidepressants with atypical antipsychotic medications for treatment-resistant major depressive disorder: a meta-analysis. J Clin Psychiatry. 2007 Jun;68(6):826-31.

Rapaport MH. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: the state of the art. J Clin Psychiatry. 2007;68 Suppl 8:42-6.

Rohan KJ, Roecklein KA, Tierney Lindsey K, et al. A randomized controlled trial of cognitive-behavioral therapy, light therapy, and their combination for seasonal affective disorder. J Consult Clin Psychol. 2007 Jun;75(3):489-500.

Ruhé HG, Huyser J, Swinkels JA, Schene AH. Switching antidepressants after a first selective serotonin reuptake inhibitor in major depressive disorder: a systematic review. J Clin Psychiatry. 2006 Dec;67(12):1836-55.

Stewart JW. Treating depression with atypical features. J Clin Psychiatry. 2007;68 Suppl 3:25-9.

Thachil AF, Mohan R, Bhugra D. The evidence base of complementary and alternative therapies in depression. J Affect Disord. 2007 Jan;97(1-3):23-35. Epub 2006 Aug 22.

Zuckerbrot RA, Cheung AH, Jensen PS, Stein RE, Laraque D; GLAD-PC Steering Group. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): I. Identification, assessment, and initial management. Pediatrics. 2007 Nov;120(5):e1299-312.

Review Date:
12/25/2007
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

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adam.com

Hodgkin's disease

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, including epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels contain stronger warnings and updated dosing-related safety information.

The FDA advises that for treating anemia associated with chemotherapy, dosing should increase hemoglobin levels to no more than 12 g/dL. Treatment with these drugs should stop as soon as the chemotherapy course is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists. The FDA is currently reviewing additional data concerning the safety of these drugs.

Preventing Infection after Cancer Treatment

Both chemotherapy and stem cell transplants increase the risk for serious infections. Patients must take precautions to avoid exposure to germs. Ways to prevent infection include:

Practice good hygiene, including regular handwashing and dental care (brushing, flossing)
Avoid crowds, especially during cold and flu season
Eat only well-cooked foods (no raw fruits or vegetables)
Boil tap water before drinking it
Do not keep fresh flowers or plants in your house as they may carry mold

Introduction

Hodgkin's disease is a type of lymphoma. Lymphomas are cancers of the lymphatic system. They are generally subdivided into two groups: Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). NHL is discussed in another report. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas.]

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people talk about swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if enlarged, are: the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

HD is the major tumor in a group known as malignant lymphomas. Most often HD starts in B cell lymphocytes located in lymph nodes in the neck area, although any lymph node may be the site of initial disease.

Click the icon to see an image of the lymph nodes in the head and neck.

The following is a possible description of the process leading to HD:

In early development, B cells normally undergo a series of genetic rearrangements until they create immunoglobulins, proteins that act as antibodies.
Antibodies are produced by the immune system. They contain receptors that match and bind to a wide array of foreign substances (such as viral proteins) called antigens. Antibodies help launch an immune attack against antigens.
B cells normally undergo limited cycles of genetic rearrangement that result in immunoglobulin production. In rare cases, however, the genetic arrangements create a mutation that does produce immunoglobulins. The results are large, abnormal cells referred to as Reed-Sternberg cells.
Without immunoglobulin, Reed-Sternberg cells can be infected by certain viruses (notably the Epstein-Barr virus -- the cause of infectious mononucleosis). Genetic byproducts of these viruses appear to inhibit a natural process of self-destruction (called apoptosis) that would normally kill off these natural cells. Instead, the abnormal B cells grow non-stop, causing most forms of HD.

Click the icon to see an image of an antibody.

Only a very small percentage (about 1%) of cells found in the affected lymph tissues of HD are actually Reed-Sternberg cells. Researchers are unable to completely explain why so few cells can cause such severe symptoms. One explanation is that these cells trigger production of very powerful immune system proteins called cytokines (including those known as interleukin-1, interleukin-6, and tumor necrosis factor). These cytokines produce an inflammatory response that can cause local pain, fever, and other symptoms typical of HD. The dominance of different kinds of cytokines may also explain why HD takes different forms.

Classical Hodgkin's Lymphoma. Based on the variations and numbers of Reed-Sternberg cells, as well as other features, four major subtypes of classical HD have been identified:

Nodular Sclerosis. Nodular sclerosis is the most common subtype, representing almost 60% of HD cases. Younger patients are more likely to have this type. The nodes first affected are often those located in the center of the chest (the mediastinum).
Mixed Cellularity. Mixed cellularity is the next most common HD form, occurring in about 25% of patients, mostly in older patients, children, and those with immune disorders, such as AIDS. It usually indicates a more severe condition.
Lymphocyte Depleted. Lymphocyte-depleted HD occurs in about 4% of patients, nearly always in elderly people. It indicates extensive disease and a poor outlook. It can easily be confused with non-Hodgkin's lymphoma.
Lymphocyte-Rich Classical Hodgkin's Lymphoma. This form is similar to nodular lymphocyte predominant HD, but has more cell characteristics that conform to classical HD.

Nodular Lymphocyte-Predominant Hodgkin's Disease. Nodular lymphocyte-predominant Hodgkin's disease (LPHD) occurs in about 5% of patients. The cells in LPHD known as lymphocytic and histolytic cells are proving to be distinctly different from classic Reed-Sternberg B cells. Patients with lymphocyte predominance are usually young men, who often have no symptoms. LPDH is very slow growing and may be associated with long survival. There is a 3% risk, however, that LPDH will transform to non-Hodgkin's lymphoma. In fact, lymphocyte-predominant HD may eventually be defined as a non-Hodgkin's lymphoma.

Lymphomas represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, which are important cells involved in defending the body against infections. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation. Its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system helps produce and transport lymphocytes, white blood cells that are a primary component of the immune system. Some lymphocytes produce antibodies that can target and attack specific foreign substances (antigens).

Lymphocytes develop in the bone marrow or thymus gland. They are categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow, but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it shrinks.
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, move out of the capillaries into the surrounding tissues. Some enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes. They lead to larger lymphatic ducts and branches, and drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In a lymph node, lymphocytes typically receive their initial exposure to foreign substances, such as bacteria. This exposure prompts the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are clustered throughout the body. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary lymphatic organs. They are composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of an antibody.

Click the icon to see an image of the immune system structures.

Risk Factors

Hodgkin’s disease accounts for about 11.5% of all types of lymphomas. According to the American Cancer Society, about 8,200 new cases of Hodgkin's disease (HD) were diagnosed in the United States in 2007 and about 1,000 people died of the disease. Experts believe that the malignant process leading to Hodgkin's disease is triggered by a combination of environmental and genetic factors along with a susceptible immune system. The exact triggers, however, are unknown.

Hodgkin's disease occurs most often in people between the ages of 15 - 40, (especially in the 20s), and in people over age 55. About 10 - 15% of Hodgkin’s disease cases are diagnosed in children and teenagers.

Hodgkin's disease is slightly more common among males than females. Women who get Hodgkin's disease appear to have a slightly lower risk for relapse after treatment than men.

Infectious mononucleosis (“mono”), which is caused by the Epstein-Barr virus (EBV), appears to increase the risk for Hodgkin’s disease. Research suggests that the virus activates some pathway within the lymphocyte cell that leads to cell proliferation. However, only 1 in 1,000 patients with mononucleosis develops Hodgkin's disease. The Epstein-Barr virus itself is present in 90% of the population and, in the great majority of these cases, causes a mild infection or none at all. Very few people who have had mononucleosis go on to develop HD. Other factors must be present to trigger the malignancy.

Hodgkin's disease runs in families in about 5% of cases. Siblings have three times more risk than the general population.

Symptoms

The onset of Hodgkin's disease symptoms is highest during late winter months, with lymph node enlargement usually being the first sign. Lymph nodes may be enlarged in the following regions:

The most common first sign of Hodgkin's disease is painless enlargement of one or more lymph nodes above the diaphragm, most often those in the neck, chest, or armpits.
Enlarged lymph nodes are often detected in the chest cavity between the lungs (the mediastinum), particularly in younger patients.
Only about 15% of cases occur exclusively below the diaphragm.

Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site.

If it spreads below the diaphragm, it usually reaches the spleen first; the disease may then spread to the liver and bone marrow.
If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.

Symptoms in or around the Lymph Nodes. Occasionally, patients may have a cough or chest pain if the disease is located in the middle of the chest, but usually the enlarged nodes produce no symptoms. Sometimes patients experience pain in the diseased lymph nodes after drinking alcohol.

Systemic (B) Symptoms. Between 20 - 40% of patients have systemic symptoms that affect the whole body rather than just the specific location of the disease. Some of systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

Systemic symptoms include:

Drenching night sweats and weight loss (B symptoms)
Fever -- may occur only at night in episodes that come and go (B symptoms)
Itching all over the body -- caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of Hodgkin's disease, histamine release is due to abnormalities in the immune system. Although itching is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
Rash (late stages)

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as “swollen glands”). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

For example, although Hodgkin's often first appears in the neck, enlarged lymph nodes in that location are much more likely to be a sign of strep throat, or other throat infections.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Recent travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause similar symptoms include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Lymph nodes play an important part in the body's defense against infection. Swelling might occur even if an infection is small or not apparent.

Non-Hodgkin's Lymphomas. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin’s disease under some circumstances. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 27.7 with two age peaks, the major one between 15 - 24 with a lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system that include Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #84: Non-Hodgkin's lymphomas or Report #86: Acute lymphocytic leukemia.]

Exposure to Chemicals. Exposure to industrial chemicals or certain medications, such as phenytoin (Dilantin), may cause enlarged nodes. In addition, other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash that may resemble Hodgkin's disease.

Diagnosis

The doctor will take a medical history and perform a physical examination. If these simple procedures point to Hodgkin's disease, a number of additional tests may be needed to either rule out other diseases or confirm HD and determine the extent of the cancer.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node is sometimes indicative of certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma (including Hodgkin's). Soft nodes suggest infection or inflammatory conditions.

Blood tests are performed to measure white and red blood cells, blood protein levels, the uric acid level, blood proteins, and the liver's function. Another blood test is the erythrocyte sedimentation rate (ESR), which is sometimes elevated in Hodgkin's disease (although it is not specific for this condition).

Click the icon to see an image of the formed elements of blood.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area, where Hodgkin's disease usually starts. It a useful step for detection of enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Computer Tomography. Computed tomography (CT) scans are more accurate than x-rays. They can detect abnormalities in the chest and neck area, as well as revealing the extent of the cancer and whether it has spread. CT scans are used to evaluate symptoms and help diagnose lymphomas, help with staging of the disease, monitor response to treatment, and evaluate when the symptoms occur. A CT scan is also often used in detecting lymphomas in the abdominal and pelvic areas, the brain, and chest area.

Click the icon to see an image of a CT machine.

Positron Emission Tomography (PET). PET scans combined with CT scans can help doctors clarify the location of the cancer. PET scans can also provide information on whether or not an enlarged lymph node is benign or cancerous and are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

A biopsy of the suspicious lymph node is the most definitive way to diagnose Hodgkin's disease. A biopsy has risks, and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually regress on their own if a temporary infection is causing the enlargement. However, some lymphomas may regress and appear to be benign, only to reappear at a later time.

The Procedure. During a biopsy, the doctor usually removes the node and checks the surrounding areas. The tissue in the node is then examined for signs of infection and blood cell or other abnormalities. Biopsies of bone marrow may also be performed in patients with existing Hodgkin's disease if the doctor suspects that it may have spread to the marrow.

Biologic markers, called biomarkers for short, are high levels of substances that are released by tumors and indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), growth factors, and other chemicals. Some under investigation include:

CD44 is a molecule that binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
Interleukin (IL) 10 is another immune factor that may indicate a poor outlook when it occurs in high levels.

Outlook

Hodgkin’s disease is considered one of the most curable forms of cancer, especially if it is diagnosed and treated early. Unlike other cancers, Hodgkin's disease is even potentially curable in late stages. About 85% of patients with Hodgkin’s disease survive at least 5 years after cancer treatment. Five-year survival rates for patients diagnosed with stage I or II Hodgkin’s disease are 90 - 95%. Patients who survive 15 years after treatment are more likely to later die from other causes than Hodgkin’s disease.

Survival rates are poorest for:

Those who relapse within a year of treatment
Patients who do not respond to the first-line therapy and have signs of disease progression

The good news about Hodgkin's disease is that treatment can cure the disease. The bad news is that survivors face a higher than average risk for long-term complications of these treatments, some very serious.

Many patients may experience chronic fatigue that could persist for years. One study indicated that aerobic exercise may significantly improve fatigue; in doing so it could have a positive effect on mood as well.

The most serious complications are secondary cancers and heart disease, which occur over the 2 - 3 decades following treatments. Secondary cancers include non-Hodgkin's lymphoma, leukemia, melanoma, stomach and lung cancers, and breast and uterine cancers. Heart disease complications include coronary artery disease, stroke, heart valve problems, and cardiomyopathy (weakening of the heart muscle). Thyroid disorders are also a potential complication. Combinations of radiation and chemotherapies are especially associated with these problems.

A 2006 study in the New England Journal of Medicine evaluated the long-term health status of adult survivors of various childhood cancers. The study found that, 30 years after treatment, patients with Hodgkin’s disease had among the highest risk of developing serious health problems. Female survivors had a significantly greater risk than male survivors. In particular, women who received chest radiation are at very high risk for developing breast cancer. Still, in a 2000 study, 20 years after treatment, 90% of patients who had survived treatments were still living.

Patients with Hodgkin’s disease should get a written record of the treatments they received as children, and the potential risks of these treatments. These records can help the doctors who later oversee their care monitor for potential health problems. Survivors of Hodgkin’s disease should receive regular screening tests for cancer and heart disease. They may need to get these tests at a younger age than most patients. In particular, patients who were treated with chest radiation should get blood tests every 5 years to measure their cholesterol levels. Female patients who received chest radiation should get early and frequent mammograms.

Although HD is highly curable, it can have many psychologic consequences. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Fatigue persists in the majority of patients for years. Still, many survivors have an excellent quality of life.

Staging and Treatment Guidelines

Multiple treatment approaches are available for patients with Hodgkin's disease at nearly every stage, often resulting in similar rates of cure. Ultimately, the choice of treatment is based on a consideration of various prognostic factors as well as treatment side effects, both short and long term. Treatment decisions are individualized, and patients should discuss the pros and cons of various approaches with their doctors.

Staging the disease according to how far the cancer has spread (I through IV) is a primary method for determining both treatment options and prognosis. There are two levels of staging: Clinical staging and pathological staging.

Clinical stages are determined by conducting a thorough examination, which may include blood tests and different kinds of x-rays.
Pathologic staging is conducted after a laparotomy and biopsy of the tissue to help determine treatment options. It involves a much more detailed examination, but is not required as often as in the past for making treatment decisions.

In general, the prognosis according to stage is as follows:

If the disease is treated in stages I or II, the cure rates are as high as 90%. (Slightly more than half of all patients are diagnosed in these stages.)
Patients in stages III or IV are usually diagnosed with advanced Hodgkin's disease. (Even in such stages, survival at 5 years can be as high as 85%.)

The staging system can be further refined according to other features or factors that indicate a more or less severe condition and can help determine whether treatments should be more or less aggressive.

Presence or Absence of B Symptoms. For example, stages I through III are further categorized as either A or B according to whether certain widespread symptoms are absent (A) or present (B). The presence of B symptoms increases the risk of relapse.

The patient is classified as B if they have unexplained weight loss of more than 10% within 6 months, unexplained fever, and drenching night sweats. Fever and weight loss are the most important indications of B symptoms; night sweats alone do not always mean that such symptoms are present. Itching by itself is not considered a reliable B symptom.
If the patient has none of these symptoms, the disease is considered at A, which is less severe than the B form at any stage.
Another letter used to further refine a stage is E, which indicates that the malignancy is still local but has gone beyond the lymph node into surrounding tissue.

Indicators for Aggressive Treatments. Certain factors are indicators of a more serious case at any stage and the need for aggressive treatment:

The malignancy is "bulky" (a large mass)
Blood tests show high levels of erythrocyte sedimentation rates
Multiple tumors in the spleen
Greater involvement in the abdomen

Even if a patient has stage II disease, the presence of a bulky tumor or multiple tumors in the spleen indicates the patient may be treated as if they had advanced Hodgkin's disease.

Cell Types. The cell type of Hodgkin's disease may also influence treatment. For example, those with mixed cellularity type might require more aggressive therapy in certain cases than those with a slower-growing form, such as lymphocyte-predominant Hodgkin's disease (LPHD). In fact, some studies suggest that LPHD is the mildest form of Hodgkin's disease and that patients with LPHD are more likely to die of treatment-related disease than from Hodgkin's itself. Some experts are investigating the role of limiting radiation doses in such patients, although the most optimal approach is not yet known.

Other Prognostic Risk Factors. The International Prognostic Factors Project on Advanced Hodgkin’s Disease has developed seven factors that help determine which patients with advanced Hodgkin's disease would benefit from more or less aggressive chemotherapy. They are also useful to help determine success in patients with relapsed or persistent HD who are undergoing stem cell transplantation. The score is determined by the number of yes answers to the following questions. The more yes answers, the more likely the patient needs to be treated aggressively:

Is the patient male?
Is the patient older than 45?
Does the patient have stage IV disease?
Does the patient have blood tests showing lower than normal albumin levels? (Albumin is a protein found throughout the body.)
Does the patient have abnormally low hemoglobin levels? (Hemoglobin is the oxygen-carrying compound in red blood cells, so low levels suggest anemia.)
Does the patient have an abnormally high white blood cell count (15,000 or more)?
Does the patient have abnormally low levels of lymphocytes?

To avoid putting patients through unnecessary treatments that may actually be as or even more lethal than the disease itself over time, doctors are attempting to identify more specifically those patients who would or would not benefit from aggressive therapy.

Preventing Infection. Both the disease and some of the treatments suppress the immune system, increasing the risk for infections. Widespread, life-threatening infection is a particular danger if the spleen has been removed and both radiation and chemotherapy are administered. A week before any treatment, patients are often vaccinated against three bacteria: pneumococcus, meningococci, and Haemophilus influenza.

Measures for Infertility. People who wish to have children should discuss the possibility for receiving treatments that may lessen the risk for infertility. Examples include the following:

Men with Hodgkin's disease may want to consider sperm freezing and assisted reproductive techniques. One encouraging study on male survivors of childhood Hodgkin's disease, reported that although treatments had reduced their sperm count and quality, the actual genetic material was healthy. Such men, then, would still be good candidates for assisted reproductive techniques.
Women should ask their doctors about the possibility for preserving fertility by taking hormonal drugs called GnRH analogs before and during chemotherapy.

[For more information on fertility preservation treatments, see In-Depth Report #67: Male infertility and In-Depth Report #22: Female infertility.]

Considerations During Pregnancy. Women who are pregnant need special preparation and treatments.

Periodic examination for recurrent Hodgkin's disease is necessary for years after treatment, since relapse is not uncommon, even after treatment for early stages, and can occur a decade or more after treatment. Chest x-rays and CT scans of the abdomen are useful for detecting relapsed disease. Relapse is more likely to occur in early-stage disease, probably because limited radiation normally used in such cases did not destroy all malignancies. Patients who had large tumors in the chest are also at higher risk for recurrence. Patients also need to be monitored for long-term effects of the treatments themselves. Conditions to watch for include inflammation in the lungs and thyroid disease from radiation in the chest and heart disease and cancers from combined treatments, chemotherapy (particularly the use of MOPP), and blood stem cell transplantation.

Because Hodgkin's disease often occurs in young adults, treatment for pregnant women is of particular concern. Therapy must be effective enough to protect the mother without hurting the fetus. Treatment choice must be individualized, taking into consideration the mother's wishes, the severity and pace of the disease, and the length of the remaining pregnancy. The treatment plan may need to be changed as the pregnancy progresses.

Early in the Term. Unfortunately, an abortion may sometimes be the most prudent approach if the disease occurs in the first trimester. Chemotherapy is rarely used during that period, because it poses a risk for birth defects. Deciding on a course of action when Hodgkin's disease occurs in the first trimester is very difficult and emotionally wrenching. Prospective parents should not be shy about consulting with more than one doctor if they are uncertain about how to proceed.

Later in the Term. If the disease develops in the second half of the pregnancy, it may be possible to postpone therapy until after an early induced delivery. Alternatively, some evidence suggests that chemotherapy in pregnant women after the first trimester may be beneficial without harming the fetus. If full-dose standard chemotherapy is not deemed possible, vinblastine alone may be beneficial; this drug is not usually associated with fetal abnormalities in the second half of pregnancy.

Steroids may also be used late in the pregnancy both because of their antitumor effect and their effect in hastening fetal lung maturity. As an alternative, a short course of radiation (with extensive shielding of the fetus) can sometimes be considered prior to delivery if the mother is experiencing lung problems because of a rapidly enlarging mass in the chest. Combination chemotherapy may also be safe in the second half of pregnancy.

In one study, the 20-year survival rate of pregnant women with Hodgkin's disease was no different from that of nonpregnant women matched for similar stage of disease and age at diagnosis.

Treatment Options by Stage

Treatment is guided by the stage of the disease and usually relies on the location and extent of the disease. Treatment may vary within a stage, depending on whether it is categorized as either A or B. (Systemic symptoms are absent in "A" and present in "B.”) The presence of B symptoms increases the risk of relapse, and so may require more aggressive treatments for that stage.

Early Stages (I or II). For disease in stages I or II, the following treatments may be used:

Treatment in Adults. Doctors usually recommend radiation first for adults with HD. It provides excellent remission rates, although studies have reported a number of serious long-term complications in some patients. Selected patients in early stages may also be candidates for radiation limited only to areas above the diaphragm (called the mantle field), which can also have excellent results although still pose a considerable risk for late serious complications.
Treatment in Children. Chemotherapy and low-dose radiation is the standard treatment for most children and adolescents who have not reached full growth. Specific chemotherapy combinations have been developed to reduce the risks for infertility, leukemia, and toxic effects on the heart and lungs. Researchers are studying the use of chemotherapy alone in this group.

Later Stages. For stage III disease, chemotherapy, often with radiation, is a standard treatment. For stage IV disease, chemotherapy alone is generally recommended. The latest chemotherapy regimens are achieving survival rates that reach 90%.

Relapse. Relapse after treatment occurs in 20 - 35% of patients. Treatments for relapse include chemotherapy, radiation, and bone marrow or blood stem cell transplantation. Many patients respond favorably to such treatments, although another relapse is still possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Disease is limited to a single node region (I) or has involved one neighboring area or a single nearby organ (IE). The standard treatment for stage I disease is usually radiation for adult patients who have determined the stage using pathologic staging with laparotomy. Chemotherapy with low-dose radiation is now the standard approach for children and adolescents. Cure rates can be greater than 90%.

Stage IA. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Radiation therapy to the mantle field (chest, neck, and arm pits) and to the lymph nodes in the upper abdomen and spleen
Radiation therapy to a mantle field in certain patients -- best candidates are females with nodular sclerosis or lymphocyte predominant cell types, who are no older than 40 years, have no "B" symptoms, and have erythrocyte sedimentation rate (ESR) levels less than 50
Radiation therapy to a mantle field, the lymph nodes in the upper abdomen, and the spleen (subtotal node irradiation)
Chemotherapy alone is under investigation

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation. Radiation therapy may be directed to the lymph nodes in the upper abdomen and pelvis, and sometimes the spleen or groin. Total nodal irradiation is an option which includes these regions plus the mantle field.

Stage IB. Treatments depend on location. For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Chemotherapy plus radiation therapy to a mantle field (in patients who have severe symptoms and did not undergo laparotomy to determine the extent of the disease below the diaphragm)
Radiation therapy to the mantle field and to the lymph nodes in the upper abdomen is sometimes considered, but relapse rate can be high if significant B symptoms are present
Chemotherapy alone under investigation for children

If the malignancy is bulky, above the diaphragm, and involves a large part of the chest, chemotherapy plus radiation therapy is commonly used.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, to the areas that contain cancer, or to the spleen. Total nodal irradiation or radiation to lymph nodes in the upper abdomen and pelvis is another option.

Disease is limited to two or more lymph nodes on the same side of the diaphragm (II) or involvement of a single neighboring organ or area and one or more nearby lymph nodes; other lymph nodes on the same side of the diaphragm may be involved (IIE).

There are few differences between treatments for stage IIA and IIB, and the approach for both depends on the extent and location of the disease:

Non-bulky disease:

Radiation alone for adult and possibly adolescent (especially male) patients
Chemotherapy with low-dose radiation is used for children

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Radiation therapy to a mantle field and to the lymph nodes in the upper abdomen
Radiation therapy to a mantle field only (See Stage I Hodgkin's Disease section above)

Chemotherapy alone or with radiation therapy (combined modality) is being evaluated for those with non-bulky stage IIA. Also under investigation is radiation therapy to a mantle field only in patients with lymphocyte predominant cell types, who are no older than 40 years.

If the malignancy is above the diaphragm and does involve a large part of the chest, chemotherapy plus radiation therapy to a mantle field is the common approach.

If the malignancy is below the diaphragm, treatment includes chemotherapy with or without radiation to the upper abdomen and pelvis, and possibly the spleen. Total nodal irradiation is another option.

Disease is in lymph nodes on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated organ or site outside the lymph node (IIIE), by involvement of the spleen (IIIS), or by both (IIIE+S). In addition, stage III may be further categorized by the extent of its spread into the spleen or where it has spread in the abdominal area. Survival rates in some cases can be as high as 90%.

Stage IIIA. Chemotherapy is the most common treatment approach for most adults and children. Radiation may be added under certain circumstances, especially to provide localized treatment of bulky areas. (Radiation does not appear to offer any survival advantage for patients whose disease is in complete remission after chemotherapy.)

For a malignancy above the diaphragm, which does not involve a large part of the chest, the following may be used:

Chemotherapy alone
Chemotherapy with radiation therapy (combined modality)
Total or subtotal nodal radiation therapy alone -- for adults if disease is only in the upper abdomen and fewer than five nodes in the spleen are affected

If the malignancy involves a large part of the chest, the following may be used:

Standard chemotherapy alone
Chemotherapy plus radiation therapy (combined modality)
Investigative treatments

Stage IIIB. Chemotherapy alone is the standard treatment for most adults and children. Radiation is often added to treat areas of bulky tumor.

Disease has spread to organs outside the lymph system, such as liver, lung, or bone marrow. Even in this population, high long-term survival rates of over 85% are possible, including in children.

Treatment may include:

Chemotherapy alone
Chemotherapy with limited radiation to places of bulky disease
A clinical trial of investigational chemotherapy regimens or of stem-cell transplantation

Click the icon to see an image of liver involvement in Hodgkin's disease.

When disease recurs or persists after initial treatment either in the same area or in another part of the body, the next round of therapy depends on where the disease returns and the previous treatment used.

If the previous treatment was radiation therapy without chemotherapy, salvage chemotherapy is the usual choice.
If the patient was previously treated with chemotherapy, the choice may be radiation therapy to the lymph nodes with or without salvage chemotherapy.
In some patients, if the disease has persisted or if relapse has occurred after chemotherapy with or without radiation, high-dose chemotherapy and stem cell transplantation may be given.

Radiation Treatments

High-dose radiation therapy, which shrinks the tumors, has been used for more than 50 years for treating Hodgkin's disease. High-dose radiation is generally reserved for adults. Radiation treatments are highly toxic for children and appear to add little benefit. In such young age groups radiation is mostly used if there are large areas of disease in the chest; otherwise, chemotherapy with possibly low-dose radiation is the best option with excellent survival rates.

Radiation is directed to specific areas depending on the location of the disease:

If HD is above the diaphragm, “extended field radiation” is delivered to the neck, chest, and under arms (called the mantle field). Extended-field radiation is sometimes expanded to include lymph nodes in the upper abdomen.
If cancer is below the diaphragm, an "inverted Y" field is sometimes used, in which radiation is directed at lymph nodes in the upper abdomen, spleen, and pelvis.
Inverted Y-field radiation therapy combined with mantle-field radiation is called “total nodal radiation.”
"Involved field radiation" targets only lymph node regions that are known to have cancer. By contrast, extended-field radiation targets lymph node regions with cancer as well as adjacent, uninvolved lymph node regions. Involved-field radiation is usually given after several rounds of chemotherapy.

A 2006 study indicated that radiation therapy alone, without chemotherapy, may help older patients with early-stage Hodgkin’s disease. If chemotherapy is given, another 2006 study suggested that involved-field is a better option than extended-field radiation for elderly adults with early-stage unfavorable Hodgkin’s lymphoma.

In general, recent research suggests that extended-field radiation adds little survival advantage and carries a greater risk of serious side effects. Involved-field radiation is now becoming the preferred method. Some researchers recommend that involved-field radiation therapy plus chemotherapy should become the standard treatment for patients with early-stage Hodgkin’s disease who have a good prognosis. More research is needed before standard practice guidelines can be implemented.

It is very important that radiation treatments cover the entire diseased area and that the radiation therapy be powerful enough to destroy the malignant cells' capacity to grow and divide. Unfortunately, this means that normal cells are also affected, which can cause serious side effects. Different approaches may be used to prevent complications.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.
Long-term complications generally occur at higher radiation doses (over 35 Gy). Investigators are studying the doses as low as 20 Gy (in children). Studies indicate that radiation alone in doses under 35 Gy can control the disease as well as higher doses in most stage I and II patients, although some patients may require more aggressive treatment.
To protect ovaries, a technique called ovarian transposition may sometimes be performed. The procedure uses a laparoscope (a thin tube containing tiny instruments and cameras) that is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Infections. Infections may be a particular problem with radiation combined with chemotherapy. All patients should be vaccinated against pneumonia and influenza.

Inflammation in the Lungs. With carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.

Click the icon to see an image of the lungs.

Infertility. Radiation therapy to the pelvic area can adversely affect later fertility in women and men. Such negative effects may be worse in women; sperm usually recover within 5 years.

Heart Disease and Stroke. Radiation is associated with a future risk of heart disease, which includes atherosclerosis (hardening of the arteries) and diseases of the heart valves. Lower doses pose less risk. Recent research suggests that adults who survived childhood Hodgkin’s disease have a four times higher risk of having a stroke than healthy patients.

Fatigue. Fatigue is significant and chronic in many survivors. It is more highly associated with intensive chemotherapy, but it also may be a late response to radiation treatment.

Secondary Cancers. Second cancers (such as breast, stomach, lung, melanoma) may develop later in areas within or at the edge of the radiation area. Thyroid, respiratory tract, and digestive tract secondary cancers may affect patients who were treated as children. The risks are twice as high with treatments that are combined with chemotherapy.

Lung cancer in survivors is highly associated with smoking after treatment, and no survivor should smoke. The risk for breast cancer increases significantly in young women after treatment, particularly with high radiation doses and combined chemotherapy and radiation. The risk can persist for 25 years or more after radiotherapy, and lifetime monitoring (including frequent mammograms) is essential.

Thyroid Disorders. Hypothyroidism (underactive thyroid) occurs in a number of patients treated with radiation treatments. There is also a 5% chance for hyperthyroidism (overactive thyroid).

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of hyperthyroidism.

Impaired Growth in Children. Children and adolescents are at special risk for impaired bone growth.

Chemotherapy

Chemotherapy uses drugs to kill cancer cells. The drugs are called cytotoxic medications. Chemotherapy is referred to as body-wide, or systemic, therapy because the drugs travel throughout the entire body.

Cytotoxic drugs may be taken by mouth or given by injection. Treatment may be administered at a medical center, doctor's office, or even a patient's home. Some patients receiving chemotherapy may need to remain in the hospital for several days so the effects of the drug can be monitored.

Patients may receive 4 - 8 cycles of chemotherapy, depending on the stage. A cycle is usually 28 days and consists of several doses of drug administration followed by a period of rest.

The standard chemotherapy regimens for Hodgkin’s disease are ABVD and Stanford V.

ABVD consists of a 4-drug combination:

Doxorubicin (Adriamycin)
Bleomycin
Vinblastine
Dacarbazine

Stanford V consists of a 7-drug combination:

Doxorubicin (Adriamycin)
Mechlorethamine (nitrogen mustard)
Vincristine
Vinblastine
Bleomycin
Etoposide
Prednisone

BEACOPP (bleomycin, etoposide, Adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is a chemotherapy regimen reserved for high-risk patients. This regimen is proving to be extremely effective, particularly in advanced stages, with studies reporting remission rates of over 95% in patients with advanced Hodgkin's. However, this regimen also increases the risk for developing secondary cancers such as leukemia. Patients who are treated with BEACOPP should receive long-term follow-up care to monitor for side effects from this therapy.

Side effects and complications of any chemotherapeutic regimen are common, are more severe with higher doses, and increase over the course of treatment, though some trials suggest that toxicities can be reduced by administering the drugs for shorter duration without loss of cancer-killing effects.

Common Side Effects. Common side effects include the following:

Nausea and vomiting -- drugs known as serotonin antagonists, including ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps 1 or 2 days a month.

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta) can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to only treat anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Infection. Patients must take precautions against infections (see "Infection Prevention" in Transplant section).
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and general aches and pains are called somatic symptoms. Fatigue is especially common after chemotherapy and can even last for years.
Many women stop menstruating after chemotherapy. The risk for infertility is highest for women with advanced stage Hodgkin’s disease who are treated after age 30. Studies indicate that the risk for infertility is higher with BEACOPP than with ABVD. Researchers are studying whether taking oral contraceptives during chemotherapy can reduce the risk.
Bone thinning (osteoporosis) may be related to steroid treatments such as prednisone.
Heart failure may occur with the use of anthracyclines (such as doxorubicin).
Bleomycin (Blenoxane), an antibiotic, is particularly toxic to the lungs. Vinblastine may also pose a risk when used in combination with radiation therapy.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Regimens. Chemotherapy (usually ABVD) plus radiation, referred to as combined modality, is a common treatment approach for patients with more advanced-stage disease and for those who have early-stage bulky (large mass) disease.

Chemotherapy with low-dose radiation is being used in children with excellent results, even for late stage cancer. In one study, 82% of the children were still disease free at 5 years. Some chemotherapy drugs or high doses of radiation may be more deleterious to a boy's future fertility than to a girl's. A gender-specific combined regimen for pediatric Hodgkin's reduces the amount of radiation given to boys and also substitutes etoposide for procarbazine in the chemotherapy mixture (procarbazine, vincristine, prednisone, and doxorubicin).

Side Effects and Long-Term Complications. Side effects of combination treatments can be very serious. Examples include:

Combined modality poses a higher risk for secondary cancers than the use or radiation or chemotherapy alone. They include breast, lung, thyroid, melanoma, and gastrointestinal cancers, which usually develop in near or in the areas treated with radiation. Of note, the risk for breast cancer is lower when chemotherapies using alkylated drugs or radiation treatments damage the ovaries, suggesting that hormone stimulation plays a role in this higher risk. Newer drugs used in combined modalities may reduce the risk, at least for breast cancer.
ABVD and other regimens containing bleomycin increase the risk for severe effects on the lungs when used before or after mantle-field radiation. EVA (etoposide, vinblastine, and doxorubicin) is considered to be an effective substitute in patients with lung disease for whom bleomycin and radiation present an unacceptable risk.

Transplantation

Patients with relapsed or progressive HD are often treated with high-dose chemotherapy followed by stem cell transplantation procedures. (Transplantation does not appear to offer an advantage compared to standard chemotherapy as initial treatment for patients with high-risk advanced HD.)

This treatment involves removal and replacement of stem cells, which are produced in the bone marrow. This allows the patient to receive high-dose chemotherapy without destroying these important cells. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them.

For Hodgkin’s disease, the most common type of transplant is an autologous procedure, using the patient’s own cells. An allogeneic transplant, using cells from a donor, is more risky for patients with Hodgkin’s disease and is generally used only when an autologous transplant has failed. (This section provides information pertinent to autologous procedures. Detailed information on allogeneic transplants, including such complications as graft-versus-host-disease, can be found in In-Depth Report #84: Non-Hodgkin’s Lymphoma.)

Stem cells must first be collected in one of the following ways:

Directly from blood (peripheral blood stem cell transplantation)
From bone marrow (bone marrow transplantation)

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Stem cells are collected several weeks before the procedure. They are frozen and stored while the patient undergoes high-dose chemotherapy. Some patients receive high-dose whole body radiation therapy along with chemotherapy.

After the patient completes the pre-transplant therapy, the frozen cells are thawed and then infused into the patient. Within a few weeks, these cells start to generate new white blood cells and then new red blood cells.

The risk for infection greatest during the first 6 weeks following the transplant. During this period, a patient usually remains in isolation and receives antibiotics and intravenous nutrition. It takes 6 - 12 months post-transplant for a patient’s immune system to fully recover.

Many patients develop severe herpes zoster virus infections (shingles) or have a recurrence of herpes simplex virus infections (cold sores and genital herpes). Pneumonia, cytomegalovirus, aspergillus (a type of fungus), and Pneumocystis carinii (a protozoan) are among the most important life-threatening infections.

It is very important that patients take precautions to avoid infections. Guidelines for infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing, and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Common side effects of stem cell transplants include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

There is a small long-term risk for leukemia after transplantation in young people. Chemotherapy itself increases the risk of secondary cancers. Recent studies suggest that transplantation after chemotherapy does not add any additional risks. In addition, use of newer chemotherapeutic drugs may not pose as high a danger as older treatments.

Other serious potential complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Immunotherapy

Investigational approaches to Hodgkin's disease include immunotherapies, which are drugs that take advantage of the patients' own immune factors to attack the disease.

One important approach uses genetically designed immune factors called monoclonal antibodies (MAb) that recognize and attack specific molecules found on the surface of cells associated with HD.

Rituximab (Rituxan) was the first monoclonal antibody to be approved for any cancer. It is an unconjugated MAb that targets the CD-20 antigen, which is found on most B-cell lymphomas and normal mature B cells (although not stem cells). It is used in non-Hodgkin's lymphomas, but it may have benefits for some patients with Hodgkin's disease as well.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.lymphoma.org -- Lymphoma Research Foundation
www.leukemia.org -- Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.marrow.org -- National Marrow Donor Program
www.oncolink.org -- Cancer information
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Fermé C, Eghbali H, Meerwaldt JH, et al. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27.

Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007 Feb 10;25(5):571-8. Epub 2007 Jan 22.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Hodgkin Disease / Lymphoma. V.1.2007.

Review Date:
1/21/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

adam.com

Bipolar disorder

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Risk Factors
Causes
Prognosis
Diagnosis
Treatment
Medications
Other Treatments
Therapy and Lifestyle Chang...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In 2007, the FDA approved risperidone (Risperdal) for short-term treatment of manic or mixed episodes of bipolar I disorder in children ages 10 - 17. Risperidone (an atypical antipsychotic) and lithium (a mood stabilizer) are the two drugs currently approved for treating pediatric patients with bipolar disorder.

Drug Warnings

Olanzapine (Zyprexa, Symbex) causes a greater risk for high blood sugar than other atypical antipsychotics, according to updated information added to the drug’s warning label. Olanzapine also causes weight gain and can increase the risk for unhealthy cholesterol levels.
All atypical antipsychotics increase the risk for diabetes. Patients who take these drugs should receive regular screenings for changes in blood sugar levels. Patients should also have their cholesterol levels monitored.

Bipolar Disorder in Children and Adolescents

Diagnoses of bipolar disorder in children have increased 40-fold in the past decade, according to an analysis in the Archives of General Psychiatry. There is debate whether bipolar disorder in children was under-diagnosed in the past or is being over-diagnosed now.
Bipolar symptoms in children differ from those of adults, with some symptoms overlapping with behavioral and conduct disorders. New guidelines from the American Academy of Child and Adolescent Psychiatry (AACP) caution that a diagnosis of bipolar disorder must be carefully made, especially considering the risks associated with drug therapy. The AACP also advises that there are currently no established criteria for diagnosing bipolar disorder in preschoolers.

Bipolar Depression

The antidepressants bupropion (Wellbutin) and paroxetine (Paxil) do not increase the risk for mania, but neither do they help ease depression any more than mood stabilizers, suggests a 2007 study in the New England Journal of Medicine.
Intensive psychotherapy in combination with medication can help improve depression outcomes, indicates a 2007 study in the Archives of General Psychiatry.

Introduction

Bipolar disorder, or manic-depressive illness, is characterized by moods that swing between two opposite poles:

Periods of mania with exaggerated euphoria, irritability, or both
Episodes of depression

Although chemical imbalances in the brain are a key component of bipolar disorder, it is a complex condition that involves genetic, environmental, and other factors.

Bipolar disorder is classified according to the pattern and severity of the symptoms as bipolar disorder I, bipolar disorder II, or cyclothymic disorder. Patients with one type may develop another. Nevertheless, they are distinct enough to merit separate classifications, and some experts believe these conditions are actually separate disorders with different biologic factors that account for their differences.

Bipolar Disorder I. Bipolar disorder I is characterized by at least one manic episode, with or without major depression, that lasts for at least 7 days. In 60 - 70% of cases, manic episodes precede or follow depressive episodes in a regular pattern. Episodes are more acute and severe than in the other two categories.

Without treatment, patients average four episodes of dysregulated mood each year. With mania, either euphoria or irritability may mark the phase. In addition, there are significant negative effects (such as sexual recklessness, excessive and impulsive shopping, and sudden traveling) on a patient's social life, performance at work, or both. Untreated mania lasts at least a week, and it can last for months. Typically, depressive episodes tend to last 6 - 12 months, if left untreated.

Bipolar Disorder II and Hypomania. Bipolar disorder II is characterized by episodes of predominantly depressive symptoms, with occasional episodes of hypomania, which last for at least 4 days. Hypomania is similar to mania, but the symptoms (typically euphoria) are less severe and do not last as long.

Patients do not experience manic or mixed episodes, and most return to fully functional levels between episodes. However, bipolar II patients have a more chronic course, significantly more depressive episodes, and shorter periods of being well between episodes than patients with type I have. It is highly associated with the risk for suicide.

Cyclothymic Disorder. While cyclothymic disorder is not as severe as either bipolar disorder II or I, the condition is more chronic. Hypomanic symptoms tend toward irritability as compared to the more euphoric symptoms of bipolar II. (One report, in fact, referred to these patients as having "darker" natures, while bipolar II patients were "sunnier.")

The disorder lasts at least 2 years, with single episodes persisting for more than 2 months. Cyclothymic disorder may be a precursor to full-blown bipolar disorder in some people or it may continue as a low-grade chronic condition.

Symptoms of the Depression Phase. The symptoms of depression experienced in bipolar disorder are almost identical to those of major depression, the primary form of unipolar depressive disorder. They include:

Sad mood
Fatigue or loss of energy
Sleep problems such as insomnia, excessive sleeping, or shallow sleep with frequent awakenings
Appetite changes
Diminished ability to concentrate or to make decisions
Agitation or markedly sedentary behavior
Feelings of guilt, pessimism, helplessness, or low self-esteem
Loss of interest or pleasure in life
Thoughts of, or attempts at, suicide

Distinguishing Between Unipolar and Bipolar Depression. It is often difficult to differentiate between unipolar and bipolar depression, particularly in patients with bipolar II disorder. They may differ in the following ways:

Bipolar depression typically lasts 2 - 3 months -- not as long as in major depression (although left untreated some bipolar disorder episodes can last 6 - 12 months or longer).
People with unipolar depression can still experience a variety of other moods, but none meet the criteria for a manic state.
Depressive symptoms in those with bipolar disorder tend to vary. For example, some patients experience increased sleep, gain weight, and feel a heaviness and slowness in their bodies. Other patients with bipolar depression experience impaired sleep, but unlike patients with unipolar depression, they do not feel sleepy the next day.
Bipolar depressive episodes tend to develop more gradually than do those caused by major depression.

Symptoms of the Acute Manic Phase. The acute pure manic phase is always characterized by mood elevation, presented in the following ways:

Exaggerated euphoria (a feeling of great happiness or well-being)
Irritability
Both euphoria and irritability

The episode lasts for at least few days but, in some cases, the episode may last weeks or even months and may be severe enough to require hospitalization.

Other symptoms must also be present to make a diagnosis. Some mental health professionals use the mnemonic device DIGFAST to identify them. In general, for a diagnosis of mania, a patient must have experienced either euphoria with three DIGFAST symptoms or irritability with four of these symptoms:

D. Distractibility. This is the most common symptom, and it is usually characterized by the inability to pay attention to any activity for very long.
I. Insomnia in mania typically means having high energy and requiring less sleep. (This differs from insomnia in depression, in which the patient has low energy plus an inability to sleep.)
G. Grandiosity. Patients with this symptom have an inflated sense of themselves, which, in severe cases, can be delusional. Close to 60% of all manic patients experience feelings of being all-powerful. Sometimes they feel that they are godlike or have celebrity status.
F. Flight of ideas. Thoughts literally race.
A. Activity. The patient may show an increase in intensity in goal-directed activities, which are related to social behavior, sexual activity, work or school.
S. Speech. The patient may talk excessively.
T. Thoughtlessness. Excessive involvement in high-risk activities is present (such as unrestrained shopping, promiscuity). Mood disturbance may be severe enough to damage one's job or social functioning or one's relationships with others. Some patients require hospitalization to prevent harm to others or to themselves.

Some patients with bipolar I may experience psychotic symptoms, including thought disorders, hallucinations, and catatonia (a state in which the patient goes into a stupor for long periods, which may give way to short periods of extreme excitement).

Hypomania. With hypomania the symptoms of mania are milder and of shorter duration (but they last at least 4 days). They do not affect social or work life as dramatically.

Mixed Mania State Symptoms. Mixed mania (also called mixed episodes or dysphoric mania) are manic episodes that also have a depressive component. In such a state, mania is present to a significant degree, but depression is present most of the day and nearly every day. Such mixed symptoms occur for at least a week.

Depressive Mixed State Symptoms. Depressive mixed state is characterized by major depression as the primary emotional state with manic features (such as irritability, distractibility, and racing thoughts). Such patients may receive an inaccurate diagnosis of unipolar depression.

Risk Factors

Between 1 - 2 million Americans may suffer from bipolar disorder. Researchers estimate that about 1% of Americans experience bipolar disorder during the course of their lifetime, but some studies indicate that prevalence may be as high as 4%. There is differing opinion on how to diagnose and categorize bipolar symptoms, which affects these estimates. The majority of people with bipolar disorder also have other psychiatric disorders, particularly anxiety and substance abuse.

Bipolar disorder affects both sexes equally, but there is a higher incidence of rapid cycling, mixed states, and cyclothymia in women. Early-onset bipolar disorder tends to occur more frequently in men and it is associated with a more severe condition. Men with bipolar disorder also tend to have higher rates of substance abuse (drugs, alcohol) than women.

Bipolar disorder frequently occurs within families, although genetic factors account for only about 60% of cases. Family members of patients with bipolar disorder also have a higher than average incidence of other psychiatric problems. They include schizophrenia, schizoaffective disorder, anxiety disorders, ADHD, and major depression.

Causes

No single cause may ever be found for bipolar disorder. Instead, a combination of biologic, genetic, and environmental factors appears to trigger and perpetuate the chemical imbalances in the brain that shape this complex disorder. Biologic factors observed or considered in bipolar disorder, as detected by use of imaging scans and other tests, include:

Oversecretion of cortisol, a stress hormone
Excessive influx of calcium into brain cells
Abnormal hyperactivity in parts of the brain associated with emotion and movement coordination
Low activity in parts of the brain associated with concentration, attention, inhibition, and judgment
A superfast "biologic clock"

The so-called biologic clock is a tiny cluster of nerves called the supra chiasmatic nucleus, or SCN. The SCN is located in the center of the brain in the hypothalamus region. It regulates a person's circadian rhythm, the daily cycle of life, which influences sleeping and waking.

The genetics of bipolar disorder are the most intensively studied of all psychiatric diseases. Multiple genes, involving several chromosomes, have been linked to its development. Bipolar disorder also may share these genetic factors with other disorders, including schizophrenia, epilepsy, and panic disorder. It is not clear if some of these disorders are variations of a single disease or separate disorders.

Bipolar Disorder and Schizophrenia. Researchers have been investigating whether common biologic factors are involved with schizophrenia, severe bipolar disorder, and other psychoses. Schizophrenia and bipolar disorder often show up in the same family. Researchers are identifying a number of common genetic and biologic pathways that they both share. Bipolar Disorder and Epilepsy. Neurotransmitters called gamma aminobutyric acid (GABA) and norepinephrine have been implicated in mania:

GABA helps prevent nerve cells from over-firing
Norepinephrine is a hormone that involves stress

Some research has associated similar biologic mechanisms in patients with epilepsy and bipolar disorder. As in epilepsy, the more episodes a bipolar disorder patient experiences early in the course of the disease, the more frequent and severe later episodes will be. Antiseizure drugs, in fact, can play an important role in the treatment of bipolar disorder.

Panic Disorder and Bipolar Disorder. Researchers are also studying the common biologic and genetic factors between panic disorder and bipolar disorder. While specific genes have not yet been identified, some researchers studying these illnesses now believe that they may represent different forms of a shared, complex condition.

Prognosis

Bipolar disorder can be severe and long-term, or it can be mild with infrequent episodes. Patients with the disease may experience symptoms in very different ways. A typical bipolar disorder patient averages 8 - 10 manic or depressive episodes over a lifetime. However, some people experience more and some fewer episodes.

Typical Bipolar Cycles. In most cases of bipolar disorder, the depressive phases far outnumber manic phases, and the cycles of mania and depression are neither regular nor predictable. Many patients experience mixed mania, or a mixed state, in which both mania and depression coexist for at least 7 days.

Rapid Cycling. About 15% of patients with the disorder have a temporary, complicated phase known as rapid cycling. With this phase the manic and depressive episodes alternate at least four times a year and, in severe cases, can even progress to several cycles a day. Rapid cycling tends to occur more often in women and in those with bipolar II. Typically, rapid cycling starts in the depressive phase, and frequent and severe episodes of depression may be the hallmark of this event. This phase is difficult to treat, particularly since antidepressants can trigger the switch to mania and set up a cyclical pattern.

Differences Between Children and Adults. Research suggests that symptoms of bipolar disorder in children and adolescents differ from those of adults. While adults with bipolar disorder usually have distinct and persistent periods of mania and depression, children with bipolar disorder fluctuate rapidly in their mood and behavior. Mania in children is characterized by irritability and belligerence whereas adults tend to experience euphoria. Children with bipolar depression are frequently angry and restless, and may have additional mood and behavioral disorders such as anxiety, attention deficit hyperactivity disorder, conduct disorder, and substance abuse problems.

Medical evidence has shown that patients with bipolar disorder have higher death rates from suicide, heart problems, and death from all causes than those in the general population. Patients who get treatment, however, experience great improvement in survival rates, including deaths from suicide and heart disease.

Bipolar disorder usually first occurs between the ages of 15 - 30 years, with an average age of onset at 25 years. However, bipolar disorder can affect people of all ages, including children. Bipolar disorder that occurs late in life often accompanies medical and neurological problems (particularly cerebrovascular disease, such as stroke). It is less likely to be associated with a family history of the disorder than earlier-onset bipolar disorder.

Patients with bipolar disorder, especially type II or cyclothymic disorder, have frequent episodes of major depression. Anxiety disorders also commonly coexist in these patients. For example, the occurrence of panic disorder in patients with bipolar disorder is 26 times that of the general population. Patients with bipolar disorder, particularly those with type II, are also subject to phobias. In one study, the presence of anxiety disorders was also associated with longer and more severe bipolar depressive episodes and with a higher risk for suicide.

Symptoms of bipolar disorder in children are often confused with attention-deficit hyperactivity disorder (ADHD). Furthermore, the two conditions can coincide. In one study, 65% of adolescents with bipolar disorder met criteria for ADHD. The risk for both diagnoses is highest in white males. Symptoms are also more severe in people with both conditions. Some researchers believe that many of these disorders may actually be variations of a single disease.

The risk for suicide is very high in patients who suffer from bipolar disorder and who do not receive medical attention. Between 10 - 15% of patients with bipolar disorder I commit suicide, with the risks being highest during episodes of depression or mixed mania (simultaneous depression and mania). Some studies suggest that the risk for suicide in patients with bipolar disorder II is even higher than it is for those with bipolar disorder I or major depressive disorder. Patients who also suffer from an anxiety disorder are also at greater risk for suicide. (Rapid cycling, although a more severe variation of bipolar disorder, does not appear to increase the suicide risk in patients with bipolar disorder.)

Many pre- and early adolescent children with bipolar disorder are more severely ill than are adults with the disease, and the risk for suicide is high. They have a higher risk for mixed mania, multiple and frequent cycles, and a long duration of illness without well periods.

Studies suggest that patients with bipolar disorder may have varying degrees of problems with short- and long-term memory, speed of information processing, and mental flexibility. Such problems persist even between episodes. They tend to be more severe when a person has more manic episodes. Medications used for bipolar disorder could be responsible for some of these abnormalities, although some evidence suggests that such traits may have a biologic basis. These mental difficulties may make it harder for these patients to comply with medications or to participate in complex psychotherapies.

A small percentage of bipolar disorder patients demonstrate heightened productivity or creativity during manic phases. More often, however, the distorted thinking and impaired judgment that are characteristic of manic episodes can lead to dangerous behavior, including:

Spending money with reckless abandon, causing financial ruin in some cases
Angry, paranoid, and even violent behaviors
Openly promiscuous behavior

Such behaviors are often followed by low self-esteem and guilt, which are experienced during the depressed phases. During all stages of the illness, patients need to be reminded that the mood disturbance will pass and that its severity can be diminished by treatment.

Cigarette smoking is prevalent among patients with bipolar disorder, particularly those who have frequent or severe psychotic symptoms. Some experts speculate that, as in schizophrenia, nicotine use may be a form of self-medication because of its specific effects on the brain.

Up to 60% of patients with bipolar disorder abuse other substances (most commonly alcohol, followed by marijuana or cocaine) at some point in the course of their illness.

The following are risk factors for alcoholism and substance abuse in patients with bipolar disorder:

Having mixed-state episodes rather than ones of pure mania
Being a man with bipolar disorder

Patients do not manifest their negative behaviors (such as spending sprees or even becoming verbally or physically aggressive) in a vacuum. They have a direct effect on others around them. It is very difficult for even the most loving of families or caregivers to be objective and consistently sympathetic with an individual who periodically and unexpectedly creates chaos around them.

Many patients and their families find it difficult to accept that these episodes are part of an illness and not simply extreme, but normal, characteristics. Such denial is often strengthened by patients who are highly articulate and deliberate, and who can intelligently justify their destructive behavior, not only to others, but also to themselves.

Family members may also feel socially alienated by the fact of having a relative with mental illness, and feel forced to conceal this information from acquaintances.

The economic burden of bipolar disorder is significant. It is estimated that the disorder costs the U.S. workplace about $14.1 billion annually in lost productivity, mostly due to poor functioning on the job. According to a 2006 study sponsored by the U.S. National Institute of Mental Health, bipolar disorder accounts for twice as much lost productivity as major depressive disorder (MDD), despite the fact that MDD is more prevalent. Each worker with bipolar disorder loses about 66 workdays a year compared with 27 workdays a year for workers with MDD. Research suggests that bipolar disorder’s depressive episodes impair productivity more than its manic episodes.

People with mental illness have a higher incidence of many medical conditions, including heart disease, asthma and other lung problems, gastrointestinal disorders, skin infections, diabetes, hypertension, migraine headaches, hypothyroidism, and cancer. Patients with bipolar disorder are also less likely to receive medical care than people without mental disorders. Substance abuse, including smoking, alcoholism, and drug abuse, also contributes to many of these problems as well as reduced access to care. Medications used for bipolar disorder can also increase the risk for medical problems.

However, people with bipolar disorder and other mental illness have a higher risk for a number of these conditions independent of these factors.

Diabetes. Diabetes is diagnosed almost three times more often in people with bipolar disorder than it is in the general population. Many patients with bipolar disorder are overweight, with about 25% meeting the criteria for obesity. Being overweight is a significant risk factor for diabetes and so it may be the common factor in both diseases. Drugs used to treat bipolar can also cause weight gain and diabetes. Common genetic factors in diabetes and bipolar disorder may cause a rare disorder called Wolfram syndrome and other problems with carbohydrate metabolism.

High Blood Pressure. Patients with bipolar disorder may be at a higher risk for high blood pressure (hypertension) than patients without the disorder. The high prevalence of hypertension among patients with bipolar disorder may also account for their greater risk for illness and death from heart-related conditions.

Migraine Headaches. Migraines are common in patients with a number of mental illnesses, but they are particularly common among patients with bipolar II disorder. Patients with bipolar II suffer from migraine more frequently than patients with bipolar I, suggesting that different biologic factors may be involved with each bipolar form.

Hypothyroidism. Hypothyroidism (low thyroid levels) is a common side effect of lithium, the standard treatment for bipolar. However, evidence also suggests that patients, particularly women, may be at higher risk for low thyroid levels regardless of which medications they use. Hypothyroidism may, in fact, be a risk factor for bipolar disorder in some patients.

Diagnosis

Bipolar disorder is more common than previously thought, but this illness, particularly bipolar disorder II, is still poorly recognized in the family-practice setting. It is estimated that only a third of affected people are accurately diagnosed.

When making a diagnosis of bipolar disorder, it is important that the doctor rule out other conditions that may be causing symptoms of bipolar disorder.

Distinguishing Mania from Normal Euphoria or Joy. A major difficulty with a diagnosis of bipolar disorder is the tendency for a patient to be unable to recognize his or her own condition, particularly when in the manic state. The patient often denies their symptoms, which may be perceived as positive feelings. The doctor should take a careful and complete history of any and all episodes of depression, mania, or both. Hypomania, the less severe variant of mania, may be particularly difficult to distinguish from normal joy or euphoria. It can often be distinguished by the following characteristics:

Hypomania persists for at least 4 days
Patients with hypomania are easily distracted and overly talkative
Patients with hypomania have difficulty functioning

Distinguishing Unipolar from Bipolar Depression. People with bipolar disorder are more likely to seek help because of a depressive episode and may not have a manic episode until they have experienced three or more depressive episodes. In such cases, the condition is often diagnosed as major depression. An accurate diagnosis is important because patients with bipolar disorder who are inappropriately medicated solely with antidepressants have a higher incidence of rehospitalization than do other bipolar disorder patients.

Bipolar disorder should be suspected in patients who have been treated for depression and who had a fast and good response, followed by the return of depression and failure to respond to other antidepressant treatment.

A family history of manic-depressive illness may make a doctor suspicious, but a diagnosis of bipolar disorder cannot be established until a manic or hypomanic episode has occurred. Patients with bipolar II disorder and those with depressive mixed state are most likely to be misdiagnosed with depression.

Attention Deficit Hyperactive Disorder (ADHD). Children or adolescents with bipolar disorder may be inappropriately diagnosed with attention-deficit hyperactivity disorder. ADHD and bipolar disorder often cause inattention and distractibility, and the two disorders may be difficult to distinguish, particularly in children. In some cases, ADHD in children or adolescents can even be a marker for an emerging bipolar disorder. The primary distinction between bipolar disorder and ADHD is the presence of a manic or hypomanic episode, which occurs in patients with bipolar disorder but not those with ADHD.

Schizophrenia. Severe manic episodes that include delusions and hallucinations may be easily confused with schizophrenia. (African-American men are more likely to be diagnosed with schizophrenia than with bipolar disorder.) The key factors that distinguish bipolar disorder from schizophrenia include:

The presence of one or more manic or hypomanic episodes in bipolar disorder, but not in schizophrenia
A flat emotional expression, with no variability in the voice among people with schizophrenia
People with bipolar disorder are typically very expressive

Substance Abuse. Up to 60% of patients with bipolar disorder abuse alcohol and drugs at some point during their illness. Both diagnosis and treatment are difficult in such cases, since substance abuse is often a method of self-treatment, and withdrawal can produce symptoms of mania or severe depression. The effects of cocaine in a heavy user can also produce abnormal mood swings that closely resemble those of bipolar disorder.

Other Causes of Mood Swings. Other conditions that can cause mood swings include:

Thyroid disorders
Adrenal disorders (Addison's disease or Cushing syndrome)
Vitamin B12 deficiency
Neurologic disorders such as Huntington's disease, epilepsy, brain tumors, encephalitis, or multiple sclerosis
Medications, including corticosteroids and certain drugs used to treat anxiety and Parkinson's disease

Patients should be tested for drugs or alcohol if the doctor suspects that they have been using these substances. Blood tests for thyroid function should also be performed.

Noninvasive imaging tests of the brain using magnetic resonance imaging (MRI) and positron-emission tomographic (PET) scans are being evaluated in clinical trials for detecting abnormalities in the brain. The results of these tests may eventually help identify bipolar disorder and test the effectiveness of various treatments. However, imaging tests do not currently play a role in diagnosing bipolar disorder.

The number of children diagnosed with bipolar disorder has increased dramatically during the past decade. Psychiatrists debate whether bipolar disorder was formerly under-diagnosed in children or whether it is being over-diagnosed now. Part of the controversy concerns the diagnostic criteria used for children and adolescents. Some bipolar symptoms, such as irritable mania, share characteristics with common childhood anger outbursts or behavioral disorders such as conduct disorder and attention deficit hyperactivity disorder. In addition, many children with bipolar disorder also have behavioral and developmental disorders. These overlapping conditions can complicate diagnosis.

The American Academy of Child and Adolescent Psychiatry (AACP) recommends that doctors use specific screening questions to diagnose bipolar disorder. These questions are designed to evaluate periods of mood changes associated with sleep disorders and restlessness. Doctors should also ask about family histories of mood disorders. The AACP cautions that the validity of diagnosing bipolar disorder in children younger than 6 years old has not been established.

Bipolar disorder is treated with powerful psychiatric drugs that can cause serious side effects. It is very important to make sure that a child’s symptoms are due to bipolar disorder, rather than emotional or behavioral issues, before prescribing these medications.

Treatment

Bipolar disorder is a recurrent disease that can be unpredictable. The major goals of treatment are to:

Treat and reduce the severity of acute episodes of mania or depression when they occur
Reduce the frequency of episodes
Avoid cycling from one phase to another
Help the patient function as best as possible between episodes

The doctor will first try to determine what may have triggered the attack and identify any accompanying medical or emotional problems that might interfere with or complicate treatment.

Some experts think that the best way to treat bipolar disorder is through a disease management model, similar to those used for treating diabetes and asthma. In this “collaborative care” model, patients are treated by a multi-disciplinary team of psychiatrists and nurses. The nurses provide patient education on medication side effects, early warning signs of symptoms, and coping skills. In several 2006 studies, patients who received this treatment model reported fewer symptoms, more productive time at work, better relationships with family members, and general improvement in quality of life.

The treatments for bipolar disorder, while very effective, pose some specific challenges for the patient:

Mood variations in bipolar disorder are not predictable, so it is sometimes difficult to tell if a patient is responding to treatment or naturally emerging from a bipolar phase.
A patient with bipolar disorder cannot always reliably inform the doctor about the state of the illness.
The patient is likely to need more than one medication during the course of the disease. This increases the risk for distressing side effects. Noncompliance is common.
Patients often have more than one medical problem and need different drugs to treat each condition. Such medications may interact with drugs used to treat bipolar disorder or increase side effects. For example, children with bipolar disorder have a higher risk for attention deficit-hyperactivity disorder, which is treated with stimulants that can complicate bipolar treatment.
Family members who have not been educated about the disorder may interfere with the treatment.
Treatment strategies for children and the elderly have not been intensively studied and have not been clearly defined.
Treatments may be costly.

The following are the treatment options for most patients with bipolar disorder, depending on the bipolar disorder phase or episode. Patients should understand that, even with aggressive therapy, either mania or depression recurs in almost three-quarters of patients.

Drugs Used in Bipolar Disorder. Mood stabilizing drugs are the mainstay for patients with bipolar disorder. They are defined as drugs that are effective for acute episodes of mania and depression and that can be used for maintenance. The standard first-line mood stabilizers are lithium and valproate. Both drugs stimulate the release of the neurotransmitter glutamate, although they appear to work through different mechanisms. Other drugs may also be used.

Lithium. Lithium has been used for years for bipolar disorder. It remains the best drug for people with pure mania characterized by euphoria and pure depression. Although imperfect, it is also an effective long-term drug for many patients with other bipolar subtypes.
Antiseizure Drugs. Valproate (valproic acid) carbamazepine (Tegretol, Carbatrol, Equetro), oxcarbazepine (Trileptal), and lamotrigine (Lamictal) are the most established antiseizure drugs. Other anti-seizure drugs used or investigated for bipolar include gabapentin (Neurontin), zonisamide (Zonegran) and topiramate (Topamax). To date, it is not clear if any of these newer drugs are useful for the treatment of acute mania.
Atypical Antipsychotics. Drugs known as atypical antipsychotics are used to treat schizophrenia and also have mood stabilizing properties that are applicable to bipolar disorder. They may be used either alone or in combination with lithium or valproate. Clozapine (Clozaril) was the first of these drugs, but it has not yet been approved for treatment of bipolar disorder. The newer atypical antipsychotics include olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), ziprasidone (Geodon), and ariprazole (Abilify).

Such drugs may be used in combination with each other. Additional drugs, such as conventional antipsychotics, antidepressants, antianxiety drugs, or experimental drugs are used as necessary.

Electroconvulsive Therapy. Electroconvulsive therapy is a very effective treatment that may be administered in certain patients for acute episodes or for maintenance.

Non-Medical Treatments. In addition to medical treatments, psychotherapy and sleep management are also parts of bipolar disorder treatment. They can help reduce symptoms and prevent relapse.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), an ongoing trial supported by the National Institute of Mental Health, is the largest treatment study ever conducted for bipolar disorder. With plans to enroll approximately 5,000 patients, STEP-BD aims to evaluate all the best-practice treatment options used for bipolar disorder, including mood-stabilizing medications, antidepressants, and atypical antipsychotics. It will also evaluate psychosocial interventions, including cognitive behavioral therapy, family-focused therapy, interpersonal and social rhythm therapy, and psychoeducation. Results of STEP-BD may clarify the best treatments for bipolar disorder.

Step 1. Determine the Need for Hospitalization and Eliminate Triggers. The first step in treating an acute manic episode is to rule out any life-threatening conditions and eliminate any triggers, such as antidepressants or other substances that can elevate moods.

Patients often require hospitalization at the onset of acute mania. The need for hospitalization depends on a number of factors:

Whether the patient is at risk for suicide or for harming others
The availability of social and emotional support at home

Step 2. Control Symptoms of Acute Manic with a Mood Stabilizer. Doctors often try different drugs to control a manic episode. If a current drug does not work well, another type of drug may be added or substituted. It may take several weeks for a mood stabilizer to take effect, and other drugs may be needed.

The following is an example of a stepped approach recommended by some experts:

Initiating a mood-stabilizing drug is the critical first step. Either valproate or lithium is the standard first drug for most manic episodes. Lithium is effective in 60 - 80% of all hypomanic and manic episodes. Carbamazepine is usually used in place of valproate to treat patients with multiple manic episodes, mixed episodes, and rapid cycling. Combinations of these mood stabilizers may be used if the patient does not respond to a single drug.
If the patient does not respond fully within a week, atypical antipsychotics may be added to one or more mood stabilizers. Atypicals include olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), apriprazole (Abilify), and ziprasidone (Geodon). Clozapine (Clozaril), the oldest atypical drug, also works well but it is not generally used because of its potential for severe side effects and the need for weekly monitoring of white blood cell counts.

Step 3. Addition of Other Treatments. Other treatments may be added to speed recovery, treat any psychosis, and achieve remission. They include:

Older antipsychotic drugs (also called typical antipsychotics), such as haloperidol (Haldol), may be used for acute mania. They can cause severe side effects, however, particularly extrapyramidal effects, which disrupt motor control. They are not generally used on a long-term basis for treating bipolar disorder.
Benzodiazepines, such as clonazepam (Klonopin) or lorazepam (Ativan), are anti-anxiety drugs that may be particularly beneficial if the patient is experiencing severe mania.
Electroconvulsive therapy. This treatment helps patients who do not respond to medication and may even be life-saving in elderly patients with severe late-onset mania.

Step 4. Terminate Some Drug Treatments. Drugs may be stopped under the following circumstances:

When side effects are intolerable
When the patient does not respond to the maximum dose
When the patient improves and recovery is sustained

In cases of improvement and sustained recovery, the neuroleptic or benzodiazepine is slowly withdrawn and only the mood-stabilizing drug is continued.

Step 5. Continuation of Mood Stabilizers. Mood stabilizers are typically continued for about 8 weeks, unless the patient shows signs of shifting to another mood state. If the patient remains stable at that time, the doctor may decide to continue maintenance treatment or to gradually withdraw medications.

Depressive episodes pose a particular challenge. They are a significant cause of suffering, yet the use of standard antidepressants poses a significant risk for triggering mania. It is also not clear if standard antidepressants work for bipolar depression. In fact, depressive episodes are very difficult and patients who do not respond to mood stabilizers may endure prolonged depressive episodes up to 2 - 3 months.

Lithium or lamotrigine are the standard first-line treatments for depressive episodes. Many studies indicate that lithium works better for controlling manic states, and that lamotrigine works better for bipolar depression.

If improvement does not occur within 2 - 4 weeks, an antidepressant may be added. Antidepressants alone are not recommended. The first choices for antidepressants are bupropion (Wellbutrin) or paroxetine (Paxil). Alternatives include one of the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), a newer antidepressant such as venlafaxine (Effexor), or a monoamine oxidase inhibitor (MAOI).

Several studies have found no additional benefits from antidepressants. Many studies indicate that antidepressants may cause patients to “switch” to a manic state. Any patient with bipolar disorder who takes antidepressants and who develops symptoms of hypomania should stop taking these drugs, because hypomania is often a sign of impending mania. All antidepressants should be tapered after the mood has been stabilized for a month.

An atypical antipsychotic combined with a mood stabilizer is another treatment option. In 2003, the Food and Drug Administration (FDA) approved a drug (Symbyax) that combines the atypical antipsychotic olanzapine and the SSRI antidepressant fluoxetine. Symbyax was the first drug to be specifically approved for treatment of bipolar depression. In 2006, quetiapine (Seroquel), which is approved for treatment of bipolar mania, received an additional approval for treatment of bipolar depression.

Other Treatments. Cognitive-behavioral therapy or other psychotherapy programs may help patients endure depressive episodes by developing ways to manage negative thoughts and behaviors. Electroconvulsive therapy is another option for depression that does not respond to less intense approaches.

The first step in treating rapid cycling is to try to identify and resolve other factors, such as drug abuse or hypothyroidism, which may have caused this condition. Many patients may require a combination of medications to control rapid cycling:

Antidepressants, particularly SSRIs, may prompt rapid cycling and should be tapered off.
Lithium or valproate is a first-line treatment for rapid cycling.
Lamotrigine is an alternative treatment for rapid cycling.
Atypical antipsychotics (olanzapine, aripiprazole, ziprasidone, risperidone) are approved to treat mixed episodes. These drugs are used either alone or in combination with lithium or valproate.
One biological mechanism involved with rapid cycling is an excessive influx of calcium into brain cells. Cardiovascular drugs called calcium channel blockers may be beneficial for ultra-rapid cycling.
Low thyroid (hypothyroidism) is involved in some cases of rapid cycling. In these cases, levothyroxine, a synthetic derivative of the thyroid hormone T4 (thyroxine), has helped stabilize rapid-cycling patients.
Electroconvulsive therapy can be useful in emergency situations.

In addition, other measures should be taken:

Patients should avoid anti-anxiety drugs, alcohol, caffeine, and stimulants.
Patients should avoid exposure to bright light.
All efforts should be made to help the patient sleep normally.

Drugs Used During Maintenance. Relapse occurs in most patients after treatment of acute attacks, and patients who are at high risk for recurring episodes should consider life-long maintenance therapy. This usually involves mood-stabilizing drugs:

Lithium is a first-line mood stabilizer used in maintenance therapy. The anti-epileptic drug valproate is also a first-line treatment. In general, the two work equally well, although valproate may be better for patients who have had multiple manic episodes. There are some differences in side effects, but the drop-out rates between the drugs are similar. Lithium has proved effective for preventing relapses of manic episodes, but may not work as well for controlling depressive symptoms.
Lamotrigine, an anti-epileptic drug, was approved in 2003 for long-term maintenance treatment. It is also used as a first-line drug for treating depressive episodes.
Carbamazepine and oxcarbazepine are other anti-epileptic drugs used as alternative maintenance treatments.
Atypical antipsychotics may be used for maintenance, particularly in combination with a mood stabilizer. In 2004, olanzapine became the first atypical antipsychotic to be approved specifically for maintenance treatment.

The general recommendations for maintenance therapy with lithium are as follows:

The earlier lithium is started in the disease process, the better. Studies suggest that patients on long-term lithium therapy have survival rates comparable to the general population, but those who permanently drop out of therapy have significantly lower survival rates due to an increased suicide risk.
Lithium still works for patients who discontinue and then restart treatment later on. In such cases, however, there may be a greater need for drug combinations. In addition, patients who stop and start again may be at higher risk for hospitalization than those who use the drug continuously.
For those who want to stop, a gradual discontinuation (over 15 - 30 days) may help to delay recurrence. Stopping lithium quickly poses a high risk for relapse and even for suicide.

Information on clinical care of pregnant women with bipolar disorder remains very limited. In fact, in one survey, almost half of women with bipolar disorder were discouraged by their doctors from becoming pregnant. Nevertheless, after careful counseling about medications, possibilities for relapse, and disease severity, nearly two-thirds of them decided to attempt pregnancy.

Risks for Bipolar Episodes. Some studies suggest the following risks for bipolar episodes during and after pregnancy:

In women who discontinue lithium during pregnancy, the chance for recurrence of bipolar disorder is the same as in non-pregnant women, which is over 50%.
Pregnant women with bipolar disorder are at particularly high-risk for recurrence in the period after childbirth. In one study, symptoms recurred in 74% of women after delivery, and another 20% were hospitalized within 90 days after giving birth. The risk for depressive or mixed states is particularly high.

Drugs for Bipolar and Pregnancy. It is not ethical to test drugs during pregnancy, so all known effects of bipolar drugs are reported anecdotally. It is well-known, however, that most mood stabilizers used for bipolar disorder carry a high risk for the fetus, particularly if they are taken during the first trimester. Taking mood stabilizers at the time of delivery may help reduce the risk of manic episodes occurring after the baby is born. However, caution is still advised. Reported effects of drugs taken during pregnancy include:

Lithium can pass through the placenta and affect the fetus. When possible, patients should avoid taking lithium during pregnancy, especially during the first 3 months. Studies report that lithium use during the first trimester may cause heart defects and thyroid problems in the baby. If taken immediately before childbirth, lithium can also cause muscle weakness and drowsiness in newborn infants. Women who must take lithium during pregnancy should take the lowest possible dosage and stop the drug 1 - 2 days before delivery. Mothers who are taking lithium should not nurse their babies, since lithium is concentrated in breast milk.
The antiseizure drugs valproate and carbamazepine both greatly increase the risk for physical malformations, developmental delay, and spina bifida in babies. They appear to have minimal effect on breastfeeding, however. Lamotrigine can cause cleft lip and palate birth defects if taken during the first trimester.
Small studies have suggested that the atypical antipsychotic olanzapine does not increase the risk for birth defects. However, it does pose a great risk for excess weight gain that could be unhealthy during pregnancy. Less is known about the effects of other atypical antipsychotics during pregnancy.

Electroconvulsive Therapy (ECT). In spite of its bad press, ECT appears to be very beneficial for women with bipolar disorder who become pregnant. The patient should discuss this option with her doctor.

Doctors are still trying to decide the best treatment of bipolar disorder in children and adolescents. The drugs used for bipolar disorder have considerable side effects, which may be even more severe in younger people. Parents should consider the potential risks and benefits of treatment for their children.

Until recently, lithium was the only drug approved for treating bipolar disorder in children (age 12 years and older). In 2007, the FDA approved the atypical antipsychotic risperidone (Risperdal) for short-term treatment of manic or mixed episodes of bipolar I disorder in children ages 10 - 17.

Lithium is generally used as the first-line treatment, with valproate and risperidone (or other atypical antipsychotics) as alternatives. If treatment with a single drug does not work, a combination of drugs may be used.

Lithium and valproate are the drugs most studied in children and adolescents. However, side effects of these drugs in children may include severely impaired thinking, acne, increased urination, weight gain (lithium), and menstrual irregularities and polycystic ovary syndrome (valproate). Side effects of risperidone may include drowsiness, fatigue, increased appetite, nausea, dizziness, dry mouth, tremor, and rash.

Pediatric prescriptions for atypical antipsychotics have been increasing in recent years. However, the safety and effectiveness of these drugs for children and adolescents has not been established. They appear to work well in the short-term, but a 2006 study noted that there is little available evidence concerning their long-term effects.

Psychotherapy is also an important addition to drug treatment. Therapy that includes the entire family is important. Electroconvulsive therapy (ECT) may benefit adolescents with bipolar I disorder who suffer severe episodes of mania or depression and who have not been helped by medication.

Medications

Lithium (Carbolith, Duralith, Lithobid, Lithizine, Eskalith, Lithane) is one of the standard mood stabilizing drugs for bipolar disorder. Lithium is extremely helpful for most patients and it significantly reduces the rate of hospitalizations in bipolar disorder. Some studies report the following advantages of lithium:

Lithium is effective in 60 - 80% of all hypomanic and manic episodes. (Valproate may be better in patients with multiple manic episodes, mixed episodes, and rapid cycling.)
It helps to prevent relapses.
It helps psychosocial functioning.
It may help reduce the risk for suicide regardless of its effects on stabilizing mood.
It works well for most patients even if they have discontinued taking it and wish to restart treatment.

Administration of Lithium. Lithium may take weeks to become totally effective, so patients should not expect an immediate response during an acute episode. Doctors may take different approaches to administering the drug:

Some doctors initially administer lithium in two low doses and gradually increase the dosage over time until an effective (therapeutic) level is achieved.
Another approach is to administer a higher dose initially and measure blood levels of the drug after 24 hours. The doctor uses this information combined with a chart called a nomogram to calculate the doses most likely to be therapeutic.

In addition to drugs, several factors may affect lithium levels:

Seasonal change -- lithium levels may be higher in summer.
Menstrual cycle -- lithium levels may drop during the premenstrual phase.
Weight loss
Changes in salt intake
Dehydration
Diarrhea

Lithium levels should be monitored regularly. Side effects can occur at therapeutic levels or at those only slightly higher than desired. Blood tests that measure drug levels should be conducted frequently during acute attacks and about every 3 months during maintenance therapy.

Lithium Toxicity. Evidence of moderate toxicity include:

Trembling hands
Nausea
Increased urine output
Blurred vision
Some loss of coordination

Severe reactions occurring at higher blood levels, include:

Vomiting
Convulsions
Uncontrolled jerky movements in arms and legs
Stupor
Coma

Very high blood levels of lithium can be fatal. If overdose occurs, drugs should be stopped immediately and one or more of the following steps taken, depending on the severity:

Patients are given fluids and drugs to increase excretion of lithium salts.
Gastric lavage, a procedure that rinses the stomach, may be used to treat very recent overdoses.
Hemodialysis, a procedure that filters lithium out of the blood, may also be performed in severe cases.

Side Effects. Even for patients who do not experience a severe response, long-term use of lithium is not without problems. Weight gain is one of the main reasons why some patients want to stop taking the drug. Other side effects include:

An unpleasant taste in the mouth
Hair loss
Skin eruptions that can resemble acne and make psoriasis worse
Low thyroid function
An increased risk for diabetes
A blunted sexual drive
Dulled emotions and lack of mental clarity
Memory loss
Lack of motor coordination
Increased sensitivity to light

In some cases, light sensitivity may slightly affect a person's ability to recognize colors. More seriously, it can cause problems with night driving. This effect occurs regardless of how long a person has been on the drug. Experts recommend that patients wear sunglasses outside and avoid extensive exposure to bright light.

Drug Interactions. Because lithium is eliminated from the body by the kidneys, any drugs or dietary factors that slow the kidneys' actions may increase lithium blood levels and should be used with great caution. Such drugs include:

Nonsteroidal anti-inflammatory drugs (NSAIDs)
Thiazide diuretics
ACE inhibitors

There have been reports of interactions between lithium and certain drugs commonly used in combination, including:

Antipsychotics
Anticonvulsants
Calcium-channel blockers

The risks associated with these drug interactions are very low, but caution is needed.

Patients should be sure to contact their doctor if they have any suspicious symptoms or illnesses.

Noncompliance. Noncompliance is common. One study of lithium users found that patients took their medication only 34% of the time. Another reported that nearly a third of patients eventually went off the drug.

Side effects are certainly one reason for noncompliance. Some patients regret the loss of their manic episodes and the exhilaration and creativity that sometimes accompany them. In one small study of artists with bipolar disorder, however, only 25% felt their work had declined, while another 25% found no change in their creative output, and 50% believed that lithium had improved their output.

Despite side effects and other concerns, this important drug saves lives. Doctors are confident that lithium, which has been in use for more than 50 years, can be taken safely, even for life, by most patients.

Antiseizure drugs, also called anti-epileptics or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. These drugs may be an alternative for patients (especially substance abusers) who do not tolerate or respond to lithium. They also may be used in combination with lithium, atypical antipsychotics, or other drugs.

Standard Antiseizure Drugs.

Valproate (Depakote), also called valproic acid or divalproex, is now a first option for many bipolar disorder patients. It works well for many patients with mania, rapid-cycling, and mixed states, as well as for patients who are substance abusers. Valproate also helps migraine headaches, a common problem among patients.
Lamotrigine (Lamictal) is approved for maintenance treatment of adults with bipolar I disorder. It appears to be particularly helpful for patients with rapid cycling and bipolar II disorder, in whom depression remains problematic after taking other mood stabilizers.
Carbamazepine (Epitol, Tegretol), a standard alternative antiseizure drug used for mood stabilizing, is usually the second anti-seizure medication of choice. In 2004, the FDA approved an extended release form of carbamazepine (Equetro). Another drug, oxcarbazepine (Trileptal), is similar to carbamazepine.
Other anti-seizure drugs used or investigated for bipolar include gabapentin (Neurontin), zonisamide (Zonegran) and topiramate (Topamax). To date, it is not clear if any of these newer drugs are useful for the treatment of acute mania.

General Side Effects. The side effects given here are associated with valproate. Other antiseizure drugs have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy and then subsiding. Valproate side effects include:

Gastrointestinal problems such as nausea, vomiting, and heartburn
Headaches
Visual disturbances
Ringing in the ear
Hair loss
Weight gain (a significant problem with valproate)
Agitation
Odd movements
Menstrual irregularities and a higher risk for polycystic ovary syndrome (PCOS)
Birth defects when taken by pregnant women
Cognitive impairment and symptoms of Parkinson's disease

Very serious side effects are possible. Stevens-Johnson syndrome (SJS) is a rare but severe and potentially life-threatening, rash that can develop as a side effect of carbamazepine, lamotrigine, oxcarbazepine and other anticonvulsants. Because this is a very serious condition, these drugs are discontinued at the first sign of rash. The risk of serious skin reactions is 10 times higher for patients of Asian ancestry than Caucasians. The FDA recommends that people of Asian ancestry get a genetic test before starting carbamazepine to determine if they are at risk for this side effect.

Other serious side effects, also rare, may include liver damage, convulsions, coma, and pancreatitis.

Atypical antipsychotics are standard drugs for schizophrenia. They are now proving to be beneficial for bipolar disorder when used alone or in combination with the mood stabilizers that treat mania. These drugs include clozapine (Clozaril) (the first atypical antipsychotic), olanzapine (Zyprexa), risperidone (Risperdal), paliperidone (Invega), quetiapine (Seroquel), aripiprazole (Abilify), and ziprasidone (Geodon).

Olanzapine was the first atypical antipsychotic approved for treatment of bipolar disorder. In 2000, the FDA approved it to treat bipolar mania and mixed states. In 2004, the drug became the first atypical antipsychotic approved for bipolar maintenance treatment.
Symbyax, a drug that combines olanzapine and the antidepressant fluoxetine, was approved in 2003 for treatment of bipolar depression.
Risperidone, ziprasidone, and ariprazole are approved for treatment of bipolar mania and mixed states. Paliperidone (Invega), which is chemically related to risperidone, was approved in 2007 for treatment of schizophrenia but has not yet been approved for bipolar disorder.
Quetiapine is approved for treatment of bipolar mania and bipolar depression, making it the only drug approved for treating both manic and depressive states.
Clozapine has not been approved for treatment of bipolar disorder, but has shown promise in investigational studies. However, this drug has more significant side effects than other atypical antipsychotics. It poses a risk of white blood cell reduction (agranulocytosis).

Side Effects. Although atypical antipsychotics have fewer severe side effects than standard antipsychotics, many patients fail to comply with regimens containing them. Common side effects include:

Nasal congestion or runny nose
Drooling
Dizziness
Headache
Drowsiness -- however, these drugs may also cause restlessness and insomnia.
Constipation
Rapid heart beat
Difficulty urinating
Skin rash
Increased body temperature
Confusion, short-term memory problems, disorientation, and impaired attention
Weight gain -- risk is highest with clozapine and olanzapine, lowest with aripiprazole and ziprasidone

More serious risks include:

Diabetes (See Diabetes Risk and Atypical Antipsychotics)
Weight gain and metabolic problems. The risk is highest for olanzapine, and lowest for aripiprazole and ziprasidone.
Unhealthy cholesterol levels. Particularly with olanzapine, increased risk for high levels of trigylcerides and total cholesterol.
Seizures
Heat stroke
Sudden drop in blood pressure (hypotension)
A significant drop in white blood cell count (neutropenia) and neutrophils (agranulocytosis) occurs in 1% or more of patients, generally in the first 6 months after starting treatment. Patients should have their white blood count and absolute neutrophil count regularly monitored if they take clozapine.
Extrapyramidal side effects, which are lack of motor coordination and involuntary movements
Cataracts and worsening of any existing glaucoma
Increased prolactin levels -- prolactin is a hormone associated with infertility and impotence. High levels can cause menstrual abnormalities and may increase the risk for osteoporosis and possibly breast cancer.

Diabetes Risk and Atypical Antipsychotics. In 2003, the FDA requested that the strongest warning be added to the product labels of all atypical antipsychotics. This so-called black box warning advises that these drugs can increase the risk of high blood sugar (hyperglycemia) and diabetes. (Olanzapine is more likely to cause high blood sugar levels than other atypical antipsychotic medicines.) The FDA recommends that:

Patients with an established diagnosis of diabetes who begin atypical antipsychotic treatment should be regularly monitored for worsening of blood sugar control.
Patients with risk factors for diabetes (obesity, family history of diabetes) should undergo fasting blood sugar testing at the beginning of atypical antipsychotic treatment and periodically during treatment.
All patients treated with atypical antipsychotics should be monitored for high blood sugar (hyperglycemia) symptoms.
Patients who develop hyperglycemia symptoms should undergo fasting blood sugar testing.

Antidepressants are sometimes used for depressive episodes in bipolar disorder, but their use is controversial. They may trigger mania in 12 - 28% of patients. In addition, a number of studies report no additional benefits from antidepressants. Specific antidepressants may be beneficial in certain circumstances. However, any patient on antidepressants who develops symptoms of hypomania should stop taking these drugs, since hypomania is often a sign of impending mania. All antidepressants should be tapered off after the mood has been stabilized for a month.

Bupropion. The antidepressant bupropion (Wellbutrin) appears to pose a lower risk for triggering mania than do other antidepressants. Side effects include restlessness, agitation, sleeplessness, headache, rashes, stomach problems, and in rare cases, hallucinations and bizarre thinking. Initial weight loss occurs in about 25% of patients. High doses may cause seizures. This side effect is uncommon and tends to occur in patients with eating disorders (anorexia or bulimia) or those with risk factors for seizures.

Selective Serotonin Reuptake Inhibitors. Serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), and paroxetine (Paxil), are sometimes used to treat bipolar depression, but their benefits have not yet been established. They may be useful in patients whose depression does not respond to lithium. They do not appear to be useful as an add-on treatment to lithium. Another antidepressant, venlafaxine (Effexor), may also be used in patients with severe cases of depression who do not respond to other treatments.

Side effects of SSRIs include:

Nausea and gastrointestinal problems, which usually wear off over time
Agitation, insomnia, mild tremor, and impulsivity
Dry mouth, which can increase the risk for cavities and mouth sores
Headache
Sexual dysfunction

Some weight loss may occur during the first few weeks of treatment, but over time patients on maintenance treatment typically return to their pretreatment weight.

Monoamine Oxidase Inhibitors (MAOIs). Older drugs known as monoamine oxidase inhibitors (MAOIs), particularly tranylcypromine (Parnate) are recommended for depression that does not respond to newer antidepressants. MAOIs can interact with certain foods and cause severe high blood pressure. Such foods have high tyramine content and include aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products. MAOIs can also have severe interactions with certain drugs, including some common over-the-counter cough medications. In such cases, severe high blood pressure or dangerous reactions can occur. It is important that patients discuss with their doctor any other medications they are taking.

Other Treatments

Electroconvulsive therapy (ECT) is a non-drug treatment for bipolar disease and other mental disorders, such as severe depression. It is commonly called shock therapy. ECT has received bad press since it was introduced in the 1930s. But, over the years it has been refined, and is now considered a very safe treatment.

Research suggests ECT may be particularly beneficial for:

Patients who need immediate stabilization of their condition and who cannot wait for medications to work
Most patients with mania -- especially elderly patients with severe mania
Patients who suffer suicidal thoughts and guilt during the depressive phase
Pregnant patients
Patients who cannot tolerate drug treatments
Patients with certain types of heart problems
Young patients

In a review of studies, about 80% of ECT-treated patients experienced improvement, and for some, it is the only treatment that works.

The Procedure. ECT is performed on an outpatient basis and does not require hospitalization. In general, the ECT procedure is performed as follows:

A muscle relaxant and short-acting anesthetic are given to the patient.
A small amount of electricity is sent to the brain, causing a generalized seizure that lasts for about 40 seconds.
The response to ECT is usually very fast, and the patient often needs less medication afterward.

Side Effects. Side effects of ECT may include temporary confusion, memory lapses, headache, nausea, muscle soreness, and heart disturbances. Taking the drug naloxone immediately before ECT may help reduce its effects on concentration and some (but not all) forms of memory impairment. Concerns about permanent memory loss appear to be unfounded.

Biologic Effects of ECT on Bipolar Disorder. The precise way that ECT benefits patients with bipolar disorder is not clear. ECT may help by:

Causing changes in the brain's physiology. For example, ECT may increase the permeability of the blood-brain barrier, produce an antiseizure effect (similar to the effects of antiseizure drugs used as mood stabilizers), and reduce blood flow in parts of the brain associated with improved mood.
Causing various hormonal changes, particularly with thyroid-related hormones.
Balancing dopamine levels. This brain chemical plays an important role in bipolar disorder as well as other conditions for which ECT is sometimes recommended, including delusional depression.
Stimulating growth of neurons in the hippocampus (the area in the brain responsible for memory).

Some studies are finding that maintenance electroconvulsive therapy (ECT) may be helpful for patients who do not respond to medications. In one study of patients with bipolar disorder, those who had intractable recurrent episodes received monthly ECT treatments for more than a year and a half. Without ECT, those patients spent an average of almost half a year in the hospital, suffering at least three episodes annually. After ECT, all the rapid cyclers achieved full or partial remission.

Transcranial Magnetic Stimulation. Repeated transcranial magnetic stimulation (rTMS) is also being studied for unipolar and bipolar depression. Unlike ECT, this procedure does not appear to cause seizures, memory lapses, or impaired thinking. The only common side effect is a mild headache.

Therapy and Lifestyle Changes

Psychotherapy is an important addition to medication. Many approaches are proving to be very useful. Trained mental health professionals can:

Educate patients about bipolar disorder and its treatments
Teach patients to recognize and manage early warning symptoms of imminent manic or depressive episodes
Help them comply with drug regimens
Monitor the patient's on-going status
Intervene early in manic and depressive episodes to reduce the severity of the attack

In addition, psychotherapy can help patients:

Adjust to the reality of the illness and understand the negative consequences of mania -- particularly important for patients who consider their mania to be positive, creative, and exhilarating
Cope with feelings of guilt and remorse that occur after manic episodes
Deal with feelings of imperfection and despair

Therapists trained in cognitive-behavioral therapy (CBT) may be particularly helpful for many patients. CBT is a structured, conscious method that aims to help a patient recognize negative thoughts and behavioral patterns and to change them. CBT is known to be helpful for other mood disorders, including depression and anxiety, and some studies suggest that it benefits bipolar disorder patients as well. For example, in one recent study, patients who were given mood stabilizers and underwent a CBT program that was specifically designed to prevent relapse experienced fewer and shorter episodes and improved social functioning compared to those on mood stabilizers alone.

Using Cognitive-Behavioral Therapy for Bipolar Disorder. Typical goals of CBT for bipolar disorder patients include learning how to:

Recognize manic episodes before they become full-blown and change behaviors during an episode
Cope with depression by developing behaviors and thoughts that may help offset the negative mood

It is very important that partners, family members, or both be involved in therapy. CBT can help them learn how to accept the condition, the need for medications, and how to protect themselves and the patient financially during manic episodes. In fact, one study indicated that when a spouse of a patient learned ways of coping with the illness, the partner's chances of sticking to a prescribed treatment improved.

Supporting the Patient. Recommendations for supporting the patient include:

Create a treatment contract as a first step. In this contract, the patient and family agree to specific steps for maintaining emotional stability. If such measures fail, all parties agree on further actions to be taken during an acute episode, including requests for hospitalization.
Be supportive. Unlike relatives of patients with alcoholism who may be encouraged to get tough, relatives of patients with bipolar disorder must be strongly supportive because of the high risk for suicide with this disorder. Simply listening attentively and being empathic can help.
Get the patient to comply with treatment, even if it means threatening a hospitalization if the patient fails to comply.
Have ready a hotline number or the telephone number of a psychiatrist authorized to commit the patient. The doctor should be willing to facilitate commitment if a patient becomes violent or the family is on the verge of collapse.
Don't feel guilty and don't make the patient feel guilty. Bipolar disorder results from an imbalance of chemicals in the brain and not from anyone's fault.

Support for the Family. Unfortunately, actions that support a bipolar disorder patient may not be intuitive, and they take their toll. Loved ones must also care for themselves or they may also follow a path to severe depression. They should to boost energy and reduce stress through:

Exercise
Meditation
Relaxation techniques
Holidays away from the patient
Involvement in hobbies
Involvement in support groups, Internet resources with chat rooms, and message boards for bipolar disorder caregivers

Interpersonal problems (such as family disputes) and disruptions in daily routines or social rhythms (such as loss of sleep or changes in meal times) may make people with bipolar disorder more susceptible to new episodes of their illness. A form of psychosocial treatment called interpersonal and social rhythm therapy (IPSRT) focuses on maintaining a regular schedule of daily activities to reduce these potential triggers and improve emotional stability. Patients also learn how to avoid problems with personal relationships. Preliminary evidence suggests that IPSRT combined with drug therapy works better than medication alone. A 2-year study of patients with bipolar 1 disorder indicated that IPSRT may help prevent new manic episodes.

Exercise. Exercise is an important part of treatment, particularly in helping manage weight gain. It also helps increase feelings of well-being.

Sleep Management. Good sleep hygiene is particularly important for patients. One study reported that techniques used to enforce healthy sleep helped reduce mood cycling.

Diet. A healthy diet low in saturated foods and rich in whole grains, fresh fruits, and vegetables is important for anyone. People with bipolar disorder should be sure to maintain a regular healthy diet. They may need to restrict calories if they are on medications that increase weight.

Some research indicates that consumption of omega-3 polyunsaturated fatty acids found in oily fish (such as mackerel, sardines, salmon, and bluefish) may help reduce the symptoms of a variety of mental illnesses, including bipolar disorder. Researchers are investigating the effects of eicosapentaneoic acid (EPA) and docosahexaenoic acid (DHA) supplements for patients who have not responded to other treatments.

Resources

www.nimh.nih.gov -- National Institute of Mental Health
www.bpkids.org -- Child & Adolescent Bipolar Foundation
www.dbsalliance.org -- Depression and Bipolar Support Alliance
www.nami.org -- National Alliance on Mental Illness
www.nmha.org -- Mental Health America
www.aabt.org -- Association for Behavioral and Cognitive Therapies
www.psych.org -- The American Psychiatric Association
www.aacap.org -- American Academy of Child and Adolescent Psychiatry

References

Gentile S. Extrapyramidal adverse events associated with atypical antipsychotic treatment of bipolar disorder. J Clin Psychopharmacol. 2007 Feb;27(1):35-45.

Jarema M. Atypical antipsychotics in the treatment of mood disorders. Curr Opin Psychiatry. 2007 Jan;20(1):23-9.

Mathews M, Muzina DJ. Atypical antipsychotics: new drugs, new challenges. Cleve Clin J Med. 2007 Aug;74(:597-606.

McClellan J, Kowatch R, Findling RL; Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2007 Jan;46(1):107-25.

Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry. 2007 May;64(5):543-52.

Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry. 2007 Apr;64(4):419-26.

Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007 Sep;64(9):1032-9.

Morriss RK, Faizal MA, Jones AP, Williamson PR, Bolton C, McCarthy JP. Interventions for helping people recognise early signs of recurrence in bipolar disorder. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004854.

Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007;68 Suppl 1:20-7.

Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007 Apr 26;356(17):1711-22. Epub 2007 Mar 28.

Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry. 2007 Apr;64(4):442-55.

Smith LA, Cornelius V, Warnock A, Bell A, Young AH. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord. 2007 Jun;9(4):394-412.

A.D.A.M. Copyright

adam.com

Acute lymphocytic leukemia

FitSugar — Wed, 08 Oct 2008 17:35:07 -0700

In This Report

Highlights
Introduction
Symptoms
Causes
Risk Factors
Diagnosis
Outlook
Treatment
Home Management
Treatment to Achieve Remiss...
Treatment During Remission...
Treatment After Relapse
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Acute Lymphocytic Leukemia (ALL)

There are four major types of leukemia. ALL is the most common type of leukemia diagnosed in children, and the least common type diagnosed in adults. About 5,200 people are diagnosed with ALL each year. Children account for two-thirds of these cases. In general, children with ALL have a better prognosis than adults. Most children with ALL can be cured of this cancer.

Symptoms and Diagnosis

Symptoms of ALL include fatigue, pale skin, recurrent infections, bone pain, bruising, and small red spots under the skin. Doctors use various tests, including blood counts and bone marrow biopsies, to diagnose ALL.

Treatment

ALL is treated with chemotherapy and, sometimes, radiation. Children receive different types of chemotherapy regimens than adults. Patients with advanced cancer that has not responded to these treatments may need a stem cell transplant.

Infection Prevention

Both chemotherapy and transplantation increase the risk for infection. Patients must take serious precautions to avoid exposure to germs. Ways to prevent infection include:

Practice good hygiene including regular handwashing and dental care (brushing, flossing)
Avoid crowds, especially during cold and flu season
Eat only well-cooked foods (no raw fruits or vegetables)
Boil tap water before drinking it
Do not keep fresh flowers or plants in your house as they may carry mold

Introduction

The word leukemia literally means "white blood" and is used to describe a variety of cancers that begin in the blood-forming cells of the bone marrow.

White blood cells (leukocytes) evolve from immature cells referred to as blasts. Malignancy in these blasts is the source of leukemias, which generally progresses as follows:

Normally, blasts constitute 5% or less of healthy bone marrow. In leukemia, however, these blasts remain abnormally immature and multiply continuously, eventually constituting between 30 - 100% of the bone marrow.
Eventually these malignant blast cells fill up the bone marrow and prevent production of healthy red cells, platelets, and mature white cells (leukocytes).

They spill out of the marrow into the bloodstream and lymph system and can travel to the brain and spinal cord (the central nervous system). As the number of normal cells decline, dangerous symptoms develop, which, if untreated, become lethal.

Leukemias are divided into two major types:

Acute (which progresses quickly with many immature white cells)
Chronic (which progresses more slowly and has more mature white cells)

Some blasts are called lymphoblasts (which become mature cells called lymphocytes) and others are called myeloblasts (which mature to myeloid cells). Acute leukemias are in turn subdivided into two classifications according to whether the malignant blasts are lymphocytes or myeloid:

Acute lymphocytic leukemia (ALL), which is the subject of this report
Acute myeloid leukemia (AML), which is not covered in this report

Acute lymphocytic leukemia (ALL) is also known as acute lymphoid leukemia or acute lymphoblastic leukemia. The majority of childhood leukemias are of the ALL type. Malignancies in this disease can arise either in T-cell or B-cell lymphocytes.

T cell ALL is diagnosed in 15% of children and adults with ALL.
About 85% of ALL cases are of the B-cell lymphocyte lineage (often referred to as "early" or "pre" B-cell lineage).

Blood Cell Lines

In adults, blood cells are produced by the bone marrow, the spongy material filling the body's bones. The bone marrow produces two blood cell groups, myeloid and lymphoid.

Myeloid Cell Line. The myeloid cell line includes the following:

Immature cells called erythrocytes that later develop into red blood cells
Blood clotting cells (platelets)
Some white blood cells, including macrophages (which act as scavengers for foreign particles), eosinophils (which trigger allergies and also defend against parasites), and neutrophils (the main defenders against bacterial infections)

Lymphoid Cell Line. The lymphoid cell line includes the lymphocytes, which are the body's primary infection fighters. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign substances (antigens).

Lymphocytes develop in the thymus gland or bone marrow and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).

Lymphocytes and the Lymph System

Understanding how acute lymphocytic leukemia (ALL) arises requires knowledge of lymphocytic development and function:

B cells develop and mature in their final form (known as differentiation) in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone. This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Once they leave the capillaries, some lymphocytes migrate into the surrounding tissues. Some of these lymphocytes (along with fluid, proteins, and other substances) then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches. They drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, which are oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or are added to the contents of the node.

Symptoms

The symptoms of ALL may be difficult to recognize. ALL usually begins abruptly and intensely, but in some cases symptoms may develop slowly. They may be present one day, and absent the next, particularly in children. Symptoms develop when:

There are not enough healthy mature white blood cells (leukocytes) to mount a defense against infection.
There are not enough healthy platelets to prevent bleeding.
The depleted oxygen-bearing red blood cells can't provide enough oxygen to organs.

Symptoms include:

Fatigue
Paleness -- patients may have poor coloring from anemia caused by insufficient red blood cells
Recurrent minor infections
Fevers
Bone pain
Bruising -- may result from only slight injury
Poor healing of minor cuts
Uncontrolled bleeding -- bleeding events increase as the bone marrow fails to produce enough platelets to make a normal blood clot, a condition called thrombocytopenia.
Small, red spots on the skin (petechiae)
Vision changes (rare)

Causes

Between 1973 - 1990, the number of acute lymphocytic leukemia cases in children under age 15 rose by 27%. The causes of the disease are not known, but experts believe that ALL develops from a combination of genetic, biologic, and environmental factors.

Advances in genetic technologies have allowed identification of a number of mutations associated with ALL. Missing or defective genes that suppress tumors are responsible for some of these cases. Identifying specific genetic allows doctors to determine how aggressive a specific case is and eventually could provide targets for developing highly specific treatments.

Translocations. Up to 65% of leukemias contain genetic rearrangements, called translocations, in which some of the genetic material (genes) on a chromosome may be altered, or shuffled, between a pair of chromosomes.

The most common genetic injury in ALL is t(12;21), which means a translocation with a genetic shift occurred between chromosome 12 and 21. This translocation is also referred to as TEL-AML1 fusion. It occurs in about 20% of patients with ALL. Researchers believe that this translocation may occur during fetal development in some patients.
About 20% of adults and about 5% of children with ALL have a genetic abnormality called the Philadelphia (Ph) chromosome [t(9;22)].
Another important chromosome translocation is t(4;11) involving the MLL gene, also called HRX or ALL-1.

Ikaros. A defective gene known as Ikaros, which regulates lymphocyte development, may play a major role in childhood ALL.

MTHFR. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. Children with certain variations in the gene for MTHRF have a reduced risk of developing ALL. Variations in the MTHRF gene may also influence response to antifolate chemotherapy.

Risk Factors

ALL in Children. ALL is the most common type of cancer diagnosed in children. ALL accounts for about 75% of cases of childhood leukemia. Each year, about 2,400 American children and adolescents are diagnosed with ALL. ALL can strike children of all ages, but is most likely to occur when children are 2 - 3 years of age.

ALL in Adults. ALL is the least common type of leukemia among adults. About 1 in 3 cases of ALL occur in adults.

Caucasian and Hispanic children have a much higher risk for ALL than African-American children.

Certain inherited disorders can increase the risk for leukemia. For example, children with Down syndrome have a 20-times greater risk of developing ALL than the general population. Other rare genetic disorders associated with increased risk include Bloom syndrome, Fanconi's anemia, ataxia-telangiectasia, neurofibromatosis, Shwachman syndrome, IgA deficiency, and congenital X-linked agammaglobulinemia.

Previous cancer treatment with high doses of radiation or chemotherapy can increase the risk for developing ALL. Prenatal exposure to x-rays also appears to increase risk in children. Lower levels of radiation (living near power lines, video screen emissions, small appliances, cell phones) are unlikely to pose any cancer risk.

Diagnosis

Laboratory tests provide the basis for diagnosing ALL.

Flow cytometry uses light to count blood cells in a stream of fluid. It is an important tool used to diagnose leukemia, determine its progress, and tell if any disease remains after treatment. It can also determine the components and structural features of individual cells. Flow cytometry can process thousands of cells in seconds.

A complete blood cell count (CBC) is the first step in diagnosing ALL. However, blood tests do not always detect leukemia. About 10% of patients with ALL have a normal blood cell count. A CBC may show various findings, including:

Presence of circulatory leukemic blast cells (may miss the cells on occasion)
Presence and severity of anemia
Count of a variety of blood cell types (a high white blood cell count indicates a more severe disease)

Click the icon to see an illustrated series detailing a complete blood cell count test.

If blood test results are abnormal or the doctor suspects leukemia despite normal cell counts, a bone marrow aspiration and biopsy are the next steps. These are very common and safe procedures. However, because this test can produce considerable anxiety, particularly in children, parents may want to ask the doctor if sedation is appropriate for their child.

A local anesthetic is given.
A needle is inserted into the bone, usually the rear hipbone. There may be brief pressure or pain. A small amount of marrow is withdrawn. Marrow looks like blood.
A larger needle is then inserted into the same place and pushed down to the bone. The health professional will wiggle the needle from side to side to loosen a larger specimen for the biopsy. The patient will feel some pressure.
The sample is then taken to the lab to be analyzed. All the results are completed within a couple of days.

Click the icon to see an image of bone marrow removal.

Normal bone marrow contains 5% or less of blast cells (the immature cells that ordinarily develop into healthy blood cells). In leukemia, abnormal blasts constitute between 30 - 100% of the marrow.

If bone marrow examination confirms ALL, a spinal tap may be performed, which uses a needle inserted into the spinal canal. The patient feels some pressure and usually must lie flat for about an hour afterward to prevent severe headache. This can be difficult, particularly for children, so parents should plan reading or other quiet activities that will divert the child during that time. Parents should also be certain that the professional administering this test is highly experienced.

Click the icon to see an image of a spinal tap.

A sample of cerebrospinal fluid with leukemia cells is a sign that the disease has spread to the central nervous system. In most cases of childhood ALL, leukemia cells are not found in the cerebrospinal fluid.

Once a diagnosis of leukemia has been made, further tests are performed to check:

Whether the cells are myeloid or lymphocytic
Stage of maturity of the ALL B cell
Specific markers, or immunologic features, on the surface of the cancer cell
The genetic makeup of the cells ( cytogenetics)
The physical characteristics of the cells ( morphology)

First, the doctors must determine the cell of origin. In other words, they want to determine if the cell is myeloid or lymphocytic. One method is to measure an enzyme called terminal deoxynucleotidyl transferase (TdT).

About 95% of all ALL types (except the subtype B cell) have elevated TdT.
Only about 20% of cases of acute myeloid leukemia (AML) express TdT, however, so its use in determining the cell line is limited.

The stage of maturity of the leukemic B cell helps determine prognosis. There are three stages:

Early precursor-B. About 80% of patients with ALL have the early precursor-B subtype, which is the least mature. It also offers the best prognosis.
Precursor-B. This is the intermediate stage.
B cell. This is the mature cell and ALL in this stage is identical to Burkitt's non-Hodgkin's lymphoma. It is therefore treated differently from other ALL cases.

A series of tests are used to determine the immunologic pattern of the leukemia cell (how it can be expected to interact with the immune system).

On the surface of malignant ALL cells are markers for certain antigens (molecules that set off a targeted attack by the immune system using antibodies). Such antigens are proving to be very helpful in predicting outcome.

An antigen is a substance that can provoke an immune response. Typically, antigens are substances not usually found in the body.

Important antigens associated with ALL include:

CD10, more frequently referred to as cALLa (common ALL antigen). This antigen occurs in about half of all ALL cases and in about 80% of ALL B-precursor patients. It is associated with a good prognosis.
CD95 (associated with a good prognosis)
CR19
DR

The surfaces of T-cell ALL cancer cells express several antigens as well. For example, the presence of one of these, CD2, suggests a favorable prognosis.

Genetic tests are useful for a number of important criteria:

Diagnosing a specific ALL subtype
Designing appropriate treatment
Deciding prognosis
Monitoring patients throughout treatment and beyond

Cytogenetics is a technique that researchers use to determine specific genetic abnormalities, which are found in nearly 65% of all leukemias. Detecting these genetic defects is helpful in making a full diagnosis of ALL and in planning the most appropriate therapy. Specific technologies called microarray chips are capable of checking up to 48,000 different genes in a single test, which holds promise for assessing prognosis and developing very targeted therapies in the future. Research on DNA microarray analysis continues to reveal different prognostic subgroups of ALL. As the precision, logistics, and cost effectiveness of DNA microarray assays improve, they may be used more commonly in the clinical setting.

MTHFR Variants. Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism. Variations in the MTHRF gene may also influence response to antifolate chemotherapy. A 2004 study showed that patients with one of two specific variations of the MTHFR gene had a lower probability of survival following treatment with methotrexate.

Translocations. Genetic translocations (swapping of genes on chromosomes) may affect outlook. Examples include:

Patients with the t(12;21) genetic translocation (also referred to as TEL-AML1 fusion) have an excellent prognosis.
Patients who carry the defective gene called ETV6 often respond well to chemotherapy.
The t(4;11), sometimes referred to as MLL, is the most common translocation in children under age 1 year. Unfortunately, anyone with t(4;11) has a poor outlook. One study suggested that this genetic variant may actually be a unique leukemia and require treatments that differ from standard ALL.
The Philadelphia translocation t(9;22) also indicates a poor outlook. It represents about 20% of adult cases and about only 5% of childhood cases.
The t(1;19) location occurs in about 5% of ALL childhood cases and requires aggressive treatment.

Ploidy. Ploidy refers to the number of chromosomes. Additional copies (hyperdiploidy) or absence of copies (hypodiploidy) of chromosomes affect prognosis. For example, in children hyperdiploidy is associated with a more favorable outcome and hypodiploidy with a poorer outcome. (Hypodiploidy occurs in only 1% of children with ALL.)

The morphology of a cell includes its physical characteristics, such as shape and structure. To determine the morphology of the leukemia cells, samples of the bone marrow are taken and particular contents of the cells are stained with a dye. They are then examined under a microscope.

Acute lymphocytic leukemia cells are grouped, according to the French-American-British (FAB) classification system, into three ALL morphologic types. (It should be noted that this system is subjective and is now used to complement other diagnostic tests mentioned above):

L1 cells. These are small blasts with scant amounts of cytoplasm (the substance in a cell between its membrane and nucleus). L1 cells usually contain a round nucleus and there is little variation among them. L1 represents the most common ALL morphology and offers the best prognosis. It occurs in about 85% of children and 30% of adults with ALL.
L2 cells. These cells are larger than L1 and have more abundant cytoplasm. They vary significantly among each other and have an irregularly shaped nucleus. L2 morphology conveys a poorer prognosis than L1, although the two cells' types are treated similarly. Subtype L2 is the most common morphologic type in ALL adults; 64% of adults with ALL have this subtype compared with only 15% of children.
L3 cells. These are uncommon. They resemble another malignancy called Burkitt's lymphoma, and their treatments are now the same.

Assays that test for cancerous cells are improving, allowing doctors to detect smaller and smaller amounts of hidden disease. For example, flow cytometry assays can detect 0.01% leukemic cells, and PCR assays can detect 0.001% leukemic cells. A new concept called minimal residual disease (MRD) is becoming an important prognostic factor in ALL. A more precise measure of disease response, MRD may soon replace existing measures such as "complete response" and "partial response" when assessing the effectiveness of ALL treatment. Ongoing studies of MRD in ALL may help identify patients in remission who are at risk of relapse. In addition, early therapeutic intervention based on the presence of MRD may improve outcome and prolong survival.

Using the results of the tests described above, patients are classified into low-, average-, and high-risk groups. This information allows the doctor to diagnosis the type of leukemia and plan the best treatment. Each classification requires unique therapies.

Doctors attempt to make a prognosis and determine an optimal treatment plan by assessing all the cell characteristics plus the white blood cell count. As examples:

Patients who have an L1 or L2 morphology, a white blood cell count of less than 15,000 mm3, a t(12;21) genetic translocation, and a cALLa-positive antigen marker have an excellent outlook.
On the other hand, patients who have an L2 morphology, a white blood cell count greater than 30,000 mm3, and who lack the cALLa marker have a poorer prognosis and require more aggressive treatment

Outlook

Acute lymphocytic leukemia is responsible for about 1,400 deaths a year in the U.S., and it can progress quickly if untreated. However, ALL is one of the most curable cancers and survival rates are now at an all-time high. People who have Philadelphia chromosome-positive ALL tend to have a poorer prognosis, although new treatments are helping many of these patients achieve remission.

Outlook in Children with ALL. More than 95% of children with ALL attain remission.

Certain children are at higher risk for a poor outcome than others:

Infants and children age 10 years and older tend to have a poorer outcome than young children (ages 1 - 9 years).
Some studies indicate a better prognosis for girls than boys. This may be partly due to boys’ risks for testicular cancer.
Survival rates for African-American and Hispanic children are lower than Caucasian and Asian children, but this may be due to poorer access to treatment.

Responding well to early treatment is a good sign regardless of the risk category. Other positive predictors include:

Less than 5% of cells being blasts after 7 - 14 days of treatment
Less than 1,000 blasts per microliter on peripheral smear after 7 days

Outlook in Adults with ALL. Adults tend to have a more severe condition than children, even if they are carrying the same ALL genes. Still, 60 - 80% of adults with ALL can expect to achieve full remission with standard treatments, and 35 - 40% survive beyond 2 years with aggressive treatments. Younger adults with ALL have better long-term survival rates than older adults with the disease.

Treatment

The aim of initial treatment is to get rid of the leukemia cells in the body (achieve complete remission) and have 5% of lower levels of blasts in the bone marrow.

There are typically four treatment stages for the average-risk patient with ALL:

Induction therapy in order to achieve a first remission
Central nervous system prophylaxis (preventive treatment), usually given along with induction therapy
Consolidation, intensive therapy to prevent relapse after remission has been achieved
Maintenance treatment, lower intensity therapy given for several years to prevent relapse after remission

The following are specific treatments used for ALL:

Chemotherapy is the primary treatment for each stage.
Radiation to the brain and spinal cord is also administered in some cases.
A bone marrow transplant is often recommended for relapsed ALL or in cases that cannot be induced into remission (refractory disease). It is also sometimes considered after remission is achieved for certain high-risk ALL types. The timing of bone marrow transplantation can be controversial, particularly after a first remission, although it has produced excellent long-term survival rates in appropriate patients.
New drugs known as biological therapies are also being used.

Drugs Used to Prevent Infections During Treatment. Half of all patients with ALL develop fever in the early stages, especially if patients also have low levels of the white blood cells called neutrophils (a condition called neutropenia).

Blood is made of red blood cells, platelets, and various white blood cells.

Neutropenia, common in ALL, is a significant risk factor for serious infection. Doctors are increasingly concerned about fungal infections, which are becoming more common in these patients, particularly after transplant procedures.

Antibiotics and Antifungal Medications. The use and timing of antibiotics and antifungal medications depend on the particular organisms and severity of the infection. In some cases of neutropenia, patients may need preventive antibiotics.
Granulocyte Colony-Stimulating Factor. Granulocyte colony-stimulating factor (lenograstim, filgrastim) is often given to patients who receive chemotherapy in order to stimulate the growth of infection-fighting white blood cells. This helps prevent neutropenia.

Intravenous Fluids. Patients may also need to receive intravenous fluids and be treated for fluid imbalances, which can cause abnormal levels of sodium, potassium, calcium, and uric acid. Such treatments might include sodium bicarbonate, allopurinol, and aluminum hydroxide or calcium carbonate.

Transfusions. Red blood cell or platelet transfusions may be needed. (Patients who may need allogeneic transplantations should not receive transfusions from potential donors.)

Home Management

A parent should call the doctor if the child has any symptoms that are out of the ordinary, including (but not limited) to:

Any fever of 101°F or higher
Any signs of a flu or cold
Shortness of breath
Severe diarrhea
Blood in the urine or stools
Trouble urinating

Tracking Neutrophils. Parents should track their child's absolute neutrophil count. This measurement for the amount of white blood cells is an important gauge of a child's ability to fight infection.

Counts over 1,000 usually provide sufficient protection so that children can engage in normal activities, including school and other functions where they are exposed to other children.
If the count is between 500 - 1,000, the child should avoid large groups.
If it falls between 200 - 500, the child should stay at home and should see only healthy visitors who have washed their hands vigorously.
Neutrophil counts below 200 indicate that the child is at high risk for infection and should have no visitors.

Maintaining Strict Hygiene. Children with ALL and anyone exposed to them, not only friends and family members but also doctors and nurses, should maintain strict hygiene:

Frequent hand washing with antibacterial soap is particularly essential.
Everyone should wash their hands before and after meals, after being outside, before preparing food, and after going to the bathroom.
When visiting the doctor, a parent should ask about a side entrance or areas where the patient will not be exposed to other sick children.

Vaccinations. Studies now suggest that young survivors of leukemia have an increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated. Children may need reimmunization. Siblings of patients with ALL who require polio vaccinations should be given the killed virus (IPV), not the live polio vaccination (OPV).

Use a soft toothbrush when counts are low to prevent gum bleeding.
Avoid common pain relievers known as nonsteroidal anti-inflammatory drugs (NSAIDs). They increase the risk for bleeding and include aspirin, ibuprofen (Motrin IB, Advil, Nuprin, Rufen), naproxen (Aleve), and ketoprofen (Actron, Orudis KT).

Some of the drugs used for leukemia cause extreme sun sensitivity. Children should wear sunblock and be covered with sun-protective clothing when going outside to avoid sunburn, which can cause skin infection.

Treatment to Achieve Remission

The aim of induction therapy, the first treatment phase, is to reduce the number of leukemia cells to undetectable levels. The general guidelines for induction therapy are as follows:

Patients are given intensive chemotherapy that uses powerful multi-drug regimens. (Infants require special regimens not discussed here.)
For both children and adults, some of these therapies are administered orally, others intravenously.
Hospitalization is usually necessary at some point to help prevent infection and to administer blood products. However, much of this therapy can be given on an outpatient basis.
After the first cycle of induction, bone marrow tests are done to determine if the patient is in remission.
Another bone marrow test is sometimes done about a week later to confirm the first results.
A bone marrow transplant is considered for patients who do not respond at all to induction treatment.

Both children and adults typically start with a 3-drug regimen. Imatinib (Gleevec) or dasatanib (Sprycel) may be added for patients with Philadelphia chromosome-positive ALL.

For children, the standard drugs are:

Vincristine (Oncovin), a vinca alkaloid drug
Prednisone or dexamethasone. These drugs are corticosteroids. Dexamethasone may be more effective than prednisone, but it increases the risk for infections and other serious side effects.
Asparaginase. Generally provided as pegaspargase (Oncaspar) in place of L-asparaginase (Elspar) for treating newly diagnosed ALL in children. With pegaspargase, patients need only 3 injections over a 20-week period instead of the 21 injections required for L-asparaginase.

For adults, the standard drugs are:

Vincristine
Prednisone
Anthracycline drug, such as such as doxorubicin, daunorubicin, or epirubicin. Some adult chemotherapy regimens also add on an asparaginase drug or cyclophosphamide (Cytoxan).

The induction chemotherapy described above does not penetrate the blood-brain barrier sufficiently to destroy leukemic cells in the brain. CNS prophylaxis is critical for preventing disease that has spread to the brain, spine, and testes (called sanctuary disease sites). Although only 3% of children with ALL have evidence of leukemia in the central nervous system (CNS) at the time of diagnosis, leukemia will spread to this region in 50 - 70% of children who don't receive preventive (prophylactic) treatment. The brain is one of the first sites for relapsing leukemia.

For children, CNS prophylaxis uses intrathecal chemotherapy, in which a drug is injected directly into the spinal fluid. Intrathecal chemotherapy is given with methotrexate alone or a combination of methotrexate, cytarabine, and hydrocortisone.

Some high-risk children also receive radiation to the skull (cranial irradiation), radiation to the spine, or both at the same time. This combination can be very toxic and can cause later learning problems. It is generally used only in children who have evidence of the disease in the central nervous system at the time of diagnosis. Later complications can include learning and neurologic problems. Using lower-dose units of radiation, however, may significantly reduce the risk for mental impairment. Cranial radiation is also associated with increased risks for stroke and secondary cancers.

Adult CNS prophylaxis is performed in one of three ways:

Cranial radiation plus intrathecal chemotherapy with methotrexate
High-dose systemic infusion of methotrexate plus intrathecal methotrexate without cranial radiation
Intrathecal methotrexate chemotherapy alone

Survival in acute leukemia depends on complete remission. Although not always clear-cut, remission is indicated by the following:

All signs and symptoms of leukemia disappear.
There are no abnormal cells in the blood, bone marrow, and cerebrospinal fluid.
The percentage of blast cells in the bone marrow is less than 5%.
Blood platelet count returns to normal.

Induction can produce extremely rapid results, and the faster the time to remission the better the outlook:

A complete remission usually occurs within the first 4 weeks. Patients who show low disease levels within 7 - 14 days have an excellent outlook, particularly if they have favorable genetic factors, and may need less-intensive treatments afterward.
Patients with high disease levels at 14 days or who require more than 4 weeks to achieve remission are at higher risk for relapse and most likely need more aggressive treatment.

Side effects and complications of any chemotherapeutic regimen and radiation therapy are common, are more severe with higher doses, and increase over the course of treatment. Administering drugs for shorter duration can sometimes reduce toxicities without affecting the drugs' cancer-killing effects.

Common Side Effects. Typical side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs, and most patients who take more powerful drugs. In one study, nearly all patients who took a combination of dexamethasone (a steroid) in combination with ondansetron within 24 hours of chemotherapy experienced either a significant or complete reduction in nausea and vomiting.
Diarrhea
Hair loss
Weight loss
Depression

Serious Side Effects. Serious side effects can also occur and may vary depending on the specific drugs used.

Infection from suppression of the immune system or from severe drops in white blood cells is a common and serious side effect. Patients should make all efforts to prevent infection. The patient at high risk for infection may need very potent antibiotics and antifungal medications as well as granulocyte colony-stimulating factors or G-CSF (lenograstim, filgrastim) to stimulate the growth of infection-fighting white blood cells. Patients should make all efforts to minimize exposure to bacteria and viruses. (See “Infection Prevention” in the Transplant section of this report.)

Other serious side effects include:

Liver and kidney damage
Immediate and short-term risks of radiation therapy may include seizures, stroke, and paralysis
Very high levels of uric acid in the blood, which can damage the kidneys
Very high levels of calcium in the blood
Abnormal blood clotting
Allergic reaction
Low blood sugar (hypoglycemia) -- a rare complication in young, thin children who are taking purine analogues such as mercaptopurine and thioguanine
Suppression of adrenal glands in children who take short-term, high-dose corticosteroids such as prednisolone

Long-Term Complications.

Fatigue is very common after chemotherapy and can be significant and long-lasting.
Combinations of intrathecal chemotherapy plus brain radiation in children can cause some serious complications, including seizures and problems in learning and concentration. Methotrexate is particularly toxic. (The effects of intrathecal chemotherapy alone on mental functioning, however, did not seem significant.) Seizures can often be treated successfully with anti-epilepsy medications.
Delayed puberty. The effects of treatment in the brain can affect regions that regulate reproductive hormones, which may affect fertility later on. Chemotherapy, cranial radiation, or both can impair fertility in male and female patients. Cranial radiation can also result in impaired growth.
Bone loss can occur after chemotherapy, particularly with corticosteroids and after bone marrow transplantation. Drugs are available, particularly bisphosphonates, which may help reduce this risk.
Pancreatic beta-cell damage. A 2004 study reported that children who have been off treatment for at least 1 year have a higher risk of impaired insulin response. This suggests that chemotherapy-induced beta cell damage persists after therapy has been stopped.
Heart damage. Some of the treatments increase risk factors for future heart disease, including unhealthy cholesterol levels and high blood pressure. Anthracyclines (doxorubicin, daunorubicin, epirubicin) have been associated with later development of heart failure. Lower doses used for many ALL children may not pose a high risk to the heart. Some anthracyclines (DaunoXome, Myocet, Doxil) now come in tiny protective capsules that may reduce toxic effects. Patients with ALL should be sure to maintain a healthy lifestyle and be regularly monitored for heart risks to help reduce these effects.
Stroke. Survivors of childhood leukemia are at increased risk of later stroke, especially if they received treatment with cranial radiation.
Obesity. Children treated for ALL are at higher risk for obesity, possibly because the treatments trigger an earlier than normal occurrence in childhood weight gain. Corticosteroid drugs used in treatments also increase appetite, which contributes to the problem.
Central nervous system. Radiation and intrathecal MTX therapy may be associated with an increased risk of mood disturbances (such as depression) among adult survivors of childhood ALL. Patients with depression may benefit from psychosocial support. Cranial radiation and drugs used in chemotherapy, especially specific corticosteroids and spinal injection treatments, may also impair mental functioning and cause neurologic problems, such as movement problems.
Infections. Some children may be more vulnerable to infections after completing chemotherapy, although the immune system tends to improve over time. Patients who have had a bone marrow transplantation or lung damage from the treatments may be particularly vulnerable. Studies suggest that young survivors of leukemia have an increased risk for measles, mumps, and rubella (MMR), even if they have been previously vaccinated. Children, then, may need reimmunization.
Secondary Cancers. Studies indicate that survivors of childhood ALL are at increased risk of later developing other types of cancers, including brain and spinal cord tumors, basal cell skin carcinoma, and myeloid (bone marrow) malignancies. Radiation and older types of chemotherapy are mainly responsible for this risk. Newer types of ALL treatment may be less likely to cause secondary cancers.

Treatment During Remission

Consolidation and maintenance therapies follow induction and first remission. The goal of consolidation and maintenance therapies is to prevent a relapse. The specific treatment choices and degree of aggressiveness after induction therapy depend on a number of factors, particularly the risk factors for relapse.

Consolidation therapy is additional treatment that is administered after induction therapy and before maintenance therapy. This is an intense regimen that is designed to prevent the high relapse rates that occur with induction therapy alone. (The benefits of this therapy are clearer in children than in older adults, who may just be given maintenance.)

Consolidation therapy usually continues for about 6 months and uses 1 - 6 courses of chemotherapy, depending on risk factors for relapse.

Examples of consolidation regimens for children at standard risk:

A limited number of courses of intermediate- or high-dose methotrexate, one of the oldest drugs used for leukemia.
An anthracycline drug, such as daunorubicin (Cerubidine), used for reinduction followed by cyclophosphamide (Cytoxan, Neosar) 3 months after remission. These are very powerful drugs, but when used in this way toxicity is limited.
Extended use of an asparaginase drug.

More intense regimens are used for children at high-risk for relapse.

Instead of chemotherapy alone as consolidation therapy, some high-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone may undergo allogeneic stem cell or autologous stem cell bone marrow transplant after the intensive chemotherapy regimens. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.

Allogeneic transplantation is an option when a well-matched donor is available. Although this treatment can be effective in keeping the leukemia away, significant complications -- such as graft versus host disease, blood clots, liver problems, and lung damage -- can occur and may be a cause of death even without a return of cancer.
Autologous stem cell bone marrow transplant (using the patient's own bone marrow cells) seems to be helpful also and may be as effective as allogeneic transplantation.

The last phase of treatment is maintenance, or continuation therapy:

Maintenance therapy typically uses weekly administration of methotrexate (usually in oral form) and daily doses of mercaptopurine. (Mercaptopurine should be given in the evening.)
Treatment continues for 2 - 3 years for most children with ALL (with the exception of those with mature B-cell leukemia). It is not yet clear if prolonged maintenance therapy benefits adults with ALL.
If children were not given CNS prophylaxis before, it may be given now.
Vincristine and a corticosteroid drug (generally dexamethasone) are often added to standard maintenance therapy, although some studies indicate that they do not provide additional benefit.

A maintenance regimen is usually less toxic and easier to tolerate than induction and consolidation. Some studies, however, indicate that overall survival could further be improved with more-aggressive maintenance therapies, including:

Vincristine and a corticosteroid added to the standard maintenance regimen
Longer term low-dose maintenance
Intense regimens similar to induction (called reinduction)

Maintenance is typically ongoing until complete remission has lasted 2 - 3 years.

Investigation is ongoing to determine the best drugs and schedules to use. For example, doctors have debated whether thioguanine is a better choice than mercaptopurine (a 2006 study recommended that mercaptopurine remain the standard thiopurine drug for treating childhood ALL). Researchers are also trying to pinpoint patients who would best benefit from aggressive maintenance treatments.

The following are factors that increase the risk for relapse after initial treatments:

Microscopic evidence of leukemia after 20 weeks of therapy (minimal disease)
Age over 30
A high white blood cell count at the time of diagnosis
Disease that has spread beyond the bone marrow to other organs
Certain genetic abnormalities, such as the presence of the Philadelphia chromosome or MLL gene translocations
Patients with high disease levels after 7 - 14 days of induction therapy
The need for 4 or more weeks of induction chemotherapy in order to achieve a first complete remission

Patients with one or more of these risk factors may be candidates for bone marrow transplantation once they are in first remission.

Treatment After Relapse

Between 50 - 70% of children and 40 - 50% of adults who achieve complete remission after initial therapy but then suffer a relapse may be able to go into a second complete remission.

Treatment for relapse after a first remission may be standard chemotherapy or experimental drugs, or more aggressive treatments such as stem cell transplants.

The decision depends on a number of factors:

Children who relapse 3 or more years after achieving a first complete remission have an excellent chance for a second remission without aggressive treatments.
Those who relapse fewer than 6 months following initial treatment, especially while on chemotherapy, have about a 20% chance of long-term freedom from disease. In such cases, remission is possible following another course of standard chemotherapy but the duration of remission is usually fewer than 6 months.

Treatment decisions also rely on prior treatments and where the relapse has occurred. Relapse can occur in the bone marrow, central nervous system, or sanctuary disease sites (brain, spine, or testicles). The incidence of relapse in sanctuary sites is about 10%.

Candidates for transplantation include:

Patients who relapse following initial remission with standard chemotherapy.
High-risk patients in first remission who are unlikely to be cured by standard chemotherapy alone. Many adult patients may fall into this category. Studies on high-risk children have been conflicting about the value of transplants during a first remission.
Patients who fail to achieve a complete remission during initial chemotherapy.

Transplantation procedures do not appear to offer any additional advantages for patients at low or standard risk.

Many different drugs are used to treat ALL relapses. These drugs include vincristine, asparaginase, anthracyclines (doxorubicin, daunorubicin), cyclophosphamide, cytarabine (ara-C), and epipodophyllotoxins (etoposide, teniposide). Corticosteroids, such as prednisone or dexamethasone, may also be used.

In 2004, the Food and Drug Administration (FDA) approved clofarabine (Clolar) for treatment of relapsed or refractory ALL in children. This drug was the first new leukemia treatment approved specifically for young patients in more than a decade. In 2005, nelarabine (Arranon) was approved to treat adults and children with relapsed or refractory T-cell acute lymphocytic leukemia (T-ALL). In 2006, the FDA approved imatinib (Gleevec) for treating patients with Philadelphia chromosome-positive ALL that has not responded to or has returned after treatment. Also in 2006, the FDA approved dasatinib (Sprycel) for patients who are not helped by imatinib.

Tyrosine kinase inhibitors. Tyrosine kinase is a growth-stimulating protein. Tyrosine kinase inhibitor drugs block the cell signals that trigger cancer growth. Several tyrosine kinase inhibitors, including imatinib (Gleevec) and dastinib (Sprycel), have recently been approved for treating Philadelphia chromosome-positive ALL. In 2006 clinical trials, Nilotinib (AMN-107) produced excellent results in patients with Philadelphia chromosome positive ALL who are resistant to imatinib.

Monoclonal antibodies (MAbs). Used alone or in combination with chemotherapy, MAbs target specific antigens on ALL blast cells. Although MAbs have been studied primarily in the treatment of B-cell non-Hodgkin's lymphoma, drugs demonstrating benefit in preliminary trials of ALL include anti-CD20 (rituximab) and anti-CD22 (epratuzumab). Alemtuzumab (MabCampath) is also showing promise in treating relapsed or refractory T-ALL. More studies are needed to determine the best MAb regimens in ALL.

In order to administer high-dose chemotherapy for advanced cancer cases, stem cell transplantation procedures may be used. These procedures are based on removal and replacement of stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected either from:

Bone marrow (bone marrow transplantation)
Blood (peripheral blood stem cell transplantation). Evidence suggests that peripheral blood stem cell transplantation may be the superior approach. Studies report survival rates of 45% in bone marrow transplant patients compared to 65 - 70% in stem cell transplant patients, with benefits being significant in those with more severe disease.
Fetal umbilical cord or placentas. This procedure uses donor cells but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, however, so at this time its use is limited to children and sometimes adults with low weight. (Some studies indicate success for adults with normal weights.)

Donor or Patient Cells. The sources of marrow or blood cells can be taken from the patient or a donor:

If the bone marrow or stem cells are taken from a donor, the transplant is referred to as allogeneic. Allogeneic transplants from genetically matched sibling donors offer the best results in ALL. With new techniques, donor bone marrow from unrelated but immunologically similar donors is proving to work as well as those from matched siblings. This approach is still reserved for patients in second remission or beyond. A 2006 study indicated that allogeneic transplant is also a good treatment option for patients with Philadelphia chromosome-positive ALL who are resistant to imatinib (Gleevec).
If the marrow or blood cells used are the patient's own, the transplant is called autologous. Autologous transplants in patients with ALL are generally not beneficial, since there is some danger that the cells used may contain tumor cells and the cancer can regrow. Treatment advances that reduce this risk, however, may make autologous transplantation feasible in patients without family donors.

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim) to stimulate stem cell growth.
The donor (or patient in an autologous procedure) then undergoes apheresis. With this process, the blood is withdrawn from one of the patient's veins and passed through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are then frozen.

The patient is given high-dose chemotherapy with or without radiation -- a treatment known as conditioning. The point is to inactivate the immune system and to kill any residual malignant cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning includes radiation with drugs.
A few days after treatment, the patient is rescued using the stored stem cells, which are administered through a vein. This may take several hours. Patients may experience fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient is kept in a protected environment to minimize infection, and the patient usually needs blood cell replacement and nutritional support.

Two- to 5-year survival rates after transplantation plus chemotherapy range from 40 - 80%. Certain patients with the Philadelphia chromosome, which carries a poor prognosis, may achieve significant success with an allogeneic bone marrow transplant from a closely matched related donor.

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

Blood stem cell transplantation itself is fairly dangerous and has a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now, mortality rates are below 5%. Potentially serious complications include:

Infection resulting from a weakened immune system is the most common side effect. Because the stem cell procedure is done more swiftly, the risk period is shorter than with bone marrow transplantation. The risk for infection is most critical during the first 6 weeks following the transplant, but it takes 6 - 12 months post-transplant for a patient’s immune system to fully recover. Immune systems of patients with graft-versus-host disease can take even longer to function normally

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about hand washing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. To reduce the risk for GVHD, doctors remove some immune T cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T cell depletion.

Acute GVHD occurs in 30 - 50% of allogeneic transplants, usually within 25 days. Its severity ranges from very mild symptoms to a life-threatening condition (more often in older patients). The first sign of acute GVHD is a rash, which typically develops on the palms of hands and soles of feet and can then spread to the rest of the body. Other symptoms may include nausea, vomiting, stomach cramps, diarrhea, loss of appetite and jaundice (yellowing of skin and eyes). To prevent acute GVHD, doctors give patients immune-suppressing drugs such as steroids, methotrexate, cyclosporine, tacrolimus, and monoclonal antibodies.

Chronic GVHD can develop 70 - 400 days after the allogeneic transplant. Initial symptoms include those of acute GVHD. Skin, eyes, and mouth can become dry and irritated, and mouth sores may develop. Chronic GVHD can also sometimes affect the esophagus, gastrointestinal tract and liver. Bacterial infections and chronic low-grade fever are common. Chronic GVHD is treated with similar medicines as acute GVHD.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems, including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (thinning of bones) and hypothyroidism (underactive thyroid)

Resources

www.leukemia-lymphoma.org -- Leukemia and Lymphoma Society
www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.bmtnews.org -- Blood and Marrow Transplant Information Network
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.aspho.org -- American Society of Pediatric Hematology/Oncology
www.candlelighters.org -- Candlelighters Childhood Cancer Foundation
www.clf4kids.com -- Childhood Leukemia Foundation

References

Belson M, Kingsley B, Holmes A. Risk factors for acute leukemia in children: a review. Environ Health Perspect. 2007 Jan;115(1):138-45. Campbell LK, Scaduto M, Sharp W, et al. A meta-analysis of the neurocognitive sequelae of treatment for childhood acute lymphocytic leukemia. Pediatr Blood Cancer. 2007 Jul;49(1):65-73.

Hijiya N, Hudson MM, Lensing S, et al. Cumulative incidence of secondary neoplasms as a first event after childhood acute lymphoblastic leukemia. JAMA. 2007 Mar 21;297(11):1207-15.

Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as postremission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 Trial. J Clin Oncol. 2007 Jan 1;25(1):16-24.

Waber DP, Turek J, Catania L, et al. Neuropsychological outcomes from a randomized trial of triple intrathecal chemotherapy compared with 18 Gy cranial radiation as CNS treatment in acute lymphoblastic leukemia: findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J Clin Oncol. 2007 Nov 1;25(31):4914-21.

A.D.A.M. Copyright

adam.com

Non-Hodgkin's lymphoma

FitSugar — Wed, 08 Oct 2008 17:35:06 -0700

In This Report

Highlights
Introduction
Risk Factors
Symptoms
Diagnosis
Outlook
Staging and Treatment Guide...
Chemotherapy
Biologic Therapy (Immunothe...
Radiation
Transplantation
Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

Chemotherapy can cause anemia, a drop in red blood cell (hemoglobin) levels. Erythropoiesis-stimulating drugs, which boost the production of red blood cells, are administered to counteract this complication. However, these drugs, which include epoietin alfa (Epogen, Procrit) and darbepoietin alfa (Aranesp), can also cause serious side effects and adversely affect survival when hemoglobin levels are raised too high.

In 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. The new labels have stronger warnings and updated dosing-related safety information.

Positron Emission Tomography (PET) Scans and Lymphoma

PET scans are used to help diagnose and stage lymphoma, and they may also be helpful in assessing treatment outcomes for some types of lymphoma. In 2007, an international team of cancer specialists drew up new guidelines for evaluating how well lymphoma responds to treatment in clinical trials. The guidelines now recommend that PET scans be used to help determine if a patient has achieved remission.

Introduction

Lymphomas are malignancies of the lymph system that are generally subdivided into two groups, Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL). Hodgkin's disease accounts for about 15% of all lymphomas. [For more information, see In-Depth Report #83: Hodgkin's disease.]

Non-Hodgkin's lymphomas is a term for malignancies that range from a very slow disease to an extremely aggressive but curable condition. They have certain features in common.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people refer to swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged include the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Lymphomas, such as non-Hodgkin's lymphomas and Hodgkin's disease, represent tumors of the lymphatic system. This system is a network of organs, ducts, and nodes. The system interacts with the blood's circulatory system to transport a watery clear fluid called lymph throughout the body. The lymphatic system contains lymphocytes, important cells involved in defending the body against infectious organisms. This system also restores 60% of the fluid that leaks out from blood capillaries back into circulation, and its ducts provide transportation for fats, proteins, and other substances collected from the body's tissues.

Lymphocytes. The lymphatic system is involved in the production and transportation of lymphocytes, white blood cells that are a primary component of the immune system. Among other vital functions, certain lymphocytes are responsible for producing antibodies, factors that can target and attack specific foreign proteins (antigens). To understand the lymphatic system, it is helpful to track part of the life cycle of these lymphocytes:

Lymphocytes develop in the bone marrow or thymus gland and are therefore categorized as either B cells (bone marrow-derived cells) or T cells (thymus gland-derived cells).
B cells complete their structural growth and definition (known as differentiation) and mature in the bone marrow.
T cells also start out in the bone marrow but differentiate and mature in the thymus gland, located beneath the breastbone (sternum). This small gland is active mostly in the fetal stage through the first 10 years of life, after which it atrophies (shrinks).
B-cell and T-cell lymphocytes leave these organs through the bloodstream, which eventually branches out into the tiny blood vessels called capillaries.
Some lymphocytes, along with fluid, proteins, and other substances, migrate out of the capillaries into the surrounding tissues. A proportion of these lymphocytes and other substances then enter the lymphatic vessels.
Lymphatic vessels begin as tiny, blind-ended tubes and lead to larger lymphatic ducts and branches until they drain into two ducts in the neck, where the fluid re-enters the bloodstream.
Along the way, the fluid passes through lymph nodes, oval structures composed of lymph vessels, connective tissue, and white blood cells. Here, the lymphocytes are either filtered out or added to the contents of the node.

Lymph Nodes. In the lymph node, lymphocytes receive their initial exposure to foreign substances (antigens), such as bacteria or other microorganisms, activating the lymphocytes to perform their immune functions. The size of a lymph node varies generally from that of a pinhead to a bean. Most nodes are in clusters located throughout the system. Important node clusters are found in the neck, lower arm, armpit, and groin.

Other Structures in the Lymphatic System. The tonsils and adenoids are secondary organs composed of masses of lymph tissue that also play a role in the lymphatic system. The spleen is another important organ that processes lymphocytes from incoming blood.

Click the icon to see an animation about lymph nodes.

Click the icon to see an image of lymph nodes in the head and neck.

Click the icon to see an image of the immune system structures.

Non-Hodgkin's lymphomas occur most often in lymph nodes in the chest, neck, abdomen, tonsils, and the skin. NHLs may also develop in sites other than lymph nodes such as the digestive tract, central nervous system, and around the tonsils.

About 85% of non-Hodgkin's lymphomas (NHLs) arise in B cells; the rest occur in T cells. Activation of a gene called BCL-2 is believed to be partly responsible for many B-cell lymphomas. This defect prevents apoptosis (a natural process whereby cells self-destruct) in the lymphoma cells.

There are more than 20 distinct types of non-Hodgkin's lymphomas. Most first arise in the lymph nodes, but about 20 - 30% of cases are now found outside the nodes, most often in the stomach, small intestine, skin, and brain.

Even experts disagree about the exact groupings. Lymphomas are categorized in a number of ways.

Classification by Cell Type, Appearance, and Genetic Make-up: The REAL System. Different classification systems for lymphoma have been proposed. The system used in this report is called REAL (Revised European-American Lymphoma Classification). It classifies all lymphomas by appearance, cell type, and genetic make-up:

Non-Hodgkin's lymphomas are first grouped as B cell or T cell.
Next, they are categorized by whether the B-cell and T-cell lymphomas were derived from immature (precursor) cells or mature (peripheral) cells.
The peripheral B and T cells are then classified by their appearance, genetic make-up, and specific chemical "markers," which further identify them.

T-cell lymphomas, Hodgkin's disease, and certain leukemias and aggressive lymphomas are covered in the REAL classification but are not discussed in any depth in this report.

Groups by Slow or Fast Growth. Each non-Hodgkin's lymphoma is further defined by its grade, or how aggressive it is:

Indolent (slow-growing), also called low-grade
Aggressive (fast-growing), also called intermediate- or high-grade

According to one report, half of new cases are now intermediate-grade lymphomas. Low-grade makes up 30%, while high-grade makes up 10% of all lymphomas.

Groups by Properties. Lymphomas are also grouped by certain properties:

Size (large versus small)
Shape (round versus irregular)
Whether they are or resemble blood plasma cells
Whether they are follicular (organized in round clusters) or diffuse (spread evenly throughout the lymph node)

Staging. Staging the disease is the next important step in classifying lymphomas. The stage (I - IV) of an NHL is determined by the number of tumors and whether they are still localized or have spread beyond the lymph node. In general, the higher the stage, the poorer the outcome, but other factors are important for a precise prognosis.

Indolent (Slow-Growing) Lymphomas (also Called Low-Grade Lymphomas)

Follicular lymphomas (FLs). Follicular small cleaved cell lymphoma (grade I) and follicular mixed small and large cell lymphoma (grade II). FLs account for 70% of indolent tumors and 20% of all NHLs in industrialized countries. It is very rare in developing countries and in Asia.

Lymphoplasmacytoid/Waldenstrom's macroglobulinemia. Often found in bone marrow, lymph nodes, and spleen. Can cause blood to become viscous and "sticky."

Marginal zone lymphomas (MZL). MZLs often occur as a result of a pre-existing disorder such as hepatitis C, bacterial infection in the stomach (H. pylori ), or an autoimmune disorder (Sjögren syndrome in the salivary glands or Hashimoto's thyroiditis in the thyroid gland). They may be classified as:

Monocytoid B-cell lymphoma, which involves only lymph nodes
Splenic marginal zone lymphoma, which affects the spleen, blood, and bone marrow
Mucosa-associated lymphoid tissue (MALT) lymphoma, which usually involves the gastrointestinal tract, thyroid, lung, breast, or skin

There is some controversy over whether MALT is a variation of MZL or a completely separate type of lymphoma that is more suitably classified as a separate low-grade lymphoma. At this time, it is classified as an MZL.

Aggressive Lymphomas (also Called Intermediate- and High-Grade Lymphomas)

Diffuse large-cell lymphomas (DL). DLs are the most common NHLs, accounting for about 40% of all cases. Subtypes include the following:

Primary mediastinal large B-cell lymphoma
Follicular large cell lymphoma
Anaplastic large cell lymphoma
T-cell lymphomas (not covered in this report)

In about 40% of cases, these DL lymphomas appear in areas outside lymph nodes, including digestive tract, skin, bone, thyroid, and testes.

Burkitt's lymphoma/diffuse, small noncleaved cell lymphoma. This is the most common childhood NHL. In African children, it often involves facial bones and is associated with Epstein-Barr infection.

Mantle cell lymphoma. Mantle cell lymphomas are found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis). This lymphoma is similar to indolent lymphomas at the time of diagnosis, but it is more aggressive.

Lymphoblastic lymphoma. This lymphoma often occurs in young people. It is associated with a large mediastinal mass (occurring in chest cavity between the lungs) and carries a high risk for spreading to bone marrow and central nervous system.

Risk Factors

About 63,000 Americans were diagnosed with non-Hodgkin's lymphomas in 2007, and nearly 19,000 people died of the disease. For the past 25 years, the incidence in NHL has increased continuously. Most of this increase has occured in people over age 65.

Part of the reason for the dramatic rise was AIDS, which increases the risk for high-grade lymphomas. However, even after eliminating changes in diagnosing NHLs and known causes (such as AIDS), the incidence over the past 40 years is 40% higher. The number of cases in which lymphomas first occur outside the lymph nodes has also increased compared to those limited to the nodes. (This observed increase, however, may in large part be due to different methods of diagnosing lymphomas).

The cancer can develop in people at all ages, including children, although it is most common in those ages of 45 - 60. In general, the incidence of NHL is 50% higher in men than in women. This higher rate has been observed in many countries. Nevertheless, recent reports suggest that the rate is leveling off or even declining in men, but is increasing in women, particularly African-American women. Overall, the risk is slightly higher in Caucasians than in African-Americans.

The risks for NHL among men versus women and among African-Americans versus Caucasians may vary by lymphoma subtype. For example, follicular lymphomas were significantly higher in Caucasians than in African-Americans, and there was little gender difference. High-grade lymphomas were the most rapidly increasing type, particularly among men, with follicular lymphomas increasing most rapidly in African-American men.

Other studies have also reported ethnic differences by specific lymphoma subtypes. For example, follicular lymphomas constitute 20% of all NHLs in Western nations but are very uncommon in Asia and in developing countries.

The brother or sister of a person with the disease has more than twice the risk of developing NHL than the general population. Some cases of NHL in such cases are due to inherited disorders of the immune system. Studies suggest, however, that such family clusters are more likely to be due to environmental conditions that trigger the genetic factors.

Because of the rapid rise in NHL, investigators are looking for lifestyle factor that may contribute to this increase. No real association between lymphomas and body weight or shape or amounts of exercise has been found.

A number of reports suggest an influence of diet in the development of non-Hodgkin's involvements. However, for the most part a strong association remains speculative. Some of the possible dietary risk factors include:

A number of studies have observed an association between an increased risk for non-Hodgkin's lymphomas and high consumption of red meat (beef, pork, and lamb).
A higher risk for lymphoma has also been suggested for trans fatty acids (hydrogenated polyunsaturated fats, which are contained in hard margarines and commercial baked goods and fast foods). There appears to be no higher risk with natural polyunsaturated fats (found in most vegetable and fish oils).
Fish may be protective.
Some evidence suggests that milk may also be protective.
One major study observed a reduction in risk with high intake of vegetables. Another found no protection from vegetables, but did with diets rich in fruit.
Vitamin supplements have no effect on NHL.

Despite these kinds of reports, the influence of diet on the development of non-Hodgkin's lymphomas remains speculative.

Alcohol Use. Studies on alcohol have been mixed, with some showing a higher risk, some a lower risk, and some no difference at all.

Smoking. There is no evidence that smoking increases the risk for NHL itself, although it has been linked with high-grade and follicular NHLs in people with lymphomas.

Viruses or other microorganisms also play a role in some lymphomas. A number are being investigated:

Epstein-Barr virus, the cause of mononucleosis, is highly associated with Burkitt's disease and NHLs associated with immunodeficiency diseases. It is also a risk factor for Hodgkin's disease
Adult T-cell leukemia-lymphoma, which appears to be caused by a virus known as HTLV-I, has been found in southwestern Japan, the Caribbean, and the southeastern United States.
People who have stomach inflammation due to Helicobacter pylori or H. heilmannii bacteria are at increased risk for mucosa-associated lymphoid tissue lymphomas (MALT). (The use of antibiotics to get rid of the bacteria may cause remission in some patients who have an early stage form of lymphoma in an early stage.)
Human herpes virus 8 has been associated with NHL.
Borrelia burgdorferi, the bacteria that causes Lyme disease, has been associated with primary B-cell lymphoma.
Heavy antibiotic use during adulthood may increase risk. A 2005 study found that adults who used antibiotics more than 10 times had 1.8 times the risk of developing NHL than nonusers. However, researchers were not certain if antibiotics themselves, or the underlying infections they treated, were responsible for the increased risk.

Click the icon to see an image of Lyme disease.

Studies are reporting a higher prevalence of viral hepatitis C and B in patients with lymphomas, although such viruses do not appear to play a major role in triggering lymphoma.

Patients with diseases or conditions that affect the immune system may be at higher risk for lymphomas:

HIV-positive patients and those with full-blown AIDS are at higher risk for NHL, and the disease is more likely to be widespread in these patients than in those without the immune disease. Most AIDS-related NHLs are high-grade lymphomas. Burkitt's lymphoma is often seen in patients with AIDS. Although these patients have had a very poor prognosis, advances in antiviral therapy for HIV now allow better management of NHL with some success in achieving favorable outcomes. Part of the dramatic increase in NHL incidence over the past decades can be traced to AIDS.
Patients with a history of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus, Hashimoto's thyroiditis, Crohn's disease, and Sjögren syndrome, are at an increased risk for certain NHLs, such as marginal zone lymphomas.
People who have organ transplants are at higher risk for NHL, probably due to multiple factors, including the drugs used to suppress the immune system and the transplanted organ itself.
Patients who have had high-dose chemotherapy with stem-cell transplantation are at higher risk.
Other immunodeficiency syndromes that put people at risk for NHL include Chediak-Higashi syndrome, ataxia-telangiectasia, B-cell lymphoproliferative syndrome, Bruton agammaglobulinemia, common variable immunodeficiency, and Wiskott-Aldrich syndrome.

Note on Allergies: There appears to be no association between NHL and allergies, overactive responses of the immune system. Allergies are the most common immune disorder.

Overexposure to a number of industrial and agricultural chemicals has been frequently linked to an increased risk for lymphomas. The data, however, are not consistent.

Organochlorines are chemicals produced when solid waste is burned. These by-product chemicals include dioxin, polychlorinated biphenyls (PCBs), and furans. Many studies have indicated that exposure to these chemicals increases the risk of developing NHL.
A number of studies have found an association between NHL and certain pesticides and herbicides, although more research is needed to confirm any definitive risk.
White spirits, thinners, phenoxy herbicides, wood preservative, aviation gasoline, plastic, and rubber chemicals have been associated with a higher risk for lymphomas. Specifically, in one study, painters and lumberjacks had a higher risk for NHL, while office and house workers had a lower risk.
Some studies have found an association with long duration and early use of permanent dark hair dyes. There is no consistent evidence, however, that hair dye increases the risk for lymphomas.

Symptoms

The most common first sign of lymphomas is painless enlargement of one or more lymph node, usually in the neck, armpits, or groin. Patients should see their doctors if these symptoms do not go away within 2 - 3 weeks.

The most common lumps or swellings in the neck are enlarged lymph nodes. They can be caused by bacterial or viral infections, cancer, and other rare causes.

Lymphomas sometimes cause systemic symptoms -- symptoms that affect the whole body, rather than a specific location. Some systemic symptoms are referred to as B symptoms. Patients who have B symptoms have a more severe condition than asymptomatic patients with the same cancer stage or tumor location or size.

B systemic symptoms include:

Drenching night sweats and weight loss
Fever (may occur sporadically and only at night)

Other systemic symptoms include:

Itching all over the body caused by the release of histamines, substances ordinarily triggered by an allergic response. In the case of NHL, this is due to abnormalities in the immune system. Although this is a systemic symptom, it is not usually considered a B symptom if other systemic symptoms are not also present.
In late stages, some patients develop a skin rash.
Tumor masses in the chest can cause coughing or breathlessness.
Lymphomas in the stomach can cause nausea and vomiting.

Many patients seek medical help for abnormally swollen lymph nodes (commonly referred to as "swollen glands"). Swollen glands can be caused by many conditions, most often infections, and are rarely serious.

Infections. In the great majority of cases, swollen glands are caused by an infection:

Enlarged lymph nodes in the neck are much more likely to be a sign of strep or other throat infection than NHL.
Infectious mononucleosis (caused by the Epstein Barr virus) is a common cause of swollen lymph nodes in young people.
Travel, particularly to countries with a high incidence of tropical diseases, can trigger similar symptoms.
Other infections that cause swollen glands include cat scratch fever, Lyme or other tick-borne disease, HIV, tularemia, tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, and hepatitis.

Hodgkin's Disease. Although both Hodgkin's disease and non-Hodgkin's lymphomas are malignancies of the lymph nodes, they can usually be distinguished by certain characteristics. It is extremely important to differentiate between Hodgkin's lymphomas and non-Hodgkin's lymphomas, since the treatments for these two conditions differ. In particular, a subtype of lymphoma called anaplastic large-cell lymphoma (ALCL) might be confused with Hodgkin's disease under some circumstances. [For more information, see In-Depth Report #83: Hodgkin's disease.]


Characteristics	Hodgkin's Disease	Non-Hodgkin's Lymphomas
Age and Prevalence	Average age is 28 with two age peaks, the major one occuring between 15 - 24, anda lesser peak after age 55. It is less common than NHL.	Average age is about 67. It is more common than HD.
Location	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. However, in HD it is also more likely to appear in the chest cavity between the lungs (the mediastinum), particularly in younger patients. Only about 15 - 20% of cases are found in areas below the diaphragm. Disease occurs outside the nodes in about 4% of cases.	In both malignancies, the disease occurs most often in lymph nodes above the collarbone. In NHL, however, it is also more likely to appear in the nodes in the abdomen (called the mesenteric nodes). The disease occurs in the chest cavity in less than 40% of patients. (An exception, lymphoblastic lymphoma, which is seen most often in young people, is likely to first appear in the chest.) Disease occurs outside the nodes in about 23% of patients. Slow-growing lymphomas are common in the liver and bone marrow.
Symptoms	More likely than NHL (40%) to have systemic symptoms (such as fever and night sweats) at the time of diagnosis.	Less likely to have systemic symptoms (27%) at the time of diagnosis.
Progression	Less likely than NHL to be diagnosed in stage IV (10%). Hodgkin's disease usually progresses in an orderly way from one lymph node region to the next. This process may be slow, particularly in younger people, or very aggressive. The disease typically spreads downward from the initial site. If it spreads below the diaphragm, it usually reaches the spleen first; the disease then may spread to the liver and bone marrow. If the disease starts in the nodes in the middle of the chest, it may spread outward to the chest wall and areas around the heart and lungs.	More likely than HD to be diagnosed in stage IV (36%). The lymphomas are less predictable in their course than Hodgkin's disease and they are more apt to spread.

Other Cancers or Serious Conditions in the Lymphatic System. Other cancers that can travel to lymph nodes include breast cancer and leukemia.

Very serious causes of enlarged lymph nodes include disorders of the lymph system, such as Castleman's disease, lymphomatoid granulomatosis, and angioimmunoblastic lymphadenopathy. These lymph system disorders, although noncancerous, involve abnormal lymph cells. They are often fatal and can be very difficult to distinguish from lymphomas. Many of the other serious illnesses involving diseased lymph nodes develop simultaneously at multiple sites, while Hodgkin's nearly always starts at one location before spreading to nearby nodes. [For more information, see In-Depth Report #83: Hodgkin's disease or Report #86: Acute lymphocytic leukemia.]

Exposure to Medications. Exposure to certain medications such as phenytoin (Dilantin) may cause enlarged nodes. Other drugs, such as cephalosporins, penicillins, or sulfonamides, can cause enlarged nodes and other symptoms, including fever and rash, which may resemble Hodgkin's disease.

Diagnosis

The doctor will first ask questions about the patient's medical history and perform a physical examination to detect any node enlargements. If these steps point to lymphoma, additional tests will be done to rule out other diseases or to confirm the diagnosis and extent of the lymphoma.

It is sometimes reasonable to wait a little while for the swelling and symptoms to go away before deciding that additional testing is necessary. In some cases, lymph node swelling may be due to a temporary infection. However, some lymphomas cause off and on lymph node swelling. This is particularly true with small cleaved cell lymphoma (the most common NHL). Lymph nodes should be checked periodically for any return of swelling.

The doctor will examine not only the affected lymph nodes but also the surrounding tissues and other lymph node areas for signs of infection, skin injuries, or tumors. The consistency of the node sometimes indicates certain conditions. For example, a stony, hard node is often a sign of cancer, usually one that has metastasized (spread to another part of the body). A firm, rubbery node may indicate lymphoma. Soft nodes suggest infection or inflammatory conditions.

Blood tests help rule out infection and other diseases. Such tests include those blood counts and blood chemistries for kidney and liver function, uric acid, calcium, and phosphate levels. In a patient already diagnosed with lymphoma, blood tests that measure the enzyme lactate dehydrogenase are important in determining the prognosis. High levels indicate bulkier tumors. The presence of anemia may indicate specific NHLs, such as diffuse, small lymphocytic lymphoma.

A biopsy is the most important test for diagnosing lymphomas and can be used to tell the difference between non-Hodgkin's and Hodgkin's disease. A biopsy has risks and should be performed only by a qualified and experienced doctor. Sometimes a doctor may choose to wait and observe the involved lymph nodes, which will usually go away on their own if a temporary infection is causing the swelling. (However, some lymphomas may go away and appear to be benign, only to reappear at a later time.)

The Procedure. The doctor removes the node and checks the surrounding areas. The tissue in the node is then examined under a microscope for signs of infection and abnormalities indicating cancer or other conditions.

Results. Even if biopsies do not show any problems, disease may still be present in some cases. The doctor should continue to observe the patient until swelling or other signs of disease are gone. Biopsied tissue samples should be frozen in case special tests are later required. Such tests may include detection of particular antibodies, genetic and immune factors, and certain markers (substances that may indicate disease) located on the surface of the cells. If lymphoma has been diagnosed, the tissue will be examined for its histology, the cellular structures that will determine the lymphoma type.

Bone marrow aspirate and biopsy are routinely performed to determine whether the disease has spread. With bone marrow aspirate, bone marrow cells are sucked out through a special needle. A biopsy may be performed before or after the aspiration. In this procedure, a special needle removes a core of the marrow that is structurally intact.

Click the icon to see an image of bone marrow aspiration.

Chest X-Ray. A chest x-ray shows the lymph nodes in the chest and neck area. It is particularly useful in detecting Hodgkin's disease and enlarged lymph nodes.

Click the icon to see an image of an x-ray machine.

Click the icon to see an image of a CT machine.

Magnetic Resonance Imaging (MRI). MRIs may be used to detect the spread of the disease to the brain, spine, chest, pelvis, and abdomen.

Click the icon to see an image of a MRI machine.

Positron Emission Tomography (PET). PET scans can help tell whether or not an enlarged lymph node is benign or cancerous. PET scans are more accurate than CT scans or other imaging tests for staging lymphomas. PET scans may also help doctors determine how well a patient has responded to treatment, if any residual cancer exists, and if a patient has achieved remission.

Tests of lymphoma's DNA are in use or are being developed to detect particular genetic abnormalities that help determine outlook and may eventually lead to new treatments. Examples of such abnormal genetic arrangements are those that affect normal cell death, resist chemotherapy, or trigger aggressive cancer growth.

An advanced approach called the microarray technique uses chips that contain up to thousands of DNA sequences that represent specific normal and abnormal genes. Such sequences have been compiled for lymphomas. Eventually, experts may be able to match a patient's DNA to these patterns and identify specific subtypes.

Biologic markers, also called biomarkers, are high levels of substances released by tumors. They indicate the level of cancer activity. Biomarkers can be found in sputum, blood, and tissue samples. Biomarkers can be enzymes, hormones, amino-acid compounds, antigens (identified by antibodies that specifically target them), and growth factors. Some under investigation include:

CD44. This molecule binds to the surface of cells and may be involved in metastasis. High levels of this molecule may suggest a more aggressive disease.
BCL-6. This cancer gene is implicated in diffuse large B-cell lymphoma. High levels of this gene in these patients indicate a better outlook after treatment.

Outlook

Five-year survival rates for NHL range from 20 - 95%, depending on the lymphoma type, stage, age of the patient, and other variables. Because the outlook varies so widely, making a definite prognosis is very difficult. For example, patients with very slow growing (indolent) lymphomas can live many years. However, they are usually diagnosed at a late stage, after the cancer has spread, thus reducing the survival rate. Aggressive lymphomas are more likely to cause rapid death, but they are also often curable. New drugs that target specific factors in the tumor cells are improving survival rates.

Follicular lymphomas, the most common indolent (slow-growing) NHLs, are potentially curable in early stages I and II. Unfortunately, however, these slow-growing malignancies produce no symptoms until they are in advanced stages. In most cases, these lymphomas are not diagnosed until they have spread to other sites, including the spleen and bone marrow. In such cases, they are difficult to cure. Predicting outcome for indolent follicular lymphomas is more difficult than for aggressive lymphomas. Even if treatment achieves a response, these tumors almost always recur. Even after relapse, however, the tumors can be treated again if they are still very slow-growing.

In general, the average survival rate for follicular lymphoma is 7 - 10 years, depending on other risk factors. New drug treatments, particularly monoclonal antibodies, have significantly improved survival rates. According to a 2005 study, 91% of patients with follicular lymphoma now survive the first 4 years after diagnosis, compared with 69% of patients treated in the past with older types of drugs. The research team found the best 4-year survival rates for patients treated with the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy regimen followed by monoclonal antibody biologic drugs (rituximab or iodine-131 tositumomab).

Factors for Predicting Outlook in Indolent Lymphomas. Six risk factors are proving to be useful for predicting outlook:

Being male
Being older
Having stage III or IV disease
Elevated levels of the enzyme lactate dehydrogenase (LDH)
The presence of B symptoms
Erythrocyte sedimentation rate over 30

Patients with a good chance for a positive outcome (65% chance for survival rates of 10 years or greater) have one or none of these factors. Those with intermediate risk (23%) have two factors, and those likely to have a poor outcome (11%) have three or more factors. MALT lymphomas generally have a good prognosis. Primary gastric lymphomas have a 3-year survival rate of 89%.

High-grade aggressive lymphomas are often symptomatic early on and are potentially curable with aggressive treatments. Diffuse large-cell lymphomas, the most common aggressive non-Hodgkin's lymphomas, while fatal if not treated, are often curable with intensive chemotherapy combinations. If relapse occurs after chemotherapy, it usually does so within 2 years.

Most other aggressive lymphomas respond to aggressive chemotherapy. Mantle cell lymphoma is less responsive to chemotherapy. The average survival time is 3 - 5 years.

Factors for Predicting Outlook in Aggressive Lymphomas: A scoring system called the International Prognostic Index has proved to be fairly accurate for predicting outcome in patients with most aggressive B-cell lymphomas. It uses five risk factors to help predict whether the disease will be aggressive:

Being older than 60 -- this age group tends to have other medical conditions, which contribute to the poorer prognosis
Having a disseminated tumor (stage III or IV)
Disease that has spread to more than one site beyond the lymph nodes
A poor performance status
Having elevated levels of lactate dehydrogenase (LDH)

Having one or none of these risk factors indicates the best outlook. Two factors indicate a low-to-intermediate likelihood of a poor outlook. Three factors predict an intermediate-to-high likelihood of poor outlooks. Finally, four or five factors pose the highest likelihood of poor survival.

Lymphoma can spread to the central nervous system, or it can appear there first. Called primary CNS lymphomas (PCNSL), this condition is a very serious, particularly if it occurs at relapse.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

Risk Factors for CNS Involvement After a Diagnosis of NHL. AIDS-related lymphomas often involve the central nervous system (CNS), including the brain and spinal column. CNS involvement also occurs with aggressive lymphomas, such as Burkitt’s lymphoma.

Risk Factors of Primary CNS Lymphomas. PCNSL used to account for only about 2% of lymphomas, but the incidence is on the rise in all age groups and in both. The reason for the increase is not known.

Medical Problems. The radiation and chemotherapies used in treating NHL can have long-term effects on many organs in the body and can increase the risk for serious illnesses, including heart disease and certain cancers.

Negative Emotional Problems. Depression and anxiety are common in survivors, particularly those who suffer additional medical conditions. Many patients also suffer from fatigue and aches and pains, called somatic symptoms, which have no apparent physical basis. In one study, such symptoms were more highly associated with intensive chemotherapy. Women and people in lower social and economic groups are at higher risk for depression and somatic symptoms -- just as they are in the general population.

Staging and Treatment Guidelines

Treatment for non-Hodgkin's lymphoma is highly specific for each patient and is determined by the tumor classification. It includes the following factors:

Stage
Grade
Histologic type (cellular structure)
Location
Other factors, such as blood levels of lactate dehydrogenase

Treatment for lymphomas has been primarily dependent on chemotherapy (particularly intensive regimens using several drugs) or a combination of chemotherapy and radiation. For advanced or refractory lymphomas and for relapse, patients may undergo bone marrow or stem cell transplantation. New treatments, especially those known as immunotherapies, or biological response modifier (BRM) therapies, are showing promise. Some experts recommend that patients ask their doctors about getting into well-designed clinical trials as early as possible.

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

In assessing the success of a clinical trial, experts often refer to the tumor response. A complete response, for example, means that there is no longer any evidence at all of the disease by examination, blood tests, or x-ray studies. It does not necessarily mean, however, that the disease is cured. It may still recur later on.

In judging the success of a treatment for NHL, the most important criteria are overall survival and the duration of time until the disease progresses or the patient dies.

In Stage I, lymphoma is found in only one lymph node area or in only one area or organ outside the lymph nodes. Either of the following indicates stage II:

Lymphoma is found in two or more lymph node areas on the same side of the diaphragm.
Lymphoma is found in only one area or organ outside the lymph nodes and in the lymph nodes around it. Other lymph node areas on the same side of the diaphragm may also have lymphoma.

Early Stage Indolent (Low-Grade) Lymphoma. Below are the general treatment options:

Radiation therapy. Radiation to local areas can achieve a cure in 40 - 50% of patients.
Chemotherapy. Chemotherapy uses drugs to kill cancer cells.
Watchful waiting. Patients who choose watchful waiting must be aware of signs and conditions indicating the need for treatment. These include B symptoms, endangered organs, massive bulky tumors, or a steady progression that lasts at least 6 months.
Investigative treatments, such as conjugated and unconjugated monoclonal antibodies or radiation plus chemotherapy. In one study, a combination of therapies worked better than radiation alone.

The following are treatment options for some specific low-grade lymphomas:

Mucosa-associated lymphoid tissue (MALT) lymphoma. When disease is in the stomach (gastric MALT) and the patient is infected with H. pylori bacteria, antibiotics can cause regression in a significant number of patients with stage I lymphoma. In certain patients where antibiotics fail, or are not appropriate, radiation alone can achieve significant cure rates. Surgery with or without radiation, or chemotherapy with or without radiation, are possible options. Treatment options for patients with MALT localized in other sites depend on the location of the specific disease and range from radiation to chemotherapy to biologic therapies, such as interferon.
Primary gastric lymphoma (indolent). Radiation is the typical treatment for this lymphoma, which is located only in the stomach, small intestine, or other nearby regions. Surgery is being reconsidered since it seems to offer no advantage.

Click the icon to see an image of the digestive system.

Early Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options include:

Chemotherapy alone
Combinations of chemotherapy (usually CHOP) plus radiation therapy
Radiation alone (rarely)
Chemotherapy alone or with surgery for lymphoma in the gastrointestinal region
Immunotherapies (rituximab, Bexxar) with or without chemotherapy (usually CHOP), or high dose chemotherapy and bone marrow or stem cell transplantation

In stage III, lymphoma is found in lymph node areas on both sides of the diaphragm (for instance, in both the chest and the abdomen). The lymphoma may also have spread to the spleen. In stage IV, lymphoma has spread via the bloodstream to organs outside the lymph system, such as the bone marrow or brain. Lymphoma cells may or may not be in the lymph nodes near these organs.

Advanced Stage Indolent (Low-Grade Lymphomas). Treatment options are controversial because of the low-cure rate and yet slow-growing nature of these lymphomas. Patients without symptoms are often managed by watchful waiting, in which the disease is monitored closely for development of symptoms or bulky tumor masses, particularly if they threaten major organs. At such times, treatment is started. Treatment may include:

Chemotherapy combinations (CHOP, CVP, CMOPP)
Nucleoside analogs (for example, fludarabine) alone or with chemotherapy
Oral alkylating chemotherapy drugs such as cyclophosphamide or chlorambucil with or without steroids
Monoclonal antibodies (MAbs) such as rituximab alone or in combinations with CHOP or nucleoside analogs
Chemotherapy plus interferon
Clinical trials involving intensive chemotherapy and radiation followed by bone marrow or stem cell transplantation

Advanced Stage Aggressive (Intermediate- to High-Grade) Lymphomas. Treatment options may include:

Doxorubicin-based combination chemotherapy with or without rituximab
Chemotherapy plus radiation therapy
Immunotherapies with or without chemotherapy
Treatments to prevent disease from spreading to the central nervous system in high-risk patients
Clinical trials for patients at high risk for relapse, involving intensive chemotherapy, high dose chemotherapy, and bone marrow or stem cell transplantation

Indolent-Lymphomas Relapses. Nearly all patients with indolent lymphomas relapse after initial treatment, with length of remission after a first treatment averaging 18 - 50 months. Successful retreatment is often possible, but disease-free periods become increasingly shorter with each subsequent treatment.

Older patients may choose watchful waiting. Other treatment options may include:

Radiation alone or with chemotherapy -- in one study low-dose involved-field radiotherapy was very effective in recurring indolent lymphoma
Chemotherapy
High-dose chemotherapy with autologous stem cell transplant
Clinical trials involving monoclonal antibodies, radioimmunotherapy, nucleoside analogues alone or in combination with other drugs, or stem cell transplantation followed by biologic therapies

Aggressive Lymphomas Relapse. After initial treatment, more than half of patients with aggressive lymphomas are cured, while about 20% progress, and the other 30% relapse after a disease-free period. Among those who relapse, many can still be cured with aggressive treatments.

Treatment options:

Bone marrow or peripheral stem cell transplantation
Bone marrow transplantation with radiation
Clinical trials that involve continuous infusion chemotherapy, biologic therapies (monoclonal antibodies) alone or in combination with transplantation

Click the icon to see an illustrated series detailing bone marrow transplant surgery.

Treating Lymphoma Restricted to the Central Nervous System. Treatment options may include:

High-dose methotrexate regimens alone or in combination with radiation
Corticosteroids and radiation
Clinical trials that involve biologic therapies, such as rituximab or interferon alpha administered directly into the spinal fluid (intrathecal administration) for meningitis related to central nervous system lymphoma

Preventing (Prophylactic Treatment) Lymphomas in High-Risk Patients. Treatment to prevent the spread of NHL to the central nervous system may be appropriate in some patients. It is not recommended for patients with low-grade NHL. Preventive treatment may be appropriate for certain patients with high-grade NHL, such as those with lymphoblastic and Burkitt's lymphoma or if they have 4 - 5 of the following risk factors: Elevated levels in the blood of the enzyme acetate dehydrogenase and albumin (a common protein), being older than 60, and having lymph nodes beyond the peritoneum (the lining of the abdomen) and involvement of more than one site outside a lymph node.

Chemotherapy

Chemotherapy plays a role in the treatment of nearly all lymphoma patients and has achieved remarkable results, even in late stages. It uses drugs to kill cancer cells. Such drugs are called cytotoxic drugs. Chemotherapy is referred to as bodywide or systemic therapy because the drugs travel throughout the bloodstream to the entire body.

Studies indicate that chemotherapy as sole treatment is adequate for most children and young adults in early, and perhaps in many advanced, stages. (Radiation has been commonly used for these patients but can be particularly dangerous for children.)

A chemotherapy cycle is usually 21 - 28 days. Patients take the drugs for a few days, then have a period of rest. The drugs may be taken by mouth or given by injection. Chemotherapy is injected into the spinal fluid if the cancer has spread to the brain. This is called intrathecal chemotherapy. Intrathecal chemotherapy is also used as a preventive measure in patients at high risk for central nervous system involvement. Chemotherapy may be administered at a medical center or in a doctor's office. Some patients receiving chemotherapy need to remain in the hospital for several days so the effects of the drug can be monitored. Patients with lymphoblastic lymphoma may need long-term maintenance chemotherapy. Such therapy does not seem to benefit patients with small-noncleaved-cell and large-cell lymphomas.

CHOP. The current standard chemotherapy regimen for NHL is CHOP. CHOP is a combination of cyclophosphamide, doxorubicin hydrochloride (Adriamycin), vincristine (Oncovin), and prednisone. It is proving to be particularly effective for many stages of lymphoma when used in combination with rituximab (Rituxan), a monoclonal antibody. (See Biologic Therapy section.) Some studies of this combination in low-grade lymphomas have reported response rates of 70 - 100%. CHOP alone is still preferred for HIV patients, who tend to have a toxic response to rituximab.

CVP. This stands for cyclophosphamide, vincristine, and prednisone. It may be used with CHOP in certain cases.

Fludarabine and Nucleoside Analogues. Fludarabine (Fludara) is a type of drug called a nucleoside analogue. It is one of the most active drugs for treating low-grade lymphomas and may be effective for other NHLs, including mantle cell lymphomas. Promising regimens containing fludarabine are under investigation. For example, FND (fludarabine, mitoxantrone, and dexamethasone) may be helpful in combination with rituximab for certain patients, including those with indolent NHL. Other nucleoside analogues include gemcitabine and cladribine. Toxicities and infection rates from high dose nucleoside analogues have been high. Fludarabine also has been associated with a risk for leukemia.

Bendamustine. This potent drug has shown to be effective for indolent NHLs and possibly aggressive lymphomas. One study suggested that a single dose of low-dose etoposide, taken by mouth, may be beneficial for elderly patients.

Antibiotics. Antibiotics, such as doxycycline, may cure or put into complete remission about half of mucosa-associated lymphoid tissue (MALT) lymphoma cases. MALT lymphoma is a type of lymphoma that sometimes affects the eyes. It is associated with the bacterium Helicobacter pylori (H. pylori ), which also causes stomach ulcers. Recent studies indicate that antibiotics are a good alternative to chemotherapy or radiation for patients with this type of lymphoma. Patients most likely to respond positively to antibiotics are those with MALT lymphoma in its early stages.

Vorinostat. Vorinostat (Zolinza) was approved in 2006 for treatment of cutaneous T-cell lymphoma (CTCL), a rare form of NHL.

Side effects and complications of any chemotherapeutic regimen are common. They are more severe with higher doses. Side effects may increase over the course of treatment.

Common Side Effects. Common side effects include:

Nausea and vomiting -- Drugs known as serotonin antagonists, such as ondansetron (Zofran) or granisteron (Kyril), can relieve these side effects in nearly all patients given moderate drugs and in most patients who take more powerful drugs.
Diarrhea
Hair loss
Weight loss
Depression

These side effects are nearly always temporary. Most patients are able to continue with normal activities for all but perhaps a few days a month.

Serious Side Effects. Serious chemotherapy side effects can also occur and may vary depending on the specific drugs used. They include:

Neutropenia is a severe drop in white blood cells. Neutropenia increases the chance for infection from suppression of the immune system and is a potentially life-threatening condition. Drugs known as granulocyte colony stimulating factor (G-CSF) are used to help boost white blood cell count. These drugs, which include filgrastim (Neupogen) and pegfilgrastim (Neulasta), can help lessen the risk for neutropenia occurrence and, if neutropenia does occur, to reduce its length and severity.
Anemia is a lack of red blood cells. Erythropoietin stimulates red blood cell (hemoglobin) production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). In 2007, the FDA released strict dosing guidelines for these drugs. In patients with cancer, they should be used to treat only anemia associated with chemotherapy and to increase hemoglobin levels to no more than 12 g/dL. Treatment should stop as soon as chemotherapy is complete. These drugs may not be safe or appropriate for all patients.
Liver and kidney damage
Abnormal blood clotting (thrombocytopenia)
Allergic reaction

Long-Term Complications.

Fatigue and Somatic Symptoms. Chemotherapy has been associated with long-term somatic symptoms, which are general conditions, such as fatigue and aches and pains that have no apparent physical basis. Fatigue is especially common after chemotherapy and can even last for years.
The most serious long-term complications from chemotherapy are secondary cancers, particularly in people over age 40.
Infertility is a risk, particularly with the use of cyclophosphamide.
Some patients get osteoporosis (bone thinning) and damage in bone cells.
Regimens containing certain drugs, particularly doxorubicin or mitoxantrone, increase the risk for future heart failure.

Click the icon to see an image of the uterus and ovaries.

In general, these serious late side effects are dependent on the cumulative drug dose and rate of administration.

Doctors are particularly concerned about the effects of combinations of chemotherapy with radiation, especially leukemia and heart problems. Interestingly, in one study on patients with intermediate- and high-grade NHL, those on chemotherapy alone had more toxic effects than those on combined modality, most likely because it employed fewer cycles of chemotherapy. Better radiation techniques are also reducing the risks of combined modality treatments.

Biologic Therapy (Immunotherapy)

Biological response modifier therapy, also called immunotherapy, uses the body's own immune system to fight cancer using natural or laboratory-developed factors. These drugs are often combined with other treatments.

Monoclonal antibodies (MAbs) are designed in the laboratory to produce the same effects as natural antibodies and are exciting new weapons in the anti-cancer armament. They bind to specific proteins called antigens and make them vulnerable to attack by other factors in the immune system. Lymphomas carry antigens that provoke strong immune responses and so are believed to be particularly good candidates for MAb therapy.

MAbs are called either unconjugated or conjugated, depending on how they are designed to destroy the cancer cell.

Unconjugated monoclonal antibodies rely on a strong natural immune system. The antibody builds up at the tumor site until it is able to trigger an immune response against the cancer. A possible downside to this form is the potential development of tolerance to the antibody so that it loses its effectiveness. Rituximab is an unconjugated form and the first MAb to be approved for any cancer.
Conjugated monoclonal antibodies are linked to a plant or bacterial toxin or radioisotope. The antibody specifically attacks the antigen on the lymphoma cell, and the toxin or radioactive material from the isotope kills it.

Unconjugated MAbs (Rituximab). Rituximab (Rituxan) was the first monoclonal antibody approved for cancer. This drug targets the CD-20 antigen, which is found on most B-cell lymphomas.

First approved in 1997 for treatment of relapsed or refractory NHL, rituximab has received several expanded indications since that time. As of 2006, rituximab is approved for:

Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, NHL
First-line treatment of diffuse large B-cell (DLBC), CD20-positive, NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens
First-line treatment of follicular, CD20-positive, B-cell NHL in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy
Low-grade, CD20-positive, B-cell NHL in patients with stable disease or patients who have been partially or completely helped by first-line treatment with CVP chemotherapy

Rituximab in combination with CHOP (a regimen called R-CHOP, or CHOP-R) is used for first-line treatment for aggressive lymphomas, with studies reporting 3-year event-free survival of 53% compared to 35% with CHOP alone. A 2006 study also indicated that rituximab provides benefits when used as maintenance treatment after CHOP or R-CHOP induction therapy. Rituximab plus CHOP is also showing promise as a first-line treatment for mantle cell lymphoma.

Rituximab is given by infusion. The treatment has mild-to-moderate short-term side effects, including nausea, fever, chills, hives, dizziness, and headache. Uncommon and more serious side effects are severe allergic reactions, very low blood pressure, blood abnormalities, wheezing, infections, and sudden heart events.

Rituximab has also been associated with cases of progressive multifocal leukoencephalopathy (PML), a rare and potentially deadly brain infection. Patients who experience any of the following symptoms should immediately contact their doctors:

Vision problems or unusual eye movements
Confusion
Dizziness or loss of balance
Difficulty talking or walking

Patients who have previously had hepatitis B, or who are at high-risk for this viral infection, should be tested before taking rituximab because the drug has been linked to reactivation of the hepatitis B virus. Patients who are HIV-positive may experience more adverse effects from rituximab than with CHOP.

Conjugated Monoclonal Antibodies with Radioimmunotherapy. Conjugated MAbs with radioimmunotherapy contain tiny amounts of radioactive materials. When the drug is injected, the monoclonal antibody targets an antigen (protein) on the surface of the tumor. The radioisotope is then delivered directly into the tumor where it kills the cancer. Ibritumomab and tositumomab both target the CD-20 antigen. Treatment with these drugs takes about 7 - 9 days to complete, compared to several months for traditional chemotherapy treatments.

Ibritumomab (Zevalin) is approved for patients with relapsed or refractory low-grade, follicular or transformed B-cell NHL. It is also approved for patients with follicular NHL who have not responded to rituximab (Rituxan). Research indicates it may also be safe for patients with advanced NHL who have had stem cell transplantation. Zevalin uses an yttrium-90 (90-Y) radioactive isotope.
Tositumomab and Iodine I-131 (Bexxar) combines the monoclonal antibody tositumomab with the radioisotope I-131. The Bexxar treatment is approved for treatment of relapsed or refractory low-grade, follicular, or transformed B-cell NHL. Overall response rates of 56% have been reported with Bexxar, with up to 30% being complete responses (no evidence of cancer). Recent studies suggest that when Bexxar is used as a first treatment, it may produce long-term complete remission in patients with advanced stage follicular lymphoma. In a 2005 New England Journal of Medicine study, 95% of previously untreated patients with advanced follicular lymphoma responded to Bexxar, and 75% had complete responses. Seventy percent who had complete responses from Bexxar treatment were still disease-free 4 - 7 years later.

In general, these drugs cause fewer side effects than traditional chemotherapy. However, serious complications may include skin infections, severe allergic reactions, and temporary lowering of blood counts.

Other Monoclonal Antibodies. Other MAbs are being developed that target other antigens on lymphomas. For example, epratuzumab targets CD-22 and is showing promise in early studies. Some are being studied in both conjugated and unconjugated forms and also in combination with MAbs that target different antigens.

Interferon alpha (Intron A) is used as an antiviral drug that also has properties that are effective against some common forms of NHL, particularly low-grade, follicular NHL in advanced stages. It is usually combined with chemotherapy regimens such as CHOP that contain an anthracycline drug (usually doxorubicin). The combination is toxic, however, and outcomes vary. Interferon is also being studied for lymphomas in the central nervous system. It may be useful after autologous stem cell transplantation.

Side Effects. Side effects of interferon include flu-like symptoms, severe depression, irritability, weight loss, vomiting, general weakness and loss of strength, and fever. About a third of patients have a severe drop in white blood cells. About 10% of patients cannot tolerate the drug's side effects.

Cytotoxic Deoxyguanosine Analogue Prodrugs. Nelarabine (Arranon) is approved for treating T-cell lymphoblastic lymphoma (T-LBL). T-LBL is a rare form of lymphoma that accounts for less than 2% of all cases of NHL.

Proteasome Inhibitors. In 2006, bortezomib (Velcade) was approved for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.

Cyclin-Dependent Kinase Inhibitors. Flavopiridol, a drug known as a cyclin-dependent kinase inhibitor, is showing some effect in patients with mantle-cell lymphoma. This drug is designed to block enzymes that regulate cell cycles and help block their growth.

Vaccines. Although still experimental, lymphoma vaccines are used to treat -- not prevent -- cancer. They are part of an immunotherapy approach called personalized medicine; each vaccine is individually tailored to the genetic composition of the patient’s tumor. The vaccine is usually given a few months after a patient receives chemotherapy. Several different vaccines, including the BiovaxID and MYVax, are in late-stage clinical trials.

Radiation

Radiation is commonly used to treat indolent lymphomas. The dose administered ranges from 35 - 50 Gy and depends on a number of factors: The type of lymphoma, the age of the patient, whether the intent is to cure or relieve symptoms, how close sensitive organs are to the diseased area, and whether radiation is being combined with chemotherapy.

Radiation is tailored to the individual and usually limited to the diseased areas and possibly nearby regions:

If the lymphoma is confined to tissues above the diaphragm, radiation is delivered to the neck, chest, and under arms (called the mantle-field) and sometimes to lymph nodes in the upper abdomen or spleen or both.
If the lymphoma is below the diaphragm, subtotal nodal radiation may be used, which is directed to other regions, including lymph nodes in the upper abdomen, spleen, and pelvis, in addition to the mantle-field.
Radiation to the brain is called cranial radiation.
Total body irradiation is sometimes performed, although it is not clear whether its high toxicity outweighs any advantages.

Devices called planning simulators allow doctors to plan x-ray treatments that accurately conform to the patient's anatomy so that protective shields can be created to precisely protect the regions outside the treatment areas.

Side effects and complications of radiation generally depend on the target site in the body. They include:

Dental problems
Inflammation in the lungs -- with carefully conducted therapy, the risks for lung complications are small. Lung impairment may not even be evident, and the lungs usually recover after 2 - 3 years.
Hypothyroidism
Infections
Long-term risk for heart disease
Long-term risk for certain cancers -- of particular concern is a possible increased risk for breast cancer. Studies indicate that young women and adolescent girls are at highest risk, with the incidence increasing significantly 15 years after treatment. The risk is greater in those who had higher radiation doses. Radiation may also increase the risk over time for other cancers, including lymphoma and thyroid, lung, and colon cancers, although the risk is still low. Smoking, of course, increases the risk for lung cancer. Radiation of bone marrow increases the risk for leukemia.
Impaired bone growth -- children and adolescents are at special risk for bone problems caused by radiation. Experts are finding that radiation for many children and young adults in early stages or NHL is no more effective and has more serious long-term effects than chemotherapy. Some believe that radiation should play no role in the treatment of young people, except in special cases, such as lymphomas that require radiation to the brain.
Infertility -- the negative effects on fertility may be worse in women than in men; sperm usually recover within 5 years. To protect the ovaries, a technique called ovarian transposition is sometimes used. Transposition may sometimes be performed through a laparoscope, a thin tube containing tiny instruments and cameras, which is introduced through a small incision. The doctor uses the laparoscope to move the ovaries out of the range of areas being treated with radiation.

Click the icon to see an image of the lungs.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of the uterus and ovaries.

Transplantation

Stem cell procedures have proven to produce long-term survival and even cures in some patients with intermediate- and high-grade non-Hodgkin's lymphomas.

Stem cell transplantation involves removing and replacing stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments harm growing cells as well as cancer cells, and so the healthy stem cells must be replaced by transplanting them from the donor into the patient.

Sources of Cells. Stem cells must first be collected in one of the following ways:

Directly from blood, called peripheral blood stem cell transplantation
From bone marrow, called bone marrow transplantation
From umbilical cords or placentas -- this procedure uses donor cells, but has a lower risk for immune system rejection of the cells than with a standard donor transplant. It takes longer to restore blood cells with this process, so it is generally used for children and sometimes adults with low weight.

Some evidence suggests that both stem cell and bone marrow procedures produce similar benefits in terms of response rates and duration of remission. However, in one study, stem cell transplantation was associated with better overall survival rates. It also seems to be superior in terms of cost, quality of life, and the need for less supportive care.

Donor or Patient Cells. The marrow or blood stem cells can be taken from the patient (autologous) or from a matched donor (allogeneic):

In an autologous transplant, the marrow or blood cells used for replacement are taken from the patient. There is some danger, however, that these cells may contain tumor cells, and that the cancer can regrow. It is unclear if this approach improves survival compared to standard chemotherapy for newly diagnosed disease. However, it clearly has benefits in the treatment of some forms of relapsed non-Hodgkin's lymphomas. There is also a higher risk for leukemia. (This risk is lower in peripheral stem cells transplants than in bone marrow transplants.)
In an allogeneic transplant, bone marrow or stem cells are taken from a donor. Siblings are the best donors. Relapse rates can be very low with this approach, and cure may be possible in some cases. However, it is highly toxic and donor and recipient must be matched as closely as possible to avoid rejection by the immune system, a serious complication called graft-versus-host disease. Advances in techniques are reducing the toxicities associated with this approach. Older patients who cannot tolerate the preparatory treatment required for a standard allogeneic transplant may be able to receive a non-myeloblative transplant (“mini-transplant), which uses lower doses of chemotherapy and radiation.

The Blood Stem Cell Collection Procedure. With peripheral blood stem cell transplantation:

The donor is usually given a drug called granulocyte colony-stimulating factor, or G-CSF (filgrastim, lenograstim, pegfilgrastim) to stimulate stem cell growth.
The patient (or donor in an allogeneic procedure) then undergoes apheresis. With this process the blood is withdrawn from one of the patient's veins, then passes through a machine that filters out the white cells and platelets, which contain the stem cells. The blood is returned through another vein. The entire procedure takes 3 - 4 hours but needs to be repeated several times.
The stem cells are treated to remove contaminants and then are frozen to keep them alive until the patient is ready to receive them back.

Blood is the only fluid tissue in the body. Blood transports oxygen and nutrients to body tissues, and returns waste and carbon dioxide. Blood distributes nearly everything that is carried from one area in the body to another place within the body. For instance, blood helps transport hormones from the endocrine organs to their target organs. Blood also helps maintain body temperature. The protective functions of blood include clot formation and the prevention of infection.

Allogeneic transplants are preceded by chemotherapy treatment known as conditioning. The point of this treatment is to inactivate the immune system and to kill any residual malignant cells. It is extremely toxic since it also destroys non-malignant marrow cells. Drugs used are typically cyclophosphamide, carmustine, and etoposide. Alternative conditioning to reduce toxicity includes total-body radiation plus drugs. Monoclonal antibodies, such as rituximab, are promising drugs, since they have low toxicity and may add benefits for all stages of transplantation.
A few days after treatment, the patient given the stored stem cells, which are administered through a vein. This may take several hours. Patients may have a fever, chills, hives, shortness of breath, or a fall in blood pressure during the procedure.
The patient may be treated with granulocyte colony-stimulating factor after chemotherapy. The goal is to stimulate the growth of infection-fighting white blood cells. Adding thrombopoietin may help enhance stem cell production.
The patient is kept in a protected environment to minimize infection. Patients who have received an allogeneic transplant may need blood cell replacement, nutritional support, and drugs to treat graft-versus host disease. They usually can leave the hospital within 3 - 5 weeks.

Candidates. These procedures are typically used for patients with relapsed aggressive lymphoma who are still sensitive to the effects of chemotherapy. The procedures do not work for patients whose tumors are not responsive to drugs. Some evidence suggests that certain primary (non-relapsed) lymphomas initially unresponsive to a first round of chemotherapy but who respond to a second round may benefit from combination of high-dose chemotherapy and radiation followed by transplantation. Transplantation is also being investigated as first-line therapy for patients with aggressive lymphomas, although at this time evidence does not support its use.

Success Rates. Success rates vary depending on many factors. The following are survival rates reported by a few studies of patients with different lymphomas:

In patients with refractory or relapsed intermediate grade NHL who received autologous transplantation, 5-year survival rates averaged 34%.
In a study of allogeneic bone marrow transplantation, 58% of patients with late-stage low-grade lymphoma had survived after an average of 29 months.
Patients with anaplastic large-cell lymphoma were treated with autologous stem cell transplantation with intensified chemotherapy as first line-therapy. Survival rates were 87% at 5 and more years afterward. (Survival was much lower with other lymphomas.)
Patients with diffuse aggressive NHL who did not achieve a first remission but who are still sensitive to chemotherapy achieved a 5-year survival rate of up to 37% after autologous stem cell transplantation.
In one study, 35% of patients with an initial poor prognosis were still alive 5 years after an allogeneic stem cell transplantation, although mortality probability from the treatment itself was very high (48%).

Common side effects include nausea, vomiting, fatigue, mouth sores, and loss of appetite.

The procedures themselves are fairly dangerous and carry a small risk for death. When it was first used, transplantation procedures had 10 - 25% morality rates. Now mortality rates are below 5%.

It is very important that patients take precautions to avoid infections. Guidelines for post-transplant infection prevention include:

Discuss with your doctor what vaccinations you need and when you should get them.
Avoid crowds, especially during cold and flu season.
Be diligent about handwashing and make sure that visitors wash their hands.
Avoid eating raw fruits and vegetables -- food should be well cooked. Do not eat foods purchased at salad bars or buffets. In the first few months after the transplant, be sure to eat protein-rich foods to help restore muscle mass and repair cell damage caused by chemotherapy and radiation.
Boil tap water before drinking it.
Dental hygiene is very important, including daily brushing and flossing. Schedule regular visits with your dentist.
Do not sleep with pets. Avoid contact with pets’ excrement.
Avoid fresh flowers and plants as they may carry mold. Do not garden.
Swimming may increase exposure to infection. If you swim, do not submerge your face in water. Do not use hot tubs.
Report to your doctor any symptoms of fever, chills, cough, difficulty breathing, rash or changes in skin, and severe diarrhea or vomiting. Fever is one of the first signs of infection. Some of these symptoms can also indicate graft-versus-host disease.
Report to your ophthalmologist any signs of eye discharge or changes in vision. Patients who undergo radiation or who are on long-term steroid therapy have an increased risk for cataracts.

Graft-versus-host disease (GVHD) is a serious attack by the patient's immune system triggered by the donated new marrow in allogeneic transplants. Mild cases of GVHD can actually be helpful as they can cause graft-versus-lymphoma where the immune system kills remaining lymphoma cells. Still, severe GVHD can pose serious complications.

To reduce the risk for GVHD, doctors remove some immune T-cells from the donor’s stem cells before the transplant. Researchers are investigating new techniques to refine this process of T-cell depletion.

Too much sun exposure can trigger GVHD. Be sure to always wear sunscreen (SPF 15 or higher) on areas of the skin that are exposed to the sun. Stay in the shade when you go outside.

Secondary cancers. There is a small long-term risk for leukemia after transplantation in young people. Use of newer chemotherapeutic drugs, however, may not pose as high a danger as older treatments.

Other potentially serious complications include:

Bleeding because of reduced platelets (highest risk within the first 4 weeks); blood transfusions may be required
Infertility
Organ complications to the liver, heart, kidney, or lungs
Failure of the transplant
Muscle problems including stiffness, cramps, and joint pain
Frequent urination and bladder control problems
Older patients should be screened for osteoporosis (bone thinning) and hypothyroidism (underactive thyroid)

Surgery

Surgery is sometimes used to remove as much malignant tissue as possible before administering chemotherapy. This is particularly useful for bulky tumors that occur in the stomach.

Surgery is sometimes performed for primary gastric lymphoma, but its advantages are uncertain. Some studies indicate that chemotherapy alone or with radiation may be sufficient and could spare many patients from surgery.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.leukemia.org -- The Leukemia and Lymphoma Society
www.canceradvocacy.org -- National Coalition for Cancer Survivorship
www.marrow.org -- National Marrow Donor Program
www.asco.org -- American Society of Clinical Oncology
www.lymphoma.org -- Lymphoma Research Foundation
www.plwc.org -- People Living with Cancer
www.oncolink.org -- Cancer information
www.fhcrc.org/science/clinical/ltfu/patient -- Fred Hutchinson Cancer Research Center -- Transplant Infection Guidelines for Patients
www.lymphomainfo.net -- Lymphoma Information Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Boffetta P, de Vocht F. Occupation and the risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007: 16(3):369-72.

Ferrara JL. Novel strategies for the treatment and diagnosis of graft-versus-host-disease. Best Pract Res Clin Haematol. 2007. 20(1):91-7.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphoma. V.3.2007.

Seam P, Juweid ME, Cheson BD. The role of FDG-PET scans in patients with lymphoma. Blood. 2007 Nov 15;110(10):3507-16. Epub 2007 Aug 20.

A.D.A.M. Copyright

adam.com

Asthma in children and adolescents

FitSugar — Wed, 08 Oct 2008 17:35:28 -0700

In This Report

Highlights
Introduction
Causes
Prognosis
Risk Factors
Symptoms
Diagnosis
Treatment
Quick-Relief Medications...
Long-Term Relief Medication...
Other Treatments
Managing Asthma
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

In 2007, the FDA requested the manufacturers of omalizumab (Xolair) to include a “boxed warning” emphasizing that this drug may cause a severe and life-threatening allergic reaction (anaphylaxis). Health care providers need to carefully observe patients for 2 hours after they receive an omalizumab injection. However, because an allergic reaction can occur up to 24 hours after the injection, patients need to know the signs and symptoms of anaphylaxis and how to self-administer emergency treatment. Omalizumab is approved for patients ages 12 and older who have moderate-to-severe asthma related to allergies.

Drug Approval

In 2006, budesonide/formoterol (Symbicort) was approved for patients age 12 years and older. Symbicort combines a corticosteroid and a long-acting beta2-agonist into a single inhaler.

Inhaled Corticosteroids

Inhaled corticosteroids may help reduce wheezing in young children with breathing problems, but they do not help prevent the development of asthma, according to several 2006 studies in the New England Journal of Medicine.
Inhaled corticosteroids work better than a corticosteroid/long-acting beta2-agonist combination or a leukotrine receptor antagonist drug in treating children with mild-to-moderate asthma, suggests a 2007 study in the Journal of Allergy and Clinical Immunology.

Long-Acting Beta2-Agonists

Long-acting beta2-agonist drugs such as salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer) may worsen asthma symptom severity and increase the risk for asthma-related death, indicates a 2006 review in the Annals of Internal Medicine.
Products that contain salmeterol and formoterol now have strengthened warning labels detailing these risks.

Childhood Asthma Statistics

Asthma death rates among children have largely declined since 1999 while doctors’ office visits for asthma treatment have more than doubled, indicates a recent report from the U.S. Centers for Disease Control and Prevention.

Introduction

The word asthma originates from an ancient Greek word meaning panting. Essentially, asthma is an inability to breathe properly. When any person inhales, the air travels through the following structures:

Air passes into the lungs and flows through progressively smaller airways called bronchioles. The lungs contain millions of these airways.
All bronchioles lead to alveoli, which are microscopic sacs where oxygen and carbon dioxide are exchanged.

The major features of the lungs include the bronchi, the bronchioles, and the alveoli. The alveoli are the microscopic blood vessel-lined sacks in which oxygen and carbon dioxide gas are exchanged.

Asthma is a chronic condition in which these airways undergo changes when stimulated by allergens or other environmental triggers. Such changes appear to be two specific responses:

The hyperreactive response (also called hyperresponsiveness)
The inflammatory response

These actions in the airway cause patients to cough, wheeze, and experience shortness of breath (dyspnea), the classic symptoms of asthma.

In the hyperreactive response, smooth muscles in the airways constrict and narrow excessively in response to inhaled allergens or other irritants. Airways in everyone's lungs respond by constricting when exposed to allergens or irritants but there are major differences in the hyperreactive response that occurs in people with asthma:

When people without asthma breathe in and out deeply, the airways relax and open in order to rid the lungs of the irritant.
When people with asthma try to take those same deep breaths, their airways do not relax but instead narrow, causing the patients to pant for breath. Smooth muscles in the airways of people with asthma may have a defect, perhaps a deficiency in a critical chemical that prevents the muscles from relaxing.

The hyperreactive stage is followed by the inflammatory response, which generally contributes to asthma in the following way:

The immune system responds to allergens or other environmental triggers by delivering white blood cells and other immune factors to the airways.
These so-called inflammatory factors cause the airways to swell, fill with fluid, and produce a thick sticky mucus.

Click the icon to see an image of a normal versus asthmatic bronchiole.

This combination of events results in wheezing, breathlessness, inability to exhale properly, and a phlegm-producing cough.

Inflammation appears to be present in the lungs of all patients with asthma, even those with mild cases, and plays a key role in all forms of the disease.

Causes

Asthma occurs in about 5 million American children. Each year about 200,000 of them are hospitalized. It is the most common chronic childhood illness. About half of all cases of asthma develop before the age of 10, and about 80% of patients develop symptoms before they are 5 years old.

The mechanisms that cause asthma are complex and vary among population groups and even individuals. For example, asthma in children is highly associated with allergies. However, only a minority of children with allergies have asthma, and allergic response cannot explain all cases of asthma. Other factors, such as genetics or environmental conditions are probably involved in the development of asthma. Most likely, several genes combine to make a child susceptible to environmental triggers, not only allergens but also possibly infections, dietary patterns, or air pollution. Physical factors, particularly having smaller lungs, affect the chances for later asthma.

Asthma and allergies often coexist, and the allergic response plays a strong role in childhood asthma. About 70 - 85% of children with asthma also have allergies. Some studies suggest that children who have allergies are also at greater risk for developing asthma as adults. A 2006 study found that children who are allergic to dust mites are three times more likely to later develop asthma than children who were not allergic.

However, the evidence is clearly mixed. Several other 2006 studies suggested that avoiding dust mites does not help prevent asthma and, in fact, early exposure to dust mites may even protect children from developing asthma and allergic responses. Some experts think that giving immunotherapy (“allergy shots”) to children with allergies may help prevent asthma development.

An asthma attack can be induced or aggravated by direct irritants to the lungs. Studies indicate that the more indoor allergens a child is allergic to, the higher the risk for severe asthma. Important irritants or allergens include the following:

Dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. These are the primary allergens in the home.
Animal dander. Cats harbor significant allergens, which can even be carried on clothing; dogs usually present fewer problems.
Molds.
Cockroaches. Cockroaches are major asthma triggers and may reduce lung function even in people without a history of asthma.
Pollen. An asthma attack from an allergic response to pollen is more likely to occur during extreme air changes, such as thunderstorms. Major weather changes, such as El Nino, can affect the timing of allergy seasons because they cause seasonal changes (and pollen) to start earlier.
Food allergies. About 8 - 10% of children with asthma also have food allergies. These children also appear to have a high risk for very serious reactions to such foods. In infants and toddlers, allergy to eggs appears to be a predictor of asthma.
Fossil Fuels. Certain chemicals may trigger allergic rhinitis. Some experts believe that refined fossil fuels, such as diesel fuel and particularly kerosene, may be important triggers for allergic rhinitis. In people who already have allergies or asthma, exposure to such fossil fuels may worsen symptoms.

The Allergic Response. The allergic process, called atopy, and its connection to asthma are not completely understood. It involves various airborne allergens or other triggers that set off a cascade of events in the immune system leading to inflammation and hyperreactivity in the airways. One description is as follows:

The conductor in an orchestra of immune factors that contribute to allergies and asthma appears to be a category of white blood cells known as helper T cells, in particular a subgroup called Th2 cells.
Th2 cells overproduce interleukins (ILs), immune factors that are molecular members of a family called cytokines, which are involved in the inflammatory process.
Interleukins 4, 9, and 13, for example, may be responsible for a first-phase asthma attack. These interleukins stimulate the production and release of antibody groups known as immunoglobulin E (IgE). (People with both asthma and allergies appear to have a genetic predisposition for overproducing IgE.)
During an allergic attack, these IgE antibodies can bind to special cells in the immune system called mast cells, which are generally concentrated in the lungs, skin, and mucous membranes. This bond triggers the release of a number of active chemicals, importantly potent molecules known as leukotrienes. These chemicals cause airway spasms, overproduce mucus, and activate nerve endings in the airway lining.
Another cytokine, interleukin 5, appears to contribute to a late-phase inflammatory response. This interleukin attracts white blood cells known as eosinophils. These cells accumulate and remain in the airways after the first attack. They persist for weeks and mediate the release of other damaging particles that remain in the airways.

Researchers are investigating the role that T cells play in asthma. T cells are white blood cells that are involved in the immune response. Researchers had focused on the T cell called type 2 helper (ThH2) cells. However, a 2006 breakthrough study in the New England Journal of Medicine suggested that a different type of T cell may play a stronger role in asthma than previously thought.

Researchers discovered that these cells, called natural killer T cells, are far more common in the lungs of people with asthma than in the lungs of healthy people. Natural killer T cells are very rare, but researchers found them in 60% of people with moderate-to-severe persistent asthma. While this research is preliminary, it may explain why corticosteroid drugs do not work well for some patients with asthma: Steroid drugs target Th2 and other inflammatory cells, not natural killer T cells. Researchers think that further investigation of natural killer T cells may lead the way to new types of asthma drugs. If these cells prove to be involved in asthma, then drugs that eliminate them might become an important new treatment.

Over the course of years the repetition of the inflammatory events involved in asthma can cause irreversible structural and functional changes in the airways, a process called remodeling. The remodeled airways are persistently narrow and can cause chronic asthma. Researchers are trying to determine how this process occurs:

Interleukins. Some researchers are looking at potent immune factors, including interleukins 11 and 13. They have been linked to a number of processes possibly involved in remodeling, including scarring in the airways and overgrowth of cells in the smooth muscles that line the airways.

Growth Factors. Compounds known as vascular endothelial growth factor (VEGF) have been observed in the airways of patients with asthma. VEGF is a powerful promoter of cell growth in blood vessel linings and some researchers believe it may be major factor in remodeling.

About one-third of all persons with asthma share this condition with another member of their immediate family. Asthma may be more likely to be passed to children from the mother than from the father. Both allergies and asthma are strongly associated with hereditary factors, sharing certain genetic markers, but they are not always inherited together.

Research on the genetics of these conditions is confusing. Of some significant promise, researchers have identified a gene (ADAM33), which has been linked to asthma. The gene regulates one of the enzymes called metalloproteases, which are involved with the smooth muscle in the airway. A mutation of this gene could play a role in airway changes that occur after inflammation.

The role of early childhood respiratory and intestinal infections is very complex. Viral respiratory infections certainly worsen existing asthma, but the most common ones are unlikely to be causes of childhood asthma. In fact, early respiratory and intestinal infections may offer some protection against asthma.

Early Respiratory Infections as Causes of Asthma. Studies suggest that most respiratory infections are not important causes of asthma in children, except in certain cases. An important exception is the respiratory syncytial virus (RSV), which has been implicated in the development of asthma. RSV is the major viral cause of infant pneumonia. Studies also indicate that infants who have reduced lung function within a few days after birth are at increased risk of developing asthma by the time they are 10 years old.

Common Respiratory Infections Worsen Asthma. Common respiratory infections viruses that cause colds (such as the rhinovirus) may in some cases be associated with the development of asthma. A 2007 study suggested that children who have a wheezing rhinovirus during infancy are at increased risk for developing asthma by age 6. Even if these viruses do not directly cause asthma, they can worsen asthma in children who already have it. Rhinovirus has been reported to be the most common infection associated with asthma attacks. In one study, it was associated with 61% of asthma worsening in children. Some research suggests that colds promote inflammation in patients with existing asthma and increase the intensity of airway responsiveness for weeks.

The Hygiene Theory: Early Infections as Protection Against Asthma. Another blames the dramatic increase in asthma on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. The basic theory rests on the idea that infections stimulate production of specific immune factors called Th1 cells. As these cells build up, they replace other immune factors called Th2 cells, which react to allergens -- a less serious threat to the body. Without infections to stimulate the production of the Th1 infection fighters, the Th2 allergen fighters are not replaced, and they persist at high levels, making the growing child more susceptible to allergies and asthma.

A number of different studies support this theory:

Some studies suggest that being part of a large family or attending day care increases the risk for early respiratory infections but reduces the risk of childhood asthma. The occasional cold, then, may be protective.
In one study, researchers measured levels of bacterial byproducts called endotoxins in the mattress dust of 812 children. Those with the highest levels had 80% lower rates in allergies and asthma.
Another study further found a strong association between allergy development and the absence of certain beneficial bacteria (called probiotics) carried in the infant's intestines. Infants who were born in more hygienic environments tended to lack these bacteria. Antibiotic overuse and modern hygiene may be reducing these helpful organisms. (Probiotics can be obtained in active yogurt cultures and in supplements, which are being studied for protection.)

The standard vaccinations against serious childhood infections, according to several important studies, pose no risk for asthma. One of the studies even reported some lower risk for asthma and allergies in the second and third years after vaccinations. Infections killed thousands of children every year before immunization became widespread. Asthma, although serious, is rarely fatal in children. No one should stop giving their children vaccinations against childhood killers.

GERD. At least half of patients with asthma also have gastroesophageal reflux disease (GERD), the cause of heartburn. It is not entirely clear which condition causes the other or whether they are both due to common factors.

Heartburn is a condition where the acidic stomach contents back up into the esophagus causing pain in the chest area. This reflux usually occurs because the sphincter muscle between the esophagus and stomach is weakened. Standing or sitting after a meal can help reduce the reflux which causes heartburn. Continuous irritation of the esophagus lining as in gastroesophageal reflux disease is a risk factor for the development of adenocarcinoma.

Some theories for the causal connection between GERD and asthma are:

Acid leaking from the lower esophagus in GERD stimulates the vagus nerve, which runs through the gastrointestinal tract. This stimulated nerve, in turn, triggers the nearby airways in the lung to constrict, causing asthma symptoms.
Acid back-up that reaches the mouth may be inhaled into the airways (aspirated). Here, the acid triggers a reaction in the airways that cause asthma symptoms.

GERD is sometimes hard to detect and might be suspected as a contributor in the following patients:

Those who do not respond to asthma treatments.
Those whose asthma attacks follow episodes of heartburn.
Those whose attacks are worse after eating or exercise.
Those whose coughs follow episodes of acid reflux. (One study found that GERD was associated with about half of the episodes of coughs and wheezes in patients with asthma.)

Treating GERD symptoms with anti-acid drugs may resolve asthma in some (but not all) patients who share both conditions. A small 2005 observational study found that while GERD was common in patients with asthma, treatment of GERD had no effect on asthma symptoms. [See In-Depth Report #85: Heartburn and gastroesophageal reflux disease.]

Sinusitis. Almost half of children and adults with allergic asthma have sinus abnormalities, and in various studies, between 17 - 30% of patients with asthma develop true sinusitis. The presence of sinusitis, however, does not appear to increase the severity of asthma.

Click the icon to see an image of sinusitis.

Parental Migraines and Childhood Asthma. Some studies have reported a link between childhood asthma and parental migraines, with one small study suggesting that children are about five times more likely to develop asthma if their parents have a history of migraines.

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath.

About 10% of adults and some fewer children have aspirin-induced asthma (AIA). With this condition, asthma gets worse when patients take aspirin. Aspirin is one of the drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs). Although aspirin is used to reduce inflammation in other disorders, it appears to have the opposite effect in many asthma cases. It is not wholly known why this occurs. AIA often develops after a viral infection. It is a particularly severe asthmatic condition and is associated with up to 25% of asthma-related hospitalizations. In about 5% of cases, aspirin is responsible for a syndrome that involves multiple attacks of asthma, sinusitis, and nasal congestion. Such patients also often have polyps (small benign growths) in the nasal passages.

Patients with aspirin-induced asthma (AIA) should avoid aspirin and most likely NSAIDs, including ibuprofen (Advil) and naproxen (Aleve).

Acetaminophen (Tylenol) has been the traditional alternative for relief of minor pain for patients who are aspirin-sensitive. Unfortunately, recent evidence has muddied these recommendations. Moreover, some asthmatic episodes have been linked to high consumption of acetaminophen among adults. And a study of children with asthma reported that those who took ibuprofen were less likely to be hospitalized for asthma than those taking acetaminophen. This is of particular concern, since acetaminophen is the pain reliever of choice in small children.

Asthma occurs primarily at night (nocturnal asthma) in as many as 75% of patients with the condition. Attacks often occur between 2 - 4 a.m. Factors that might play role in nocturnal asthma may include one or more of the following:

Chemical and temperature changes in the body during the night that increase inflammation and narrowing of the airways
Delayed allergic responses from exposure to allergens during the day
The wearing off of inhaled medications toward the early morning
An increase in acid reflux (back up of stomach acid) that causes airways to narrow
Postnasal drip that occurs during sleep
Conditions relating to sleep, such as sleep apnea or sleeping on one's back, which may worsen any asthma attack that occurs at night

Some experts believe that nocturnal asthma may actually be a unique form of asthma with its own specific biologic mechanisms that occur only at night and which reduce natural steroid hormones (which block inflammation).

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath. This condition generally occurs in children and young adults, most often during intense exercise in cold dry air. Symptoms are generally most intense about 10 minutes after exercising and then gradually resolve.

EIA is triggered only by exercise and is distinct from ordinary allergic asthma in that it does not produce a long duration of airway activity, as allergic asthma does. (However, some people have both forms of asthma.) People who have only EIA do not appear to require long-term maintenance therapy. A study of military recruits with EIA also reported that the condition does not hinder a person's overall physical performance.

Medications. Cromolyn, a mild anti-inflammatory drug, or short-acting beta2-agonists have been the treatments of choice for preventing EIA. Newer approaches for people who work out regularly include pretreatment with long-acting beta2-agonists, such as salmeterol (Serevent) or the regular use of inhaled corticosteroids.

Hints for Reducing EIA. EIA occurs only after exercise and is more likely to occur with regular paced activities in cold, dry air. The following are some suggestions for reducing its impact:

Warm-up and cool-down periods are important.
Patients with EIA might do better with activities that involve short bursts of exercise (tennis, football) than with exercises involving long-duration regular pacing (cycling, soccer, and distance running).
Breathing through a scarf or through the nose helps warm up the airways.
Restricting dietary salt might help reduce EIA.

Click the icon to see an image of exercise-induced asthma.

Prognosis

Asthma is the third major cause of hospitalization in children under age 15. The condition can be very serious in children, particularly those younger than age 5, because their airways are very narrow.

The severity of asthma is graded as mild intermittent and mild, moderate, and severe persistent. A patient in any of these categories, even mild intermittent, can still experience a severe and even life-threatening attack. According to one report, 30% of asthma deaths occur in patients with mild asthma.

Asthma is rarely fatal in children, with only 187 asthma deaths reported in 2002 in children under age 18. In fact, a 2006 study from the U.S. Centers for Disease Control and Prevention reported that asthma death rates for children have steadily declined since 1999. (During the same time, the number of doctor visits for asthma treatment more than doubled.) Even low mortality numbers are unacceptable, however, since asthma deaths are largely preventable.

Factors associated with an increased risk of death from asthma in children include:

Previous life-threatening episodes of asthma
Lack of adequate and ongoing health care. (Most likely the reason for the higher fatalities rates in minority children.)
Significant behavioral problems
Underestimating the severity of an acute attack poses the greatest threat. Unfortunately, one study of children found that nearly 40% of them were unaware of asthmatic symptoms when they occurred.

African American children have more than six times the death rate of Caucasians in the age groups of 4 years and younger and 15 - 24 years. Hispanic children also have a higher risk.

The following signs and symptoms may indicate a life-threatening situation:

As the chest labors to bring enough air into the lungs, breathing often becomes shallow.
Lacking sufficient oxygen, the skin becomes bluish.
The flesh around the ribs of the chest appears to be sucked in.
The patient may begin to lose consciousness.

Asthma often progresses very slowly to a serious condition or may develop to a fatal or near-fatal attack within a few minutes. It is very difficult to predict when an attack will become very serious. Early symptoms or lack thereof do not always reflect the ultimate severity of an attack. Some studies even suggest that people at high risk for fatal or near-fatal asthma attacks are those with poor awareness of their own reduced ability to breathe and who are slow in seeking help. Monitoring peak flow rates is, therefore, an important management component, since it provides a more accurate assessment of lung function than symptoms alone.

In a 2003 study, researchers followed people with asthma for longer than 30 years. About a third of children had outgrown their asthma in adulthood. In general, the more severe the childhood asthma, the greater the likelihood that it will persist. For example, only 23% of children who experienced wheezy bronchitis (wheezing during respiratory infections) suffered from frequent or persistent asthma in adulthood.

There is evidence that severe asthma can cause long-lasting damage and possibly permanent scarring in some patients. The risk for such injury is highest, however, when asthma strikes children in the first 3 - 5 years. There does not appear to be any significant risk for long-term lung damage for children who develop mild-to-moderate persistent asthma between ages 5 - 12. Children adapt well to living with asthma, and even with severe asthma they can function as well as healthy children in virtually all areas of life.

Studies are mixed over the effects of emotional disorders on the severity of asthma. One study indicated that parents of children with asthma may suffer greater psychological stress than their children. A 2000 study reported that mild-to-moderate asthma does not significantly affect the psychological well-being of most children ages 5 - 12. Teenagers and preteens may have particular difficulty coping with what they perceive as the social stigma of asthma. Parents and older children should not hesitate to seek help from support groups, doctors, friends, or family members. Support programs may help children to better manage their asthma and even reduce hospitalization.

Although there have been few studies on the effects of asthma on schooling, a 2000 study reported that nocturnal (nighttime) asthma affected school attendance and performance in children and work attendance in their parents.

Risk Factors

Asthma affects about 5 million American children between the ages of 5 - 14. Asthma has dramatically increased worldwide over the last few decades, in both developed and developing countries. From 1980 - 1994, asthma increased 160% in American children younger than 4 years and has also dramatically risen worldwide. Experts are puzzling over the cause of this phenomenon. Possible causes and risk factors that are suspects in the dramatic rise in asthma in children include:

Survival rates are now higher in low-birth-weight babies, who may be more susceptible to asthma.
Declining rates in nursing may be a contributor. Breast milk contains important anti-inflammatory substances, such as omega-3 fatty acids, which might protect against asthma.
Western dietary habits (which commonly include more fast foods and less fruits, vegetables, fiber, minerals, and other nutrients) may contribute to the development of childhood asthma.
Children are spending more time indoors watching television, playing video games, or using the computer and are, therefore, overexposed to indoor allergens.
The trend of making homes more energy-efficient may result in dust mites being trapped inside them.

Among younger children, asthma develops twice as frequently in boys as in girls, but after puberty it may be more common in girls.

Urban Life. Urban life is strongly associated with a higher risk. Although poverty plays a significant role, urban life has been associated with a higher risk for asthma in any income group and among both children and adults. In some urban areas, as many as 25% of children have asthma or show signs of wheezing. In fact, it may be greatly underdiagnosed in city children. A 1999 study reported that almost a third of children in inner-city kindergartens had asthma symptoms without a diagnosis of the disorder; 10% had actually been diagnosed with asthma, mainly because their symptoms were severe.

Ethnicity. Since 1980, asthma rates have risen the most dramatically among African American children, and they have significantly higher rates of asthma than Caucasian children. Hispanic children are also at higher risk. Both groups of minority children are more likely to have fatal asthma than Caucasian children.

Some studies indicate that the difference in risk exists simply because African Americans and other minority groups are more likely to live in urban areas. Poverty and lack of access to health care also play a role. However, Caucasian children who live in cities also face a high risk for asthma, and rural African American children do not.

Urban life and socioeconomic factors, however, may not fully explain the ethnic disparity.

Low Birth Weight. Infants of low birth weight are at higher risk for lung problems and asthma.

Winter Birth. Children born in the winter may have a greater risk for asthmatic allergies to cockroaches than children born at other times of the year.

Vitamin D. A 2006 study suggested a link between vitamin D intake during pregnancy and development of early childhood asthma. Pregnant women who had a higher intake of vitamin D were less likely to give birth to children who developed asthma.

Breast Feeding. Most studies on breastfeeding report some protection against wheezing and asthma in the first year of life. Breastfeeding has many other benefits for the child as well. The American Academy of Pediatrics recommends exclusively breastfeeding for the child's first 6 months of life.

Complications of Pregnancy. According to a 2000 study, complications of pregnancy, specifically those involving the mother's uterus (such as post-birth hemorrhage, pre-term contractions, insufficient placenta, and restricted growth of the uterus), are associated with an increased risk of childhood asthma. Another study reported that delivery procedures such as Cesarean section, the use of vacuum extraction or forceps also raised the risk of childhood asthma.

In both adults and children, the incidence of obesity and asthma has been increasing over recent years. Studies report a strong association between the two conditions. Some experts suggest that excess weight pressing on the lungs may trigger the hyperreactive response in the airways typical of asthma. Others believe that asthma leads to obesity by inhibiting physical activity, although several studies have found no difference in activity levels between people with or without asthma. Some studies suggest that many obese people may be misdiagnosed as having asthma when they are simply short of breath, possibly because of the increased effort required for breathing.

In any case, there is evidence that losing weight can relieve asthma symptoms. Some evidence also suggests that people who are overweight (body mass index greater than 25) have more difficulty getting their asthma under control. Weight loss in anyone who is obese and has asthma or shortness of breath reduces airway obstruction and improves lung function. [See In-Depth Report #53: Weight control and diet.].

Damp Homes. Studies suggest that children who live in damp homes have a much higher risk for asthma.

Mental Health. Research indicates that poor mental health of parents and children are significant predictors of more severe symptoms in childhood asthma. A 2000 study suggested that high stress levels can predict the onset and severity of asthma in children genetically at risk for the condition.

Symptoms

In children with asthmatic symptoms, it is important to first consider as a possible cause inhaled foreign objects such as peanuts; viral infections such as croup; and bacterial infections, which may be accompanied by high fever and progress rapidly. Any child who has frequent coughing or respiratory infections should be checked for asthma.

The classic symptoms of an asthma attack include:

Wheezing when breathing out is nearly always present during an attack. Usually the attack begins with wheezing and rapid breathing, and, as it becomes more severe, all breathing muscles become visibly active.
Shortness of breath (dyspnea). Shortness of breath is a major source of distress in patients with asthma, although severe dyspnea does not always reflect a serious attack or reduced lung function.
Coughing. In some people, the first symptom of asthma is a nonproductive cough.
Chest tightness or pain. Initial chest tightness without any other symptoms may be an early indicator of a serious attack.
Neck muscles may tighten, and talking may become difficult or impossible.
Rapid heart rate
Sweating
Chest pain occurs in about 75% of patients. It can be very severe, although its intensity is not necessarily related to the severity of the asthma attack itself.

The end of an attack is often marked by a cough that produces thick, stringy mucus. After an initial acute attack, inflammation persists for days to weeks, often without symptoms. (The inflammation itself must still be treated, however, because it usually causes relapse.)

Diagnosis

The doctor will consider a diagnosis of asthma if a child has a history of periodic attacks of shortness of breath, coughing, and wheezing, perhaps accompanied by tightness in the chest. The parent should describe the pattern of symptoms and possible precipitating factors, including:

Whether symptoms are more frequent during the spring or fall (allergy seasons)
Whether exercise, a respiratory infection, or exposure to cold air has ever triggered an attack
Any family history of asthma or allergic disorders such as eczema, hives, or hay fever

A number of disorders may cause some or all of the symptoms of asthma. Panic disorder can coincide with asthma or be confused with it. Other diseases that must be considered during diagnosis are pneumonia, bronchitis, severe allergic reactions, psychosomatic illnesses, and certain rare disorders (such as tapeworm and trichomoniasis).

If symptoms and a patient's history are indicative of asthma, the doctor will usually perform tests known as pulmonary function tests to confirm the diagnosis and determine the severity of the disease.

Using a spirometer, an instrument that measures the air taken into and exhaled from the lungs, the doctor will determine several values:

Vital capacity (VC), which is the maximum volume of air that can be inhaled or exhaled.
Peak expiratory flow rate (PEFR), commonly called the peak flow rate, which is the maximum flow rate that can be generated during a forced exhalation.
Forced expiratory volume (FEV1), the maximum volume of air expired in 1 second.

If the airways are obstructed, these measurements will fall. Depending on the results, the doctor will take the following steps:

If measurements fall, the doctor typically asks the patient to inhale a bronchodilator. This drug is used in asthma to open the air passages. The measurements are taken again. If the measurements are more normal, the drug has most likely cleared the airways, and a diagnosis of asthma is strongly suspected.
If measurement results fail to show airway obstruction, but asthma is still suspected, the doctor may perform a challenge test. It involves administering a specific drug (histamine or methacholine) that usually increases airway resistance only when asthma is present.

The patient may be given skin or blood allergy tests, particularly if a specific allergen is suspected and available for testing. Allergy skin tests may be the best predictive test for allergic asthma, although they are not recommended for people with year-round asthma.

One of the most common methods of allergy testing is the scratch test or skin prick test. The test involves placing a small amount of the suspected allergy-causing substance (allergen) on the skin (usually the forearm, upper arm, or the back), and then scratching or pricking the skin so that the allergen is introduced under the skin surface. The skin is observed closely for signs of a reaction, which usually includes swelling and redness of the site. With this test, several suspected allergens can be tested at the same time, and results are usually available within about 20 minutes.

Tests that either rule out other diseases or obtain more information about the causes of asthma include the following:

A complete blood count
Chest and sinus x-rays
Computed tomography (CT) scans. CT scans may be helpful in certain cases, such as for determining wall thickness in airways in patients who are difficult to treat, which could signify a higher risk for lung damage.
Examination of the patient's sputum for eosinophils (white blood cells that in high levels are associated with severe allergic asthma).
Researchers are investigating measurements of certain chemicals in sputum or exhaled air that indicate airway inflammation. Such chemical markers include nitric oxide and hydrogen peroxide. For example, high levels of nitric oxide may prove to be a simple and noninvasive way of diagnosing asthma.

Treatment

Treating an Acute Attack in the Hospital. An acute attack may require hospitalization. Laboratory tests, an electrocardiogram (ECG), and a chest x-ray are performed to determine lung function, oxygen levels, and other indications of severity or rule out other causes. Depending on the results, the following treatments may be given:

Beta2-agonists are the standard therapy. They are typically administered with a nebulizer (a device that administers the drug in a fine spray). Studies suggest, however, that even very small children may be able to use metered-dose inhalers (MDIs), which are just as effective and more convenient than nebulizers. (Intravenous delivery is not recommended in most cases.)
An anticholinergic drug (ipratropium) is sometimes added to improve symptoms.
A corticosteroid (commonly called a steroid) given within the first hour helps reduce the need for hospitalization. Steroids may be administered intravenously, as a shot, or orally. Children may respond well to oral steroids.
Oxygen is usually administered, and can be life saving in severe cases.
Infusions of magnesium sulfate open airways and are an important emergency treatment for adults. Its benefits for children need to be further demonstrated.
In life-threatening situations, the patient may require mechanical ventilation.

Antibiotics are not useful for asthma attacks if there is no strong evidence of the presence of a bacterial infection. Viral infections, most often colds and the flu, are more likely to trigger an asthma attack. In such cases, antibiotics are not helpful and may have adverse effects.

Discharge and Relapse After Hospitalization. It typically takes about 3 - 4 hours to determine if a patient can be safely sent home or if they need to stay. Patients are generally discharged when:

Symptoms are gone or minimal, and
The peak expiratory flow rate is 70% or more of the predicted rate

Despite reasonable precautions, between 12 - 16% of patients relapse within 2 weeks of leaving the hospital. Receiving a steroid shot at discharge or taking an oral corticosteroid for a few days can reduce this risk.

Avoiding allergens, following appropriate drug treatments, and home monitoring are key elements in preventing dangerous asthma attacks and hospitalization. In addition, good communication between the doctor and patient is a key factor in a successful management program.

Medications for asthma fall into two categories:

Rescue Medications. Medications that open the airways (bronchodilators, or inhalers) are used to quickly relieve any moderate or severe asthma attack. These drugs are usually short-acting beta-adrenergic agonists (beta2-agonists). Other drugs used in special cases include corticosteroids taken by mouth and anticholinergic drugs. None of these drugs have any effect on the disease process itself. They are only useful for treating symptoms.
Maintenance Medications. Simply coping with asthma symptoms without also controlling the damaging inflammatory response is a common and serious error. For adults and children over age 5 with moderate-to-severe persistent asthma, experts now recommend inhaled corticosteroids and long-acting beta2-agonists.

Parents can greatly reduce the frequency and severity of their children’s asthma attacks by understanding the difference between coping with asthma attacks and controlling the disease over time. Unfortunately, many patients do not understand the difference between medications that provide rapid, short-term relief and those that are used for long-term symptom control. Many patients with moderate or severe asthma overuse their short-term medications and underuse their corticosteroid medications. The overuse of bronchodilators can have serious consequences; not using steroids can lead to permanent lung damage.

Patients need to understand that asthma symptoms can change quickly over time and that treatment strategies may need to change in response. In 2005, the two leading U.S. allergy associations published joint guidelines on controlling asthma. The guidelines emphasize that asthma treatment decisions need to be made on an individual basis. It is important that patients have a close relationship with their doctor. The doctor needs to evaluate a patient’s asthma symptoms at each visit to determine any need for changes in medication. According to the guidelines, asthma management is classified as either “well-controlled” or “not well-controlled.” The doctor may need to change some medications, or increase or decrease the dosage, depending on whether a child’s asthma is well-controlled or not well-controlled.

These are the signs of well-controlled asthma:

Asthma symptoms occur twice a week or less
Rescue bronchodilator medication is used twice a week or less
Symptoms do not cause nighttime or early morning awakening
Symptoms do not limit work, school, or exercise activities
Peak flow meter readings are normal or the patient’s personal best
Both the doctor and the patient consider the asthma to be well controlled


Classification	Symptom Frequency	Children Age 5 Years and Younger: Recommended Treatment	Children Older Than 5 Years: Recommended Treatment
Mild intermittent	At least 2 days per week. At least 2 nights per month.	No daily medication.	No daily medication. If severe attacks occur, systemic corticosteroids recommended.
Mild Persistent	More than 2 days per week, but less than once per day. More than 2 nights per month.	Preferred treatment: Low-dose inhaled corticosteroids with nebulizer, or MDI with holding chamber with or without face mask. Alternative treatment: Cromolyn or leukotriene-antagonist.	Preferred treatment: Low-dose corticosteroids. Alternative treatment: Cromolyn, leukotriene modifier, nedocromil, OR sustained release theophylline.
Moderate Persistent	Daily daytime symptoms. More than 1 night per week.	Preferred treatment: Low-dose inhaled corticosteroids and long-acting beta2-agonists OR medium-dose inhaled corticosteroids. Alternative treatment: Low-dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline. If needed (especially if severe attacks occur): Medium-dose inhaled corticosteroids and long-acting beta2-agonists; medium-dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline.	Preferred treatment: Low-to-medium dose inhaled corticosteroids and long-acting beta2-agonists. Alternative treatment: Low-to-medium dose inhaled corticosteroids and either leukotriene receptor antagonist or theophylline, or increased medium dose inhaled corticosteroids. If needed (especially if severe attacks occur): Increase dosage of medium-dose inhaled corticosteroids with add-on long-acting beta2-agonists. Alternatively, increase dosage of medium-dose inhaled corticosteroids plus either leukotriene receptor antagonist or theophylline.
Severe Persistent	Continual daytime symptoms. Frequent nighttime symptoms.	Preferred treatment: High-dose inhaled corticosteroids and long-acting beta2-agonists plus (if needed) oral corticosteroids.	Preferred treatment: High-dose inhaled corticosteroids combined with long-acting inhaled beta2-agonists. Add, if needed: Oral corticosteroids. Repeat attempts should be made to reduce use of systemic corticosteroid and maintain control with inhaled corticosteroid.
Adapted from National Asthma Education and Prevention Program (NAEPP) Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma – Update on Selected Topics 2002 (EPR-2 Update).

Most asthma drugs are inhaled using various forms of inhalers or nebulizers. Inhaled drugs must be used regularly as prescribed and the patient carefully trained in their use in order for them to be effective and safe. Studies suggest that many children fail to use the devices properly, although newer devices are easier to use than others. The basic devices are the metered-dose inhaler (MDI), breath-actuated inhalers, dry powder inhalers, and nebulizers.

MDIs have used chlorofluorocarbons (CFCs) as their propellants. CFCs are damaging to the environment and are now being replaced with other propellants (hydrofluoroalkane) that are more environmentally safe, and do not chill the device as CFCs do. Devices that don't use any propellants are also now available.

Metered-Dose Inhaler. The standard device for administering any asthma medication is the metered-dose inhaler (MDI). This device, particularly when used with a spacer, allows precise doses to be delivered directly to the lungs. (The spacer is a tube that is attached to the inhaler. It serves as a holding chamber for the medication that is sprayed by the inhaler.) MDI-delivered drugs must be used regularly as prescribed and the patient carefully trained in their use in order for them to be effective and safe. Some patients hold the MDI too close to their mouths, or even inside them. Others may exhale too forcefully before inhalation.

The spacer helps improve medication delivery by allowing the patient additional time to inhale. They vary, however, in their effectiveness. It should be noted that MDIs can continue to deliver propellant even after the drug has been used up. Patients should track their medicine and throw the device away when the last dose has been administered.

Nebulizers (not MDIs) are typically used in very small children, both at home and in the emergency room. However, recent studies suggest spacers may be better than nebulizers for children and shorten the time spent in emergency rooms. Studies also indicate that with the use of a face mask and a spacer, the MDI works well even for infants in the emergency room and may prove to be useable at home.

Click the icon to see an illustrated series detailing a metered dose inhaler.

Breath-Actuated Inhalers. Breath-actuated rotary inhalers (Easi-Breathe and Autohaler) deliver the drug directly to the back of the throat as the user inhales. Their primary advantage over the MDI is their ease of use. They also do not use CFCs as propellants. In comparison studies, patients have been very successful with the breath-actuated inhalers. They are not recommended for children under 8 years old.

Dry Powder Inhalers. Dry powder inhalers (DPIs) deliver a powdered form of beta2-agonists or corticosteroids directly into the lungs. Such devices include Rotahaler, Spinhaler, Turbohaler, Clickhaler, Easyhaler, Diskhaler, Discus, Twisthaler, Spiros, and others. DPIs are as effective as the older devices, and generally have a better taste and are easier to manage. They may differ among themselves, however, in their ability to deliver drugs into the airways. In one study, for example, the Turbohaler was easier to use than the Diskhaler and so achieved better delivery.

Humidity or extreme temperatures can affect DPIs' performance, so they should not be stored in humid places (bathroom cabinets) or locations subject to high temperatures (glove compartments during summer months).

Dry-powder may cause tooth erosion. Children are advised to rinse their mouths out right after using these inhalers and to brush twice a day with a fluoride toothpaste.

Other Hand-Held Inhalers. Respimat delivers a fine-mist spray that is created by forcing the liquid medication through nozzles. It does not use any propellant.

Nebulizers. A nebulizer is a machine that delivers a fine spray of medication-containing liquid. Nebulizers are often used for children younger than 3 years and sometimes for older children who have difficulty using the MDI. It takes 5 - 10 minutes to administer medication using a nebulizer. Because the spray is less targeted than with the inhaler, it must deliver large amounts of the drug. This increases the risk for toxicity and severe side effects. Nebulizers should not be used by children who can manage an inhaler. Their use has been associated with a higher rate of hospitalizations and longer duration of symptoms than inhalers. A 2007 study also suggested that the misuse of home nebulizers may be an important factor in asthma deaths in children and young adults. If children must use an albuterol nebulizer, parents should be sure that it does not contain the preservative benzalkonium, which actually narrows the airways.

Click the icon to see an illustrated series detailing the use of a nebulizer.

Asthma triggers a vicious emotional-physical cycle:

Breathlessness and wheezing incite a fear of suffocation and death, even in very small children.
This anxiety produces further constriction on the muscles surrounding the airways, which makes breathing even more difficult.

Caregivers must first focus on alleviating their own anxiety, which can heighten a child's own fears. The next step is to help the child relax. One method for this is as follows:

The child sits comfortably, bending slight forward with the eyes closed.
The hands are placed gently over the navel.
The child is then told to pretend the stomach is a balloon.
The "balloon" must be "blown up" by inhalation, not exhalation. The child can tell if this working because the hands will move slightly apart.
When the child breathes out, the "balloon" will be made flat.

This exercise both relaxes the child and discourages shallow, oxygen-poor breathing. Massaging the child in gentle circles on the chest is relaxing and may also loosen mucus.

Other recommendations include:

A child may also find relief by lying stomach-down on several pillows so that the head is slightly lower than the chest while the caregiver gently pats the back between the shoulder blades.
Warm liquids, such as soup or hot cider, are effective in loosening mucus and may also relax bronchial muscles. Cold fluids, like cold air, should be avoided.
Overhydration (too much liquid) can be harmful, however, so these drinks should not be forced on the child.
Warm, moist air from vaporizers can greatly ease and moderate asthma attacks.
Daily massages and breathing and relaxation techniques to reduce stress can be very helpful.

Many adults self-manage their asthma using daily monitoring of peak air flow with adjustments of the medications as needed. This involves the use of a peak flow meter, which measures peak expiratory flow rate (PEFR).

Click the icon to see an image of a peak flow meter.

Studies suggest, however, that for most children with asthma, an educational program is just as effective for managing the condition as monitoring. Most children do not need to monitor their peak air flow on any regular basis.

Quick-Relief Medications

These medications quickly control acute asthma attacks.

Beta2-agonists do not reduce inflammation or airway responsiveness but serve as bronchodilators, relaxing and opening constricted airways during an acute asthma attack. A short-acting inhaled beta2-agonist, taken as needed, is often the only medication used by children with chronic mild asthma.

Asthma is a disease in which inflammation of the airways causes airflow into and out of the lungs to be restricted. When an asthma attack occurs, mucus production is increased, muscles of the bronchial tree become tight, and the lining of the air passages swells, reducing airflow and producing the characteristic wheezing sound.

Specific short-acting beta2-agonists include:

Albuterol (Proventil, Ventolin), called salbutamol outside the U.S., is the standard short-acting beta2-agonist in America. Other similar beta2-agonists are isoproterenol (Isuprel, Norisodrine, Medihaler-Iso), metaproterenol (Alupent, Metaprel), pirbuterol (Maxair), terbutaline (Brethine, Brethaire, Bricanyl), and bitolterol (Tornalate). Isoetharine (Bronkometer, Bronkosol) is available in nebulizers.
Newer beta2-agonists, including levalbuterol (Xopenex), have more specific actions than the standard drugs. Xopenex is administered with a nebulizer, and studies have indicated that it is as effective as albuterol with fewer side effects. The original formulation of Xopenex was administered with a nebulizer. A new metered-dose inhaler formulation was launched at the end of 2005. It is approved for children age 4 years and older.

Short-acting bronchodilators are generally administered through inhalation and are effective for 3 - 6 hours. They relieve the symptoms of acute attacks, but they do not control the underlying inflammation. If asthma continues to worsen with the use of these drugs, a doctor may prescribe corticosteroids or other drugs to treat underlying inflammation.

Side Effects of Beta2-Agonists. Side effects of all beta2-agonists may include:

Anxiety
Tremor
Restlessness
Headache
Fast and irregular heartbeats. A doctor should be notified immediately if this side effect occurs.
These drugs should be taken with caution by children with diabetes or a history of seizures.
Beta2-agonists have serious interactions with certain drugs and parents should tell the doctor about any other medications their child is taking.

Loss of Effectiveness and Overdose. There has been some concern that short-acting beta2-agonists become less effective when taken regularly over time, increasing the risk for overuse. Over time, some patients may become tolerant to many effects of short-acting beta2-agonists. The degree to which this affects the airways is uncertain. In some studies, the duration of action has declined but the peak effect appears to be preserved, making these drugs still useful for acute attacks. Regular use of long-acting beta2-agonists may increase the chances of a reduced effect from the short-acting forms.

A 2005 landmark study suggested that patients’ differing clinical response to albuterol may be based on their genotype. Albuterol targets the beta-adrenergic receptor. In the Beta-Adrenergic Response by Genotype (BARGE) trial, researchers studied the effects of albuterol on patients with two different forms of this receptor. The results suggested that patients with the arginine form of the receptor did not respond to albuterol. These patients’ asthma symptoms actually improved when albuterol was not used. By contrast, patients with the glycine form of the receptor had improved asthma control with albuterol.

Inhaled ipratropium bromide (Atrovent) acts as a bronchodilator over time. Ipratropium bromide alone is only modestly beneficial for acute asthma attacks. In fact, the drug is not approved specifically for asthma. Some parents report benefit for treating wheezing in infants. It is also sometimes used in the emergency room to treat children with severe asthma to enhance the effects of intravenous beta2-agonists.

Common oral corticosteroids include prednisone/prednisolone, dexamethasone, methylprednisolone, and hydrocortisone. They reduce inflammation very effectively. A 2006 study indicated that oral prednisolone worked better than inhaled fluticasone for treating mild-to-moderate asthma attacks in children in emergency rooms. However, children often have difficulty taking these drugs because they have a bitter taste and can cause vomiting. Taking oral dexamethasone for 2 days may be as effective and more tolerable than the standard 5-day regimen of prednisone/prednisolone. Prolonged use of oral steroids has widespread and sometimes serious side effects, so they are not generally give to children for longer than a few days.

[See In-Depth Report #4: Asthma in adults.]

Long-Term Relief Medications

These medications are taken on a regular basis to prevent asthma attacks and control chronic symptoms.

Corticosteroids, also called glucocorticoids or steroids, are powerful anti-inflammatory drugs. Steroids are not bronchodilators (they do not relax the airways) and have little effect on symptoms. Instead, they work over time to reduce inflammation and prevent permanent injury in the lungs. They can also help prevent asthma attacks from occurring. Many studies have shown that the use of inhaled corticosteroids in patients with moderate-to-severe asthma significantly reduces the rate of rehospitalizations and deaths from asthma.

Inhalation of corticosteroids makes it possible to provide effective local anti-inflammatory activity in the lungs with minimal systemic effects. (By contrast, oral steroids have considerable side effects throughout the body.) Inhaled corticosteroids are recommended as the primary therapy under the following circumstances:

For any asthmatic condition more serious than occasional episodes of mild asthma. (Low-doses of inhaled steroids may even be safe and effective for some people with mild asthma, particularly those who find themselves using beta2-agonists daily.)
When treatment with bronchodilators is not effective.

Examples of inhaled corticosteroids:

Inhaled steroids include fluticasone (Flovent), budesonide (Pulmicort), triamcinolone (Azmacort and others), and flunisolide (AeroBid). In general, the newer drugs are more powerful than the older generation of inhaled drugs. Budesonide (Pulmicort Respules) is available in a jet nebulizer for children from 12 months to 8 years. It is the first such medication to be approved for children in this age group.
The FDA approved a new inhaled corticosteroid, mometasone furoate (Asmanex) was approved in 2005 for patients age 12 and older.
The older corticosteroid inhalants are beclomethasone (Beclovent, Vanceril) and dexamethasone (Decadron Phosphate Respihaler and others). They are less powerful than the newer steroids when delivered with standard inhalers. New inhalers that use very fine sprays (QVAR, Autohaler) to deliver the drugs deep into the lungs may prove to be as effective as the newer, more potent steroids.
Inhalers that combine both long-acting beta2-agonists and corticosteroids are also available. These include Symbicort (budesonide/formoterol), which was approved in 2006 for patients ages 12 years and older.

Expert guidelines recommend inhaled corticosteroids as the preferred first-line therapy for children with mild-to-moderate asthma. Nevertheless, they are still significantly underprescribed in the patients who need them most. An important 2007 study of 6 - 14 year old children with asthma compared inhaled corticosteroid therapy (fluticasone) with an inhaled corticosteroid/long-term beta2 agonist (fluticasone/salmeterol) and a leukotrine receptor antagonist (montelukast). The results indicated that fluticasone alone worked better than the other two treatments.

Researchers have been investigating whether early treatment with corticosteroids can help prevent the development of asthma in at-risk children. Two important 2006 studies in the New England Journal of Medicine suggested that while inhaled corticosteroids helped ease symptoms and reduce breathing problems in pre-school children at risk for asthma, they did not help protect against asthma development.

For now, experts caution against corticosteroids for infants and toddlers with mild asthma and urge close monitoring especially for children under age 5 with severe asthma who are receiving high doses. Because the newer potent drugs, particularly fluticasone, may produce major side effects similar to oral steroids, it is important when treating all children to aim for the lowest effective dose possible. Fortunately, studies suggest that low doses of fluticasone may achieve the same benefits as with high ones, thus reducing risks for serious side effects. Better delivery methods may also allow lower doses.

Side effects of inhaled steroids may include:

The most common side effects are throat irritation, hoarseness, and dry mouth. These effects can be minimized or prevented by using a spacer device and rinsing the mouth after each treatment.
Rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising are also possible but not common with inhalators.
Some children experience changes in mood, memory, and behavior. These changes are not permanent.
Some studies have suggested a higher risk for gum inflammation.
Oral steroids reduce bone density. Research reports that inhaled steroids -- both older and newer drugs -- may also affect bone growth and density. However, a number of studies report only a slight effect (about half an inch) on children's growth, which may be only temporary. It is still unknown if these drugs have any significant long-term effect on bone density. Calcium supplements may help prevent bone loss that is due to inhaled steroids.
It is not yet known whether inhaled steroids affect lung growth in very young children. Steroids administered using nebulizers are of particular concern.
There is also some concern that the stronger drugs, particularly fluticasone, suppress the adrenal system to a greater degree than other steroid inhalants. This effect, in turn, reduces levels of natural steroids -- notably cortisol, the major stress hormone. (This is a serious side effect of oral steroids).

Long-acting beta2-agonists are used in combination with inhaled corticosteroids for treating children with moderate-to-severe asthma. These drugs include include salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer). A single inhaler (Advair Diskus) that combines both salmeterol and the corticosteroid fluticasone is available for children age 4 years and older, and an inhaler (Symbicort) combining formoterol and the corticosteroid budesonide is approved for children age 12 years and older.

Long-acting beta2-agonists are used for preventing an asthma attack (not for treating attack symptoms). The effects of one dose of a long-acting beta2-agonist last for about 12 hours, so they are particularly effective during the night. These drugs also may be used for prevention of exercise-induced asthma in people and to protect against aspirin-induced asthma.

However, research indicates that long-acting beta2-agonists can worsen asthma by increasing symptom severity. These drugs may also increase the risk for asthma-related deaths. Experts are still trying to determine when long-acting beta2-agonists should be added to an asthma treatment plan. If a child’s symptoms do not improve or if symptoms worsen with this type of drug, the doctor will recommend discontinuing it. Patients should not, however, stop taking this drug or other asthma medications without first talking with their doctors.

Side Effects. Side effects of long-acting beta2-agonists are similar to the short-acting drugs.

Specific Warning on Salmeterol and Formoterol. In 2003 a "black box" warning was added to product packaging for drugs that contain salmeterol, including Serevent Diskus, and Advair Diskus. Serevent and Advair are approved for patients age 12 years and older. The warning was based on a study that demonstrated more serious and even fatal asthma episodes in patients who used the drug than in patients who used a placebo.

In 2006, the FDA updated the warning to include formoterol (Foradil Aerolizer, approved for patients 5 years and older). Warnings for salmeterol and formoterol products emphasize that these medicines can increase the risk of severe asthma episodes. Long-acting beta2-agonists require up to 20 minutes to achieve effectiveness, and there is a danger of overdose if a patient is not aware of this delay and takes additional doses to achieve faster relief. The FDA recommends that patients:

Use long-acting beta2-agonists only if other medicines (such as steroids) have not helped control asthma.
Use a short-acting bronchodilator, not a long-acting beta2-agonist, to treat sudden wheezing.
Do not use long-acting beta2-agonists to treat wheezing that is getting worse. Call your doctor if this situation occurs.
Do not stop using any asthma medicines without first talking to your doctor.

Cromolyn sodium (Intal) is both an anti-inflammatory drug and has antihistamine properties that block asthma triggers such as allergens, cold, or exercise. Cromolyn has been the anti-inflammatory drug of choice for prevention of asthma attacks in children over age 4 with chronic moderate asthma. It is not as effective as inhaled corticosteroids, however, for reducing hospitalization rates, improving symptoms, and reducing the use of beta2-agonists in children with persistent asthma. Still, cromolyn has a well-known long-term safety record, while the long-term adverse effects of corticosteroids in children are still not fully known. Many children who need asthma maintenance therapy will still do well on cromolyn. (It may not provide any real benefit for children under age 4.)

Nedocromil (Tilade) is similar to cromolyn and needs to be taken only once a day. It also prevents asthmatic reactions to cold and exercise. It is not used in very young children. A cromolyn nasal spray called Nasalcrom has been approved for over-the-counter purchase, but only to relieve nasal congestion caused by allergies. Patients should not use it for self-medication without the advice of a doctor.

Side Effects. Side effects of cromolyn include nasal congestion, coughing, sneezing, wheezing, nausea, nosebleeds, and dry throat. Nedocromil has an unpleasant taste, and some people have complained of nausea, headache, and spasms in the airways, but no serious side effects have been reported.

Leukotriene-antagonists (also called anti-leukotrienes or leukotriene modifiers) are oral medications that block leukotrienes. Leukotrienes are powerful immune system factors that, in excess, produce a battery of damaging chemicals that can cause inflammation and spasms in the airways of people with asthma. As with other anti-inflammatory drugs, leukotrienes are used for prevention and not for treating acute asthma attacks.

Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). These drugs are proving helpful for long-term prevention of asthma, including exercise-induced asthma and aspirin (or NSAID) -induced asthma. However, most studies to date have reported better success with inhaled corticosteroids than with the leukotriene-antagonists. A 2006 study of children with mild-to-moderate persistent asthma indicated that the corticosteroid fluticasone worked better than the leukotriene-antagonist montelukast in controlling symptoms. Nevertheless, some studies suggest that montelukast, which comes in a chewable tablet, may be particularly useful for managing asthma in small children (ages 2 - 5), since they have trouble with inhaled steroids.

Side Effects and Complications. Gastrointestinal distress is the most common side effect of leukotriene-antagonists. Very few other side effects have been reported. In general, these drugs appear to be safe and well-tolerated.

Of some concern are reports of Churg-Strauss syndrome in a few people taking zafirlukast or montelukast. Churg-Strauss syndrome is very rare, but it causes blood vessel inflammation in the lungs and can be life threatening. Oral steroids quickly resolve the problem. In fact, usually the syndrome has occurred in patients who were tapering off steroids and changing over to the leukotriene-antagonists. Some experts believe that, in such cases, the steroids may simply have masked the presence of the disorder, which then developed when the steroid drugs were withdrawn. Symptoms include severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

Other concerns are indications of liver injury in patients taking zileuton and zafirlukast when taken at higher than standard doses. No adverse effects on the liver have been reported to date with montelukast.

Theophylline (Theo-Dur, Theolair, Slo-Phyllin, Slo-bid, Constant-T, Respbid) is a mild-to-moderate bronchodilator that has been used to treat childhood asthma for more than 30 years. It is useful for treating nocturnal asthma and may also have anti-inflammatory qualities even in low doses.

Available in tablet, liquid, and injectable forms, some theophylline sustained-release tablets and capsules have a long duration of action and can therefore be taken once or twice a day with good results.

Side effects may include changes in behavior, mood, and memory. If theophylline is not taken exactly as prescribed, an overdose can easily occur. Toxicity can cause nausea, vomiting, headache, insomnia, and, in rare cases, disturbances in heart rhythm and convulsions. Contact a doctor immediately if any of these side effects occur.

The risks for these adverse effects are small if the drug is taken exactly as prescribed but the following precautions should be noted:

Infants tend to metabolize the drug extremely slowly and, therefore, should receive very low doses.
By the time children reach age 1, however, they metabolize the drug faster than adults. There is a risk, therefore, of toxic effects.
Fever and certain antibiotics may slow down the rate at which theophylline is eliminated from the body. In such cases, the doctor may want to reduce the dosage of theophylline.

If a child is taking theophylline on an ongoing basis, the doctor should monitor the drug level at the start of therapy and at regular intervals thereafter.

Omalizumab (Xolair) is FDA-approved for patients age 12 and older who have moderate-to-severe persistent asthma related to allergies. The first drug of this type to be approved for asthma, omalizumab is a monoclonal antibody (MAb), a genetically developed drug designed to attack very specific targets. Omalizumab is administered by injection every 2 - 4 weeks. It is used only to treat patients whose symptoms are not controlled by inhaled corticosteroids.

Omalizumab prevents the antibody immunoglobulin E (IgE) from triggering the inflammatory events that lead to asthmatic attacks. Studies have shown excellent benefits of the drug, including a reduced need for corticosteroids, fewer hospitalizations, and significant symptomatic improvements.

However, about 1 in 1,000 patients who take omalizumab develop anaphylaxis (a life-threatening allergic reaction). In 2007 the FDA requested the manufacturers of omalizumab to put a “boxed warning” on the medicine’s label emphasizing the drug’s risk for anaphylaxis. The boxed warning notes that patients can develop anaphylaxis after any dose of omalizumab, even if they had no reaction to a first dose. Anaphylaxis may occur up to 24 hours after the dose is given.

The FDA recommends that healthcare providers observe patients for at least 2 hours after an injection. Patients should also carry emergency self-treatment for anaphylaxis (such as an Epi-Pen) and know how to administer it. With an Epi-Pen, or similar auto-injector device, patients can quickly give themselves a life-saving dose of epinephrine.

Anaphylaxis symptoms include:

Difficulty breathing
Chest tightness
Dizziness
Fainting
Itching and hives
Swelling of the mouth and throat

[See In-Depth Report #4: Asthma in adults.]

Other Treatments

Alternative therapies are widely used by children, adolescents, and adults with asthma. In one study, nearly half of asthma or allergy sufferers resorted to alternative treatments. To date, however, evidence does not support most alternative therapies, including high-dose vitamins, urine injections, homeopathic remedies, and most herbal remedies.

Relaxation and Stress-Reduction Techniques. Patients report benefits from many stress reduction and physical techniques, such as acupuncture, hypnosis, breathing relaxation techniques, the Alexander technique, massage therapy, and meditation practices. There have been very few well-conducted studies supporting their use, however.

Acupuncture, hypnosis, and biofeedback are alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Breathing Exercises. Some studies have suggested that breathing exercises or training may be helpful. A number of different methods are available. One example is the Buteyko breathing method, an experimental approach designed to increase levels of carbon dioxide in the body. To do this, patients are trained to reduce their volume of breath and to avoid hyperventilation (over-breathing). Some studies report that patients using this method reduce their use of medications and improve their quality of life. The system originated in Australia and is not yet widely available in the U.S.

Probiotics. Probiotics are beneficial bacteria that may possibly help protect against allergies and asthma. Antibiotic overuse and modern hygiene may specifically be reducing these helpful organisms. Look for probiotics in active yogurt cultures and in supplements, which are being studied for protection.

Herbal Remedies. Butterbur (also known as Petasites hybridus, butter dock, blatterdock, bog rhubarb, and exwort), is a traditional herbal remedy used for seasonal allergies and asthma. In a 2002 study, it was as effective and less sedating than a commonly prescribed antihistamine for treating seasonal allergies over a 2-week period. However, little research exists on its effect on asthma. Overall, there is scant evidence supporting the benefits of herbs and nutritional supplements for asthma control.

Managing Asthma

The more allergies a child has, the more severe the asthma. Making lifestyle changes to reduce allergy attacks and other triggers is extremely important.

House dust is a reservoir for pollen and dust mites. Some experts believe that reducing household allergens and pollutants in the home could reduce asthma in children by 40%.

Controlling for Dust. Spray furniture polish is very effective for reducing both dust and allergens. Air cleaners, filters for air conditioners, and vacuum cleaners with High Efficiency Particular Air (HEPA) filters can help remove particles and small allergens found indoors. Neither vacuuming nor the use of anti-mite carpet shampoo, however, is effective in removing mites in house dust. Vacuuming actually stirs up both mites and cat allergens. If possible, avoid carpets and rugs.

Click the icon to see an image of a HEPA air filter.

Bedding and Curtains. Many experts recommend reducing exposure to dust mites by enclosing mattresses and pillows in semipermeable coverings. (Vinyl mattress covers limit airflow and may also worsen, or even cause, asthma in children. Synthetic pillows may pose a significantly higher risk for severe asthma attacks in children than feather or no pillows.) However, several 2005 studies suggested that such covers do not prevent asthma or allergies. Replace curtains with shades or blinds, and wash bedding using the highest temperature setting.

Click the icon to see an image of dust mite prevention.

One study found that children sleeping in bottom bunk beds are significantly more likely to develop asthma than siblings occupying the upper bunks. Families with children who have asthma or allergies should avoid bunk beds or be sure that children with asthma sleep in the top bunk. Even with standard beds, it may be useful to have them sleep as high off the floor as possible.

Exterminating Pests (Cockroaches and Mice). Use professional exterminators to eliminate cockroaches. (One study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves.) Exterminate mice, and attempt to remove all dust, which might contain mouse urine and dander.

Reducing Humidity in the House. Although warm, moist air from vaporizers can greatly ease and moderate asthma attacks, living in a damp house is counterproductive. Dust mites thrive in humidity and damp houses increase the risk for mold, so on-going humidifiers can be unhelpful. If they are used, humidity levels should not exceed 40%, and humidifier should be cleaned daily with a vinegar solution.

Controlling Pets. People with asthma who already have pets and are not allergic to them probably have a low risk for developing such allergies later on. When children are exposed to more than one dog or cat during their first year, they have a much lower risk for allergies and asthma.

For children who have an existing allergy to pets, however, the pets should be given away or kept outside. If this isn't possible, they should at least be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens, which can even be carried on clothing; dogs usually present fewer problems. Washing animals once a week can reduce allergens. Dry shampoos, such as Allerpet, are now available for both cats and dogs to remove allergens from skin and fur and are easier to administer than wet shampoos.

Many of the same substances trigger both allergies and asthma. Common allergens include pollen, dust mites, mold and pet dander. Other asthma triggers include irritants like smoke, pollution, fumes, cleaning chemicals, and sprays. Asthma symptoms can be substantially reduced by avoiding exposure to known allergens and respiratory irritants.

Preventing Exposure to Cigarette and Cooking Smoke. Parents who smoke are strongly urged to quit. Studies indicate that exposure to second-hand smoke in the home increases the risk for asthma and asthma-related emergency room visits in children. Even smoky cooking can worsen asthma.

Parental smoking has been shown to increase the airway responsiveness of infants as early as the first 2 - 10 weeks of life. This extends even to the fetus of pregnant women who smoke. Such mothers tend to have babies born at a low birth weight, which affects lung function and increases babies' risks for asthma.

Avoiding Outdoor Allergens. The following are some recommendations for avoiding allergens outside:

Avoid scheduling camping and hiking trips during times of high pollen count (generally, May and June for grass pollen and mid-August to October for ragweed).
Patients should avoid strenuous activity when ozone levels are highest, which usually occur in early afternoon, particularly on hot hazy summer days. Levels are lowest in early morning and at dusk.
Asthma attacks are often higher during thunderstorms. Some evidence points to a build-up of ozone that accompanies such storms. Other evidence suggests that the changing airflow patterns bring a sudden downdraft of air containing concentrations of pollens, small particles and allergens.
Patients who are allergic to mold should avoid barns, hay, raking leaves, and mowing grass.
Exposure to automobile fumes may worsen asthma. Fungi in car air conditioners can also be a problem.

Reducing Exposure to Air Pollution. Children breathe faster than adults, taking in more pollutants, and therefore are particularly susceptible to soot and other small particles in the air. A 2001 study found an association between higher rates of asthma and other health problems in children who were exposed to high levels of specific pollutants (particularly sulfur dioxide and nitrogen dioxide). Diesel fuel exhaust has also been associated with worsening asthma in children.

Some experts point out that asthma rates in North America have increased over recent years while the prevalence of many common air pollutants have declined. So pollution is unlikely to be a primary cause of asthma. Regardless of whether pollution is an important cause of asthma, evidence strongly suggests that it can affect existing asthma.

Patients with asthma and chronic allergic rhinitis may require daily medications. Patients with severe seasonal allergies may be advised to start medications a few weeks before the pollen season, and to continue it until the season is over.

Immunotherapy ("allergy shots") may help reduce asthma symptoms, and the use of asthma medications, in patients with known allergies. They may also help prevent the development of asthma in children with allergies. Immunotherapy poses some risk for severe allergic reactions, especially for children with poorly controlled asthma, so it is important that the doctor carefully evaluates the child’s asthma condition.

[See In-Depth Report #77: Allergic rhinitis.]

Weight Loss. Children who are both asthmatic and overweight may reduce asthma symptoms simply with weight loss.

Fruits, Vegetables, and Whole Grains. Healthy foods are important for lung function. Specific foods that may be important for healthy lungs contain antioxidants (deep green and yellow-orange fruits and vegetables), selenium (fish, red meat, grains, eggs, chicken, liver, garlic), plant chemicals called flavonoids (apples, onions), and magnesium (green leafy vegetables, nuts, whole grains, milk, and meats).

Fish Oil. Omega-3 fatty acids, found in cold water oily fish and in supplements (preferably DHA-EPA, the important compounds in fish oil) have anti-inflammatory effects. Some evidence suggests they may be helpful for people with asthma.

Caffeine. Caffeine has properties that are similar to the asthma drug theophylline. A major analysis of studies reported that caffeine improved lung function for up to 4 hours after consumption. Although tea and coffee are the major sources of caffeine, some sodas contain it and should be avoided when children have an asthma attack. (People who are going to have their lung function tested should avoid drinking coffee, tea, or other caffeinated beverages for at least 4 hours beforehand.)

Food Allergies. Although about 70% of people with asthma believe their symptoms are aggravated by food allergies, studies indicate that this belief may be true in only 5% of cases. If young children show signs of or test positive for food allergies, however, parents should be extra cautious in preventing exposure to any asthma trigger. Some doctors now counsel all children with asthma to avoid nuts entirely, and, of course, children who experience reactions to any foods should avoid them.

Chemicals that may pose some risk for an allergic reaction are monosodium glutamate, or MSG (found in some canned soups, cheese, and certain vegetables), and sulfites (preservatives in foods, such as frozen potatoes and tuna). Contrary to what many believe, dairy products do not appear to worsen asthma symptoms in people who are not already allergic to them.

Asthma is no reason to avoid exercise. Historically, about 10% of Olympic athletes have asthma. Some studies indicate that long-term exercise may help control asthma and reduce hospitalization.

Encourage children with asthma to swim and play sports, such as baseball, that will present less difficulty for them. Intense activities lasting less than 2 minutes, such as sprinting or competitive swimming, may cause fewer problems than longer-lasting exercises.

Young people who enjoy running should probably choose an indoor track to avoid pollutants. Swimming is excellent for people with asthma. Yoga practice, which uses both stretching, breathing, and meditation techniques, may have particular benefits. One study reported that two-thirds of patients who practiced yoga regularly were able to reduce or stop taking their asthma medications.

Patients should consult their doctors before starting any exercise program. Exercise-induced asthma is a limited condition that has specific recommendations.

People with asthma should try to minimize their risk for respiratory tract infections. Washing hands is a very simple but effective preventive measure.

Patients with asthma should ask their doctor about getting the influenza ("flu") vaccine and also whether they should receive the vaccination against pneumococcal pneumonia.

Zanamivir, a new drug used for treating influenza, is considered safe for patients with asthma 12 years of age or older. In one study, patients with asthma treated with zanamivir experienced fewer flu symptoms, and their lung function improved.

People with asthma have no higher rate of anxiety or depression than the general population. However, such emotions interact with the effects of asthma and its treatments in important ways:

Negative emotions can discourage compliance with medication and the ability to cope.
Poor control of asthma symptoms, in turn, increases the risk for negative emotions.
Stress and depression have been associated with more severe symptoms and even an increased risk of fatal asthma attacks.

Some evidence suggests that stress reduction techniques, a positive attitude, and relaxation techniques may be very helpful in the long-term management of asthma.

Resources

www.lungusa.org -- The American Lung Association
www.acaai.org -- American College of Allergy, Asthma & Immunology
www.aaaai.org -- American Academy of Allergy, Asthma, and Immunology
www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
www.asthma-carenet.org -- Childhood Asthma Research and Education Network
www.njc.org -- National Jewish Center for Immunology and Respiratory Medicine
www.aafa.org -- Asthma and Allergy Foundation of America
www.aanma.org -- Allergy and Asthma Network, Mothers of Asthmatics

References

Akinbami L; Centers for Disease Control and Prevention National Center forHealth Statistics. The state of childhood asthma, United States, 1980-2005. Adv Data. 2006 Dec 12;(381):1-24.

Bisgaard H, Hermansen MN, Loland L, Halkjaer LB, Buchvald F. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med. 2006 May 11;354(19):1998-2005.

Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for beta-agonist treatment of acute asthma. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD000052.

Douwes J, van Strien R, Doekes G, Smit J, Kerkhof M, Gerritsen J, et al. Does early indoor microbial exposure reduce the risk of asthma? The Prevention and Incidence of Asthma and Mite Allergy birth cohort study. J Allergy Clin Immunol. 2006 May;117(5):1067-73.

Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006 May 11;354(19):1985-97.

Haland G, Carlsen KC, Sandvik L, Devulapalli CS, Munthe-Kaas MC, Pettersen M, et al. Reduced lung function at birth and the risk of asthma at 10 years of age. N Engl J Med. 2006 Oct 19;355(16):1682-9.

Marks GB, Mihrshahi S, Kemp AS, Tovey ER, Webb K, Almqvist C, et al. Prevention of asthma during the first 5 years of life: a randomized controlled trial. J Allergy Clin Immunol. 2006 Jul;118(1):53-61.

National Asthma Education and Prevention Program Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics -- 2002. Rockville, MD. National Heart, Lung, and Blood Institute, US Dept of Health and Human Services; 2003. NIH publications 02-5074.

O'Byrne PM, Pedersen S, Busse WW, Tan WC, Chen YZ, Ohlsson SV, et al. Effects of early intervention with inhaled budesonide on lung function in newly diagnosed asthma. Chest. 2006 Jun;129(6):1478-85.

Salpeter SR, Buckley NS, Ormiston TM, Salpeter EE. Meta-analysis: effect of long-acting beta-agonists on severe asthma exacerbations and asthma-related deaths. Ann Intern Med. 2006 Jun 20;144(12):904-12.

Schuh S, Dick PT, Stephens D, Hartley M, Khaikin S, Rodrigues L, Coates AL. High-dose inhaled fluticasone does not replace oral prednisolone in children with mild to moderate acute asthma. Pediatrics. 2006 Aug;118(2):644-50.

Sorkness CA, Lemanske RF Jr, Mauger DT, Boehmer SJ, Chinchilli VM, Martinez FD, et al. Long-term comparison of 3 controller regimens for mild-moderate persistent childhood asthma: the Pediatric Asthma Controller Trial. J Allergy Clin Immunol. 2007 Jan;119(1):64-72.

Review Date:
3/26/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Asthma in adults

FitSugar — Wed, 08 Oct 2008 17:35:00 -0700

In This Report

Highlights
Introduction
Symptoms
Causes
Prognosis
Risk Factors
Diagnosis
Treatment
Quick-Relief Medications...
Long-Term Relief Medication...
Other Treatments
Managing Asthma
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Warning

In 2007, the FDA requested the manufacturers of omalizumab (Xolair) to include a “boxed warning” emphasizing that this drug may cause a severe and life-threatening allergic reaction (anaphylaxis). Omalizumab is approved for patients who have moderate-to-severe asthma related to allergies and whose symptoms are not controlled by inhaled corticosteroids. It is given by injection in a doctor’s office every 2 - 4 weeks. The warning indicates that patients may develop anaphylaxis after any dose of omalizumab, even if they had no reaction to the initial shot. Health care providers need to observe patients carefully for 2 hours after they receive an omalizumab injection. However, because an allergic reaction can occur up to 24 hours after the injection, patients need to know the signs and symptoms of anaphylaxis and how to self-administer emergency treatment.

Anaphylaxis symptoms include:

Difficulty breathing
Chest tightness
Dizziness
Fainting
Itching and hives
Swelling of the mouth and throat

Drug Approval

In 2006, the FDA approved budesonide/formoterol (Symbicort). Symbicort combines a corticosteroid and a long-acting beta2-agonist into a single inhaler.

Long-Acting Beta2-Agonists

Long-acting beta2-agonist drugs, such as salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer), may worsen asthma symptom severity and increase the risk for asthma-related death, indicates a 2006 review in the Annals of Internal Medicine.
Products that contain salmeterol and formoterol now have strengthened warning labels detailing these risks.

Asthma and Heartburn

Studies have suggested an association between heartburn, also known as gastroesophageal reflux disease (GERD), and asthma that gets worse at night (nocturnal asthma). A 2006 study tested whether a proton pump inhibitor drug might help improve morning breathing in patients who suffer from these two conditions. The results suggested that the drug provided only a moderate benefit.

Introduction

Air passes into the lungs and flows through progressively smaller airways called bronchioles. The lungs contain millions of these airways.
All bronchioles lead to alveoli, which are microscopic sacs where oxygen and carbon dioxide are exchanged.

The major features of the lungs include the bronchi, the bronchioles, and the alveoli. The alveoli are the microscopic blood vessel-lined sacks in which oxygen and carbon dioxide gas are exchanged.

Asthma is a chronic condition in which these airways undergo changes when stimulated by allergens or other environmental triggers. Such changes appear to be two specific responses:

The hyperreactive response (also called hyperresponsiveness)
The inflammatory response

These actions in the airway cause patients to cough, wheeze, and experience shortness of breath (dyspnea), the classic symptoms of asthma.

In the hyperreactive response, smooth muscles in the airways of the lungs constrict and narrow excessively in response to inhaled allergens or other irritants. Everyone's airways respond by constricting when exposed to allergens or irritants, but a special hyperreactive response occurs in people with asthma:

When people without asthma breathe in and out deeply, the airways relax and open to rid the lungs of the irritant.
When people with asthma try to take those same deep breaths, their airways do not relax and narrow, causing patients to pant for breath. Smooth muscles in the airways of people with asthma may have a defect, perhaps a deficiency in a critical chemical that prevents the muscles from relaxing.

The hyperreactive stage is followed by the inflammatory response, which generally contributes to asthma in the following way:

In response to allergens or other environmental triggers, the immune system delivers white blood cells and other immune factors to the airways.
These so-called inflammatory factors cause the airways to swell, to fill with fluid, and to produce a thick sticky mucus.
This combination of events results in wheezing, breathlessness, inability to exhale properly, and a phlegm-producing cough.

Click the icon to see an image of a normal bronchiole versus an asthmatic bronchiole.

Inflammation appears to be present in the lungs of all patients with asthma, even those with mild cases, and plays a key role in all forms of the disease.

Symptoms

Asthma symptoms vary in severity from occasional mild bouts of breathlessness to daily wheezing that persists despite taking large doses of medication. After exposure to asthma triggers, symptoms rarely develop abruptly but progress over a period of hours or days. Occasionally, the airways have become seriously obstructed by the time the patient calls the doctor.

The classic symptoms of an asthma attack include:

Wheezing when breathing out is nearly always present during an attack. Usually the attack begins with wheezing and rapid breathing, and, as it becomes more severe, all breathing muscles become visibly active.
Shortness of breath (dyspnea). Shortness of breath is a major source of distress in patients with asthma. However, the severity of this symptom does not always reflect the degree to which lung function is impaired. Some patients are not even aware that they are experiencing shortness of breath. Such patients are at particular risk for very serious and even life-threatening asthma attacks, since they are less conscious of symptoms. Those at highest risk for this effect tend to be older, female, and to have had the disease for a longer period of time.
Coughing. In some people, the first symptom of asthma is a nonproductive cough. Some patients find this cough even more distressing than wheezing or sleep disturbances.
Chest tightness or pain. Initial chest tightness without any other symptoms may be an early indicator of a serious attack.
Neck muscles may tighten, and talking may become difficult or impossible.
Rapid heart rate.
Sweating.
Chest pain occurs in about 75% of patients. It can be very severe, although the pain's intensity is not necessarily related to the severity of the asthma attack itself.

The end of an attack is often marked by a cough that produces thick, stringy mucus. After an initial acute attack, inflammation lasts for days to weeks, often without symptoms. (The inflammation itself must still be treated, however, because it usually causes relapse.)

Causes

Asthma has dramatically risen worldwide over the past decades, particularly in developed countries, and experts are puzzled over the cause of this increase. The mechanisms that cause asthma are complex and vary among population groups and even from individual to individual. Many asthma sufferers have allergies, and some researchers are targeting common factors in both these conditions. Not all people with allergies have asthma, however, and not all cases of asthma can be explained by allergic response.

Asthma is most likely to be caused by a convergence of factors that can include genes and various environmental and biologic triggers (infections, dietary patterns, hormonal changes in women, and allergens).

Nearly half of adults with asthma have an allergy-related condition, which, in most cases developed first in childhood. (In patients who first develop asthma during adulthood, the allergic response usually does not play a strong causal role.) Important irritants or allergens include:

Dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. These are the primary allergens in the home.
Animal dander.
Pollen. An asthma attack from an allergic response to pollen is more likely to occur during extreme air changes, such as thunderstorms. Major weather changes, such as El Nino, can affect the timing of allergy seasons. For example, in 1998, when the effects of El Nino were very strong, allergy and asthma attacks occurred earlier and were markedly increased.
Molds. A 2002 study suggested that molds might produce a worse asthma attack in adults than other allergens.
Fungi.
Cockroaches. Cockroaches are major asthma triggers and may reduce lung function even in people without a history of asthma.
Fossil Fuels. Certain chemicals may trigger allergic rhinitis. Some experts believe that refined fossil fuels, such as diesel fuel and particularly kerosene, may be important triggers for allergic rhinitis. And, in people who already have allergies or asthma, exposure to such fossil fuels may worsen symptoms.

The Allergic Process. The allergic process, called atopy, and its connection to asthma is not completely understood. It involves various airborne allergens or other triggers that set off a cascade of events in the immune system leading to inflammation and hyperreactivity in the airways. One description is as follows:

The conductor in an orchestra of immune factors that contribute to allergies and asthma appears to be a category of white blood cells known as helper T cells, in particular a subgroup called Th2 cells.
Th2 cells overproduce interleukins (ILs), immune factors that are molecular members of a family called cytokines, which are involved in the inflammatory process.
Interleukins 4, 9, and 13 may be responsible for a first-phase asthma attack. These interleukins stimulate the production and release of antibody groups known as immunoglobulin E (IgE). (People with both asthma and allergies appear to have a genetic predisposition for overproducing IgE.)
During an allergic attack, these IgE antibodies can bind to special cells in the immune system called mast cells, which are generally concentrated in the lungs, skin, and mucous membranes. This bond triggers the release of several active chemicals, importantly potent molecules known as leukotrienes. These chemicals cause airway spasms, overproduce mucus, and activate nerve endings in the airway lining.
Another cytokine, interleukin 5, appears to contribute to a late-phase inflammatory response. This interleukin attracts white blood cells known as eosinophils. These cells accumulate and remain in the airways after the first attack. They persist for weeks and mediate the release of other damaging particles that remain in the airways.

The Immune Response. Researchers are investigating the role that T cells play in asthma. T cells are white blood cells that are involved in the immune response. Researchers had focused on the T cell called type 2 helper (Th2) cells. However, a 2006 breakthrough study in the New England Journal of Medicine suggested that a different type of T cell may play a stronger role in asthma than previously thought.

Growth Factors. Compounds known as vascular endothelial growth factor (VEGF) have been observed in the airways of patients with asthma. VEGF is a powerful promoter of cell growth in blood vessel linings, and some researchers believe it may be major factor in remodeling.

About one-third of all persons with asthma share this condition with another member of their immediate family. Asthma may be more likely to pass to children from their mother than from their father. Both allergies and asthma are strongly associated with hereditary factors, sharing certain genetic markers, but they are not always inherited together.

Hormones or changes in hormone levels appear to play a role in the severity of asthma in women.

Menstrual-Related Asthma. Between 30 - 40% of women with asthma experience fluctuations in severity that are associated with their menstrual cycle. One study indicated that women with menstrually associated asthma tend to have the following characteristics:

Older age
Had asthma for a long time
Had severe asthma attacks that were likely to occur 3 days before and 4 days into the menstrual period

Oral contraceptives (OCs) theoretically should help asthma sufferers by leveling out hormonal changes, but they do not appear to have much effect. (There have been a few reports of asthma exacerbation with OCs, but these are uncommon events.)

Asthma during Pregnancy. During pregnancy, one-third of women with asthma suffer more from the condition, one-third suffer less, and one-third experience no difference in severity. Some studies suggest that expectant mothers carrying a female baby tend to have more severe asthma symptoms than do those who are bearing a male.

Menopause and Asthma. Around the time of menopause (called perimenopause) when estrogen declines, the risk for hospitalization in women with asthma increases fourfold compared to previous years. Studies have not demonstrated that hormone replacement therapy (HRT), which contains estrogen, has much benefit.

About 10% of adults and some fewer children have aspirin-induced asthma (AIA). With this condition, asthma gets worse when patients take aspirin. Aspirin is one of the drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs). Although aspirin is used to reduce inflammation in other disorders, it appears to have the opposite effect in many asthma cases. It is not wholly known why this occurs. AIA often develops after a viral infection. It is a particularly severe asthmatic condition, associated with up to 25% of asthma-related hospitalizations. In about 5% of cases, aspirin is responsible for a syndrome that involves multiple attacks of asthma, sinusitis, and nasal congestion. Such patients also often have polyps (small benign growths) in the nasal passages.

Patients with aspirin-induced asthma (AIA) should avoid aspirin and most likely other NSAIDs, including ibuprofen (Advil) and naproxen (Aleve).

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath.

Asthma occurs primarily at night (nocturnal asthma) in as many as 75% of patients with asthma. Attacks often occur between 2 and 4 a.m. Factors that might play role in nocturnal asthma may include one or more of the following:

Chemical and temperature changes in the body during the night that increase inflammation and narrowing of the airways
Delayed allergic responses from exposure to allergens during the day
The wearing off of inhaled medications toward the early morning
An increase in acid reflux (back up of stomach acid) that causes airways to narrow
Postnasal drip that occurs during sleep
Conditions relating to sleep, such as sleep apnea or sleeping on one's back, which may worsen any asthma attack that occurs at night

Some experts believe that nocturnal asthma may actually be a unique form, with its own specific biologic mechanisms that occur only at night and which reduce natural steroid hormones (which block inflammation).

Infections. The role of infections in asthma is complicated. Respiratory infections may play a role in some cases of adult-onset asthma, but may be protective against asthma in small children. (In both children and adults with existing allergic asthma, however, an upper respiratory tract infection often worsens an attack.)

Researchers are particularly interested in the organisms Chlamydiapneumoniae and Mycoplasmapneumoniae adenovirus. They are major causes of both mild and serious respiratory infections and are becoming important suspects in many cases of severe adult asthma. (If such respiratory infections occur in young children, they are unlikely to affect adult-onset asthma.)

In one study, patients whose asthma occurred after infections had more severe conditions than those whose asthma was due to other causes. The infection-initiated asthma, however, lasted only 5.6 years compared to 13.3 years in the non-infection group.

In any age group, respiratory infections worsen existing asthma in people who have it already. Rhinovirus (the common cold virus) has been reported to be the most common infection associated with asthma attacks. In one study, it was associated with 61% of asthma exacerbations in children and 44% in adults. Some research suggests that colds promote allergic inflammation and increase the intensity of airway responsiveness for weeks.

GERD. At least half of patients with asthma have gastroesophageal reflux disease (GERD), the cause of heartburn. It is not entirely clear which condition causes the other or whether they are both due to common factors.

Heartburn is a condition where the acidic stomach contents back up into the esophagus causing pain in the chest area. This reflux usually occurs because the sphincter muscle between the esophagus and stomach is weakened. Standing or sitting after a meal can help reduce the reflux that causes heartburn. Continuous irritation of the esophagus lining as in gastroesophageal reflux disease is a risk factor for the development of adenocarcinoma.

Some theories for the causal connection between GERD and asthma are:

Acid leaking from the lower esophagus in GERD stimulates the vagus nerve, which runs through the gastrointestinal tract. This stimulated nerve triggers the nearby airways in the lung to constrict, causing asthma symptoms.
Acid backup that reaches the mouth may be inhaled into the airways (aspirated). Here, the acid triggers a reaction in the airways that cause asthma symptoms.

GERD is sometimes hard to detect and might be a contributor in the following patients:

Those who do not respond to asthma treatments
Those whose asthma attacks follow episodes of heartburn
Those whose attacks worsen after eating or exercise
Those whose coughs follow episodes of acid reflux. (One study found that GERD was associated with about half of the episodes of coughs and wheezes in patients with asthma.)

Treating GERD symptoms with anti-acid drugs may resolve asthma in some (but not all) patients who share both conditions. A small 2005 study found that while GERD was common in patients with asthma, treatment of GERD had no effect on asthma symptoms. A 2006 study indicated that the proton pump inhibitor esomeprazole (Nexium) slightly helped patients who had both GERD and asthma symptoms that occurred at night. [See In-Depth Report #85: Heartburn and gastroesophageal reflux disease.]

Click the icon to see an image of sinusitis.

EIA is triggered only by exercise and is distinct from ordinary allergic asthma in that it does not produce a long duration of airway activity, as allergic asthma does. (It should be noted that some people have both forms of asthma.) People who have only EIA do not appear to require long-term maintenance therapy. A study of military recruits with EIA also reported that the condition does not hinder a person's overall physical performance.

Medications

Cromolyn, a mild anti-inflammatory drug, or short-acting beta2-agonists have been the treatments of choice for preventing EIA. Newer approaches for people who work out regularly include pretreatment with long-acting beta2-agonists, such as salmeterol (Serevent), or the regular use of inhaled corticosteroids.

Hints for Reducing EIA

EIA occurs only after exercise and is more likely to occur with regularly paced activities in cold, dry air. The following are some suggestions for reducing its impact:

Warm-up and cool-down periods are important.
Patients with EIA might do better with activities that involve short bursts of exercise (tennis, football) than with exercises involving long-duration regular pacing (cycling, soccer, and distance running).
Breathing through a scarf or through the nose helps warm up the airways.
Some evidence suggests that restricting dietary salt might help reduce EIA.

Click the icon to see an image of exercise-induced asthma.

Prognosis

About 450,000 American adults are admitted to an emergency room with asthma each year. The number of deaths from asthma increased from about 2,900 in 1908 to a high of 5,667 in 1996. The numbers appear to be declining slightly, and in 2002 about 4,260 people died because of asthma. Death from asthma is still a very uncommon event, considering that an estimated 20 million people in the U.S. have this condition. Most deaths from asthma, even when they occur in elderly adults, are preventable. It is very rare for a person who is receiving proper treatment to die of asthma. And, studies suggest that the use of inhaled corticosteroids can reduce the risk for death by 90%. In spite of this and similar research, these important drugs are greatly underused.

About 55% of U.S. deaths from asthma occur among the elderly (over age 65), and an estimated 25% occur in adults aged 45 - 64. Women have a higher risk for fatal asthma than men. Being poor is also a significant risk factor for severe asthma. Hispanics and African Americans are at higher risk for death from asthma than Caucasians. Other specific risk factors for fatal asthma include:

Previous history of respiratory failure
Frequent visits to the emergency room
Lack of continuous care and poor compliance with medications
Having stopped treatment, particularly withdrawal from corticosteroids
Having an emotional or psychiatric disorder. (Some evidence suggests that depression, anxiety, and stressful life situations can worsen asthma.)
Being a drug abuser
Being in a lower socioeconomic and educational group

The following signs and symptoms may indicate a life-threatening situation:

As the chest labors to bring enough air into the lungs, breathing often becomes shallow.
Lacking sufficient oxygen, the skin becomes bluish.
The flesh around the ribs of the chest appears to be sucked in.
The patient may begin to lose consciousness.

It should strongly be noted that early symptoms or lack thereof do not always reflect the ultimate severity of an attack. In fact, some studies suggest that people at high risk for fatal or near-fatal asthma attacks are those with poor awareness of their own reduced ability to breathe and who are therefore slow in seeking help. Those at highest risk for this effect tend to be older, female, and have had the disease for a longer period of time. Monitoring peak flow rates is an important management component since it provides a more accurate assessment of lung function than symptoms alone.

The severity of asthma is graded using the following categories: mild intermittent and mild, moderate, and severe persistent. A patient in any of these categories, even mild intermittent, can still experience a severe and even life-threatening attack. In fact, according to one report, 30% of asthma deaths occur in patients with mild asthma.

Asthma is usually chronic, although it occasionally goes into long periods of remission. Long-term outlook generally depends on severity:

In mild-to-moderate cases, asthma can improve over time, and many adults even become symptom free.
Even in some severe cases, adults may experience improvement depending on the degree of obstruction in the lungs and the timeliness and effectiveness of treatment.
In about 10% of severe persistent cases, changes in the structure of the walls of the airways lead to progressive and irreversible problems in lung function, even in aggressively treated patients.

Lung function declines faster than average in people with asthma, particularly in those who smoke and in those with excessive mucus production (an indicator of poor treatment control). Overall, one study reported that 72% of men and 86% of women with asthma had symptoms 15 years after an initial diagnosis. Only 19% of these people, however, were still seeing a doctor, and only 32% used any maintenance medication.

Patients who develop occupational asthma often experience asthmatic symptoms for years, even after avoiding the harmful triggers. Improvement does occur over time in most people who leave such jobs.

Emotional Problems. Even when it is not life-threatening, asthma is debilitating and frightening. It significantly lowers the quality of life.

Sleep Disorders. Sleeplessness and daytime sleepiness are common problems. Studies indicate that between 80 - 93% of people with asthma have sleeping problems about three times a week. In one poll, 40% missed work an average of 11 days a year because of sleep disturbance. Asthma has been associated with snoring and obstructive sleep apnea, a condition in which blockage of the upper airway causes the sleeper to temporarily stop breathing, then resume with a gasp, often many times during each hour of sleep.

Asthma and Pregnancy. Uncontrolled asthma in pregnant women puts them at higher risk for complications that can include early labor, hypertension, gestational diabetes, and hemorrhage. Asthma also places the babies at risk for lower birth weight and breathing disorders. Teenage mothers with asthma face higher risks than older women. Fortunately, studies indicate that most asthma drugs are safe to take during pregnancy, and good control of asthma reduces these risks to normal levels.

New guidelines released in 2005 by the National Asthma Education and Prevention Program (NAEPP) emphasize that most asthma medications are safe for pregnant women. The guidelines recommend that pregnant women with asthma have albuterol available at all times. Inhaled corticosteroids should be used for persistent asthma. Patients whose persistent asthma does not respond to standard dosages of inhaled corticosteroids may require a higher dosage or the addition of a long-acting beta agonist to their drug regimen. For severe asthma, oral corticosteroids may be required. The NAEPP notes that while it is not clear if oral corticosteroids are safe for pregnant women, uncontrolled asthma poses an even greater risk for a woman and her fetus.

Heart Disease. There have been some reports of an association between asthma and a heightened risk for heart disease. Some experts believe that the inflammatory process may be the common factor linking the two conditions, although there is no evidence to date confirming any causal association.

Risk Factors

According to a major national 2001 survey, American adults have a 10% lifetime risk for developing asthma. As of 2002, an estimated 20 million adults had the disorder. Between 1980 - 1996 the prevalence of asthma increased by nearly 74%, but it may be stabilizing. Other respiratory diseases, sinusitis, and ear infections are also on the rise, suggesting that airborne or environmental factors may be at work that affects all of these conditions, including asthma.

Before puberty, asthma occurs more often in males, but after adolescence, it appears to be more common in females. In adults with similar cases of actual airway obstruction, women are likely to report more severe symptoms than men are. In addition, women may be at much greater risk of death from asthma than men.

In both adults and children, the incidence of obesity and asthma has been increasing in parallel over recent years. Studies report a strong association between the two conditions. Some experts suggest that excess weight pressing on the lungs may trigger the hyperreactive response in the airways typical of asthma. Others believe that asthma leads to obesity by inhibiting physical activity, although several studies have found no difference in activity levels between people with or without asthma. Some studies suggest that many obese people may be misdiagnosed as having asthma when in fact they are simply short of breath, possibly because of the increased effort required for breathing.

In one study of elderly people with severe adult-onset asthma, smoking was the most significant risk factor for developing this condition. Smoking, in any case, contributes to decline in lung function in everyone.

Urban Life and Poverty. African Americans have higher rates of asthma than Caucasians or other ethnic groups. They are also more likely to die of the disease. Ethnicity and genetics, however, are less likely to play a role in these differences than socioeconomic differences, such as having less access to optimal health care. Poverty is a consistent risk factor in most studies. Both the elderly and the urban poor have the highest risk for severe asthma and death. Urban life, in fact, has been associated with a higher risk for asthma in all income groups and among both children and adults. Twin studies also suggest that people who have lower educational levels (as well as those who exercise less) are at higher risk for adult-onset asthma, further suggesting a link to lower economic status.

Geographical Differences. Asthma rates vary widely among different populations regardless of socioeconomic or other factors. For example, asthma and hospitalization rates are dramatically higher in New York Puerto Ricans than in Hispanic Americans who live in Los Angeles or the Southwest. Among the U.S. states, rates are lowest in Louisiana and highest in Maine.

There are significant differences among nations. In a 2001 study of 22 nations, the countries with the highest asthma rates were Britain, Ireland, Australia, New Zealand, and the U.S. (According to another study, asthma rates are also significantly higher in Canadian adults than they are in comparable European groups.) Low rates were reported in Iceland, Norway, Spain, Germany, Italy, Algeria, India, and Eastern European nations. The reasons for these variations are still unknown.

Diagnosis

When asthma is suspected, the patient should describe for the doctor any pattern related to the symptoms and possible precipitating factors, including:

Whether symptoms are more frequent during the spring or fall (allergy seasons).
Whether exercise, a respiratory infection, or exposure to cold air has ever triggered an attack.
Any family history of asthma or allergic disorders, such as eczema, hives, or hay fever.
Any occupational or long-term exposure to chemicals. Early detection of occupational asthma is very important. If symptoms improve on weekends and vacation and are worse at work, the job is likely to be the source of the asthma, although this is not always the case. Asthma is common, and exacerbation at work may be coincidental.

A number of disorders may cause some or all of the symptoms of asthma:

Asthma and chronic obstructive lung diseases (chronic bronchitis and emphysema) affect the lungs in similar ways and, in fact, may all be present in the same person. Unlike other chronic lung conditions, asthma usually first appears in patients younger than age 30 and with chest x-rays that are normal. Still, it may be difficult to distinguish these disorders in some adults with late onset asthma.
Panic disorder can coincide with asthma or be confused with it.
Gastroesophageal reflux disorder (GERD) is a common companion in asthma and may affect treatment.
Other diseases that must be considered during diagnosis are pneumonia, bronchitis, severe allergic reactions, pulmonary embolism, cancer, heart failure, tumors, psychosomatic illnesses, and certain rare disorders (such as tapeworm and trichomoniasis).

If symptoms and a patient's history suggest asthma, the doctor will usually perform tests known as pulmonary function tests to confirm the diagnosis and determine the severity of the disease.

Using a spirometer, an instrument that measures the air taken into and exhaled from the lungs, the doctor will determine several values:

1. Vital capacity (VC), which is the maximum volume of air that can be inhaled or exhaled.

2. Peak expiratory flow rate (PEFR), commonly called the peak flow rate, which is the maximum flow rate that can be generated during a forced exhalation.

3. Forced expiratory volume (FEV1), which is the maximum volume of air expired in one second.

Spirometry is a painless study of air volume and flow rate within the lungs. Spirometry is frequently used to evaluate lung function in people with obstructive or restrictive lung diseases such as asthma or cystic fibrosis.

If the airways are obstructed, these measurements will fall. Depending on the results, the doctor will take the following steps:

If measurements fall, the doctor typically asks the patient to inhale a bronchodilator. This drug is used in asthma to open the air passages. The measurements are taken again. If the measurements are more normal, the drug likely has cleared the airways and a diagnosis of asthma is strongly suspected.
If measurement results fail to show airway obstruction, but asthma is still suspected, the doctor may perform a challenge test. This involves administering a specific drug (histamine or methacholine) that usually increases airway resistance only when asthma is present. The challenge test may be quite useful in ruling out occupational asthma. It is not always accurate, particularly in patients whose only symptom is persistent coughing.
Administering cold air is another method for inducing airway resistance. This test is very accurate for ruling out asthma, but it is not sensitive enough to accurately identify adults who actually have asthma.

The patient may be given skin or blood allergy tests, particularly if a specific allergen is suspected and available for testing. Allergy skin tests may be the best predictive tests for allergic asthma, although they are not recommended for people with year-round asthma.

Click the icon to see an image of allergy testing.

Tests that either rule out other diseases or obtain more information about the causes of asthma include:

A complete blood count.
Chest and sinus x-rays.
Computed tomography (CT) scans. CT scans may be helpful in certain cases, such as for determining wall thickness in airways in patients who are difficult to treat, which could signify a higher risk for lung damage.
Examination of the patient's sputum for eosinophils (white blood cells that in high levels are associated with severe allergic asthma). One 2002 study suggested that treatment goals based on achieving a normal eosinophil count might effectively manage asthma.
Researchers are investigating measurements of certain chemicals in sputum or exhaled air that indicate airway inflammation. Such chemical markers include nitric oxide and hydrogen peroxide. For example, high levels of nitric oxide in exhaled air is proving to be a simple and noninvasive way of diagnosing asthma.
If aspirin-induced asthma (AIA) is suspected, a non-invasive test called acoustic rhinometry may be useful. A solution of lysine acetylsalicylic acid (L-ASA) is instilled into the patient's nostril. Patients who experience symptoms such as sneezing, itching, congestion, and secretion are likely to have AIA.

Treatment

Beta2-agonists are the standard therapy. They may be administered with a nebulizer (a device that administers the drug in a fine spray) or given hourly with an inhaler. Studies are suggesting the use of an inhaler is equally or possibly more effective than a nebulizer. Intravenous delivery is not recommended in most cases.
A corticosteroid (commonly called a steroid) given within the first hour helps reduce the need for hospitalization. Steroids are typically administered intravenously or as an injection in adults. Lower doses work as well as higher ones in these situations.
Intravenous magnesium opens airways and is an important emergency treatment for patients with very severe asthma.
Oxygen is usually administered, and can be life-saving in severe cases.
In life-threatening situations, the patient may require mechanical ventilation.
Antibiotics are not useful for asthma attacks if there is no strong evidence of the presence of a bacterial infection. (Viral infections, most often colds and the flu, are more likely to trigger an asthma attack. In such cases, antibiotics do not appear to be beneficial and may have adverse effects.)

Discharge and Relapse After Hospitalization. It typically takes 3 - 4 hours to determine if a patient can be safely sent home or if they need to stay in the hospital. Patients are generally discharged under the following circumstances:

When symptoms are gone or are minimal, and
The peak expiratory flow rate is 70% or more of the predicted rate

Discharged patients generally take oral corticosteroids for 5 - 7 days. Despite reasonable precautions, about 20% of patients relapse within 2 weeks, although the risk is very low if they keep taking their medication after they leave.

Avoiding allergens, following appropriate drug treatments, and home monitoring are key elements in preventing dangerous asthma attacks and hospitalization. A combination of medications is important for both treating and preventing asthma attacks. In addition, good communication between the doctor and patient is a key factor in a successful management program. Written action plans, which instruct individual patients how to properly respond to changes in their unique symptoms, are a very important element in successful self-management of asthma.

Medications for asthma fall into two categories:

Rescue Medication. Medications that open the airways (bronchodilators, or inhalers) are used to quickly relieve any moderate or severe asthma attack. These drugs are usually short-acting beta-adrenergic agonists (beta2-agonists). Other drugs used in special cases include corticosteroids taken by mouth and anticholinergic drugs. None of these drugs have any effect on the disease process itself. They are only useful for treating symptoms.
Maintenance Medication. Simply coping with asthma symptoms without also controlling the damaging inflammatory response is a common and serious error. For adults and children over age 5 with moderate-to-severe persistent asthma, experts now recommend inhaled corticosteroids and long-acting beta2-agonists.

Patients can greatly reduce the frequency and severity of asthma attacks by understanding the difference between coping with asthma attacks and controlling the disease over time. Unfortunately, many patients do not understand the difference between medications that provide rapid short-term relief and those that are used for long-term symptom control. Many patients with moderate or severe asthma overuse their short-term medications and underuse their corticosteroid medications. The overuse of bronchodilators can have serious consequences; not using steroids can lead to permanent lung damage.

Patients need to understand that asthma symptoms can change quickly over time and that treatment strategies may need to change. In 2005, the two leading U.S. allergy associations published joint guidelines on controlling asthma. The guidelines emphasize that asthma treatment decisions need to be made on an individual basis. It is important that patients have a close relationship with their doctor. The doctor needs to evaluate a patient’s asthma symptoms at each and every visit to determine if there should be any changes in medication.

According to the guidelines, asthma management is classified as either “well-controlled” or “not well-controlled.” Your doctor may need to change some of your medications, or increase or decrease the dosage, depending on whether your asthma is well-controlled or not well-controlled.

These are the signs of well-controlled asthma:

Asthma symptoms occur twice a week or less
Rescue bronchodilator medication is used twice a week or less
Symptoms do not cause nighttime or early morning awakening
Symptoms do not limit work, school, or exercise activities
Peak flow meter readings are normal or the patient’s personal best
Both the doctor and the patient consider the asthma to be well controlled

Most asthma drugs are inhaled using various forms of inhalers or nebulizers. Inhaled drugs must be used regularly as prescribed and the patient carefully trained in their use in order for them to be effective and safe. The basic devices are the metered-dose inhaler (MDI), breath-actuated inhalers, dry powder inhalers, and nebulizers.

MDIs have used chlorofluorocarbons (CFCs) as their propellants. CFCs are damaging to the environment. CFCs are now being replaced with other propellants (such as hydrofluoroalkane) that are equally effective to CFCs, are environmentally safe, and do not chill the device as CFCs do. Devices that don't use propellants at all are also now available.

Metered-Dose Inhaler. The standard device for administering any asthma medication has been the metered-dose inhaler (MDI). This device, particularly when used with a holding chamber, allows precise doses to be delivered directly to the lungs.

Click the icon to see an image of a holding chamber.

MDI-delivered drugs must be used regularly as prescribed, and the patient carefully trained in their use, for the drugs to be effective and safe. Some patients hold the MDI too close to their mouths, or even inside them. Others may exhale too forcefully before inhalation. The holding chamber, or spacer, allows the patient additional time to inhale the medication, improving delivery. They vary, however, in their ability to deliver medication. Often MDIs continue to deliver propellant after the drug has been used up. Patients should track their medicine and throw the device away when the last dose has been administered.

Click the icon to see an illustrated series detailing metered dose inhaler use.

Dry Powder Inhalers. Dry powder inhalers (DPIs) deliver a powdered form of beta2 agonists or corticosteroids directly into the lungs. They also do not use CFCs. Such devices include Rotahaler, Spinhaler, Turbohaler, Clickhaler, Easyhaler, Diskhaler, Discus, Twisthaler, Spiros, and others. DPIs are as effective as the older devices, and generally have a better taste and are easier to manage. They may differ among themselves, however, in their ability to deliver drugs into the airways. In one study, for example, the Turbohaler was easier to use than the Diskhaler, achieving better delivery. The Discus is another effective DPI. It has a dose counter and protects against exhalation effects.

Humidity or extreme temperatures can affect these inhalers' performance, so they should not be stored in humid places (bathroom cabinets) or locations subject to high temperatures (glove compartments during summer months).

Dry-powder may cause tooth erosion, and children are advised to rinse their mouths out right after using a DPI and to brush twice a day with a fluoride toothpaste.

Other Hand-Held Inhalers. Respimat delivers a fine-mist spray that is created by forcing the liquid medication through nozzles. It does not use any propellant.

Nebulizers. A nebulizer is a device that administers the drug in a fine spray that the patient breathes in. They are mostly used in hospital settings or when the patient cannot use an inhaler. Nebulizers may be important for delivering newer drugs used in asthma treatment.

Click the icon to see an illustrated series detailing nebulizer use.

People who self-manage their asthma using daily monitoring of peak air flow and adjusting their medications as needed have fewer hospitalizations, fewer unplanned doctors visits, and, generally, a better quality of life than those who rely only on the occasional doctor or emergency room visit to control symptoms. Doctors recommend that patients with even mild asthma monitor their own conditions.

In general, monitoring involves the following steps:

A peak flow meter is the standard monitoring device for measuring peak expiratory flow rate (PEFR).

Click the icon to see an image of a peak flow meter.

Patients with severe asthma should take PEFR readings two or three times a day. The overall goal should be to achieve less than a 20% (and ideally only 10%) variation in readings between evening and morning rates. For mild-to-moderate asthma, a single determination each morning usually suffices, but patients should check with their doctors.
It is important to use the meter at the same times each day and to stand or sit in the same position to keep an accurate record.
Patients should keep an ongoing record of their peak flow readings to help them detect worsening of their condition.
They should also record attacks, exposure to any allergens or triggers, and medications taken.
After about 2 months, patients and doctors can use the recorded data for administering medications effectively and to recognize problems before they become serious.

In general, many people fail to monitor their asthma. Experts believe that, ideally, portable monitors should be available to measure forced expiratory volume (FEV1), a more accurate gauge of lung function, and the results should be electronically transmitted to the doctor.

New monitoring devices are showing promise in accomplishing one or more of these goals, although they are not covered by most insurers. For example, the AirWatch is a handheld digital monitor that measures and displays the rate of airflow and compares it to the rates from previous days. Once a month, or whenever there is a problem, the patient plugs the device into a standard telephone jack, and the daily readings are sent to an automated data center that creates tables and charts for the patient and the doctor.


Medication Purpose	Drug Class	Generic Name	Brand Names	Administration
Quick-Relief Medications (control acute attacks)	Short-Acting Beta2 Agonists	Albuterol	Proventil, Ventolin, AccuNeb	Inhaler, nebulizer
		Levalbuterol	Xopenex	Nebulizer
		Metaproterenol	Alupent	Inhaler
		Pirbuterol	MaxAir	Inhaler
		Ipratropium / Albuterol	Combivent	Inhaler
	Anticholinergics	Ipratropium	Atrovent	Inhaler
		Tiotropium	Spiriva	Inhaler
	Systemic Corticosteroids	Cortisone	Cortone	Pill
		Dexamethasone	Decadron	Pill
		Hydrocortisone	Cortef	Pill
		Methylprednisolone	Medrol	Pill
		Prednisolone	Orapred, Prelone	Syrup
		Prednisone	Various	Pill
		Triamcinolone	Aristocort	Pill
Long-Term Relief Medications (prevent attacks and control chronic symptoms)	Inhaled Corticosteroids	Beclomethasone	QVAR	Inhaler
		Budesonide	Pulmicort	Inhaler, nebulizer
		Budesonide / Formoterol	Symbicort	Inhaler
		Flunisolide	AeroBid	Inhaler
		Fluticasone	Flovent	Inhaler
		Fluticasone / Salmeterol	Advair	Inhaler
		Mometasone	Asmanex	Inhaler
		Triamcinolone	Azmacort	Inhaler
	Long-Acting Beta2-Agonists	Formoterol	Foradil	Inhaler
		Salmeterol	Serevent	Inhaler
	Anti-inflammatories	Cromolyn	Intal	Nebulizer
		Nedocromil	Tilade	Inhaler
	IgE-inhibitor	Omalizumab	Xolair	Injectable
	Leukotriene Modifiers	Montelukast	Singulair	Pill
		Zafirlukast	Accolate	Pill
		Zileuton	Zyflo	Pill
	Methylxanthine	Theophylline	Uniphyl, Quibron, Theo-24	Pill, syrup

Quick-Relief Medications

These medications quickly control acute asthma attacks.

Beta2-agonists do not reduce inflammation or airway responsiveness but serve as bronchodilators, relaxing and opening constricted airways during an acute asthma attack. They are used alone only for patients with mild and intermittent asthma. Patients with more severe cases should use them in combination with other drugs.

Specific short-acting beta2-agonists include:

Albuterol (Proventil, Ventolin), called salbutamol outside the U.S., is the standard short-acting beta2-agonist in America. Other similar beta2-agonists are isoproterenol (Isuprel, Norisodrine, Medihaler-Iso), metaproterenol (Alupent, Metaprel), pirbuterol (Maxair), terbutaline (Brethine, Brethaire, Bricanyl), and bitolterol (Tornalate). Isoetharine (Bronkometer, Bronkosol) is available in nebulizers.
Newer beta2-agonists, including levalbuterol (Xopenex), have more specific actions than the standard drugs. Studies have indicated that levalbuterol is as effective as albuterol with fewer side effects. The original formulation of Xopenex was administered with a nebulizer. A new metered-dose inhaler formulation became available in late 2005.

Short-acting bronchodilators are generally administered through inhalation and are effective for 3 - 6 hours. They relieve the symptoms of acute attacks, but they do not control the underlying inflammation. If asthma continues to worsen with the use of these drugs, patients should discuss corticosteroids or other drugs to treat underlying inflammation.

Side Effects of Beta2-Agonists. Side effects of all beta2-agonists include the following:

Anxiety
Tremor
Restlessness
Headache
Fast and irregular heartbeats. A doctor should be notified immediately if this side effect occurs, particularly in people with existing heart conditions. Such patients face an increased risk for sudden death from cardiac related causes. This risk is higher with oral or nebulized drugs, but there have also been reports of heart attacks and angina in some patients using inhaled beta2-agonists.

Beta2-agonists have serious interactions with certain other drugs, such as beta-blockers, and patients should tell the doctor about any other medications they are taking. Individuals with diabetes, existing heart disease, high blood pressure, hyperthyroidism, an enlarged prostate, or a history of seizures should take these drugs with caution.

Loss of Effectiveness and Overdose. There has been some concern that short-acting beta2-agonists become less effective when taken regularly over time, increasing the risk for overuse. Over time some patients may become tolerant to many effects of short-acting beta2-agonists. The degree to which this affects the airways is uncertain. In some studies, the duration of action has declined but the peak effect appears to be preserved, making these drugs still useful for acute attacks. Regular use of long-acting beta 2-agonists may reduce the effect of short-acting forms.

Patients who perceive beta2-agonists as being less effective may overuse them. Overdose can be serious and in rare cases even life-threatening, particularly in patients with heart disease.

Inhaled ipratropium bromide (Atrovent) acts as a bronchodilator over time. Ipratropium bromide alone is only modestly beneficial for acute asthma attacks. Moreover, the drug is not approved specifically for asthma. It may, however, have benefits in certain cases:

It may be useful for certain older patients with asthma who also have emphysema or chronic bronchitis.
A combination with a beta2-agonist might be helpful for patients who do not initially respond to treatment with a beta2-agonist alone.

Common oral corticosteroids include prednisone, prednisolone, methylprednisolone, and hydrocortisone. They very effectively reduce inflammation but are generally used only after hospitalization for an acute attack. In some severe cases, they may be used as maintenance.

Adverse effects of prolonged use of oral steroids include cataracts, glaucoma, osteoporosis, diabetes, fluid retention, susceptibility to infections, weight gain, hypertension, capillary fragility, acne, excess hair growth, wasting of the muscles, menstrual irregularities, irritability, insomnia, and psychosis. Osteoporosis is a common and particularly severe long-term side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, bisphosphonates, or hormone replacement therapy in post-menopausal women.

Osteoporosis is a condition characterized by progressive loss of bone density, thinning of bone tissue, and increased vulnerability to fractures. Osteoporosis may result from disease, dietary or hormonal deficiency or advanced age. Regular exercise and vitamin and mineral supplements can reduce and even reverse loss of bone density.

Long-term use of oral steroid medications suppresses secretion of natural steroid hormones by the adrenal glands. After withdrawal from these drugs, this so-called adrenal suppression persists, and it can take the body a while (sometimes up to a year) to regain its ability to produce natural steroids again. There have been a few cases of severe adrenal insufficiency that occurred when switching from oral to inhaled steroids, which, in rare cases, has resulted in death.

No one should stop taking any steroids without consulting a doctor first. If the doctor orders steroids withdrawn, regular follow-up monitoring is necessary. Patients should discuss with their doctor measures for preventing adrenal insufficiency during withdrawal, particularly during stressful times when the risk increases.

Long-Term Relief Medications

These medications are taken on a regular basis to prevent asthma attacks and control chronic symptoms.

Inhalation of corticosteroids makes it possible to provide effective local anti-inflammatory activity in the lungs with minimal systemic effects. (By contrast, steroids taken by mouth have considerable side effects throughout the body.) Inhaled corticosteroids are recommended as the primary therapy under the following circumstances:

For any asthmatic condition more serious than occasional episodes of mild asthma. (Low-doses of inhaled steroids may even be safe and effective for some people with mild asthma, particularly those who find themselves using beta2-agonists daily.)
When treatment with bronchodilators is not effective.

Examples of inhaled corticosteroids:

The most recent generation of inhaled steroids include fluticasone (Flovent), budesonide (Pulmicort), triamcinolone (Azmacort and others), and flunisolide (AeroBid). In general, these newer steroids are more powerful than the older generation of inhaled drugs. These steroids are sometimes combined with a long-acting beta2-agonist in a single inhaler.
The FDA approved a new inhaled corticosteroid, mometasone furoate (Asmanex) in 2005.
The older corticosteroid inhalants are beclomethasone (Beclovent, Vanceril) and dexamethasone (Decadron Phosphate Respihaler and others). They are less powerful than the newer steroids when delivered with standard inhalers. New inhaler systems include QVAR, which uses extra fine formulations of beclomethasone to allow deep delivery into the lungs. Such systems may prove to be as effective as the newer, more potent steroids. Beclomethasone is believed to be safe during pregnancy.
Inhalers that combine both long-acting beta2-agonists and corticosteroids are also available. These include Symbicort (budesonide/formoterol), which in 2006 was approved for patients ages 12 years and older.

Traditionally, patients have been advised to take corticosteroids on a daily basis. However, a 2005 study suggested that intermittent corticosteroid therapy may be appropriate for some patients with mild persistent asthma. In the Improving Asthma Control Trial (IMPACT), researchers found that patients with mild persistent asthma who used an inhaled corticosteroid (budesonide) on an as-needed basis to control acute symptoms had similar lung function and quality of life outcomes as patients who used the drug daily. The researchers emphasize that patients with severe asthma should adhere to a daily dosage schedule, and that all patients with asthma should consult with their doctor to discuss any changes in medication regimen.

Optimal timing of the dose is important and may vary depending on the medication. Most of the newer inhaled steroids and even some older ones are now available as a single daily dose.

Inhaled steroids are generally considered safe and effective and only rarely cause any of the more serious side effects reported with prolonged use of oral steroids. Side effects of inhaled steroids are the following:

The most common side effects are throat irritation, hoarseness, and dry mouth. These effects can be minimized or prevented by using a spacer device and rinsing the mouth after each treatment.
Rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising are also possible but not common with inhalators.
A 2001 study reported a higher risk for cataracts in patients over age 40. (No higher risk was observed in younger people.)
Some studies report a higher risk for bone loss in patients who take inhaled steroids regularly, a side effect which is known to occur with oral steroids. A number of bone-preserving medications are now available that might safely offset this effect.
There is some concern that the more potent drugs, particularly fluticasone, suppress the adrenal system (which secretes natural steroids) to a greater degree than other steroid inhalants. (This is a serious side effect of oral steroids.)

Long-acting beta2-agonists are used in combination with inhaled corticosteroids for treating patients with moderate-to-severe asthma. These drugs include salmeterol (Serevent Diskus) and formoterol (Foradil Aerolizer). Combination single inhalers are available. One combines salmeterol and the corticosteroid fluticasone (Advair Diskus), and another combines formoterol and the corticosteroid budesonide (Symbicort).

Long-acting beta2-agonists are used for preventing an asthma attack (not for treating attack symptoms). The effects of one dose of a long-acting beta2-agonist last for about 12 hours, so these medicines are particularly effective during the night. These drugs also may be used for prevention of exercise-induced asthma in people and to protect against aspirin-induced asthma.

However, research indicates that long-acting beta2-agonists can worsen asthma by increasing symptom severity. These drugs may also increase the risk for asthma-related deaths. Experts are still trying to determine when long-acting beta2-agonists should be added to an asthma treatment plan. If your symptoms do not improve or if symptoms worsen with this type of drug, your doctor will recommend discontinuing it. Do not, however, stop taking this drug or other asthma medications without first talking with your doctor.

Side Effects. Side effects of long-acting beta2-agonists are similar to the short-acting drugs.

Specific Warning on Salmeterol and Formoterol. In 2003, a "black box" warning was added to product packaging for drugs that contain salmeterol, including Serevent Diskus, and Advair Diskus. The warning was based on a study that demonstrated more serious and even fatal asthma episodes in patients who used the drug than in patients who used a placebo. The risk for serious asthma episodes with salmeterol appears to be highest in African Americans and elderly patients with severe asthma.

In 2006, the FDA updated the warning to include formoterol (Foradil Aerolizer). Warnings for salmeterol and formoterol products emphasize that these medicines can increase the risk of severe asthma episodes. If these episodes occur, they can be fatal. Long-acting beta2-agonists require up to 20 minutes to achieve effectiveness, and there is a danger of overdose if a patient is not aware of this delay and takes additional doses to achieve faster relief. The FDA recommends that patients:

Use long-acting beta2-agonists only if other medicines (such as steroids) have not helped control asthma.
Use a short-acting bronchodilator, not a long-acting beta2-agonist, to treat sudden wheezing.
Do not use long-acting beta2-agonists to treat wheezing that is getting worse. Call your doctor if this situation occurs.
Do not stop using any asthma medicines without first talking to your doctor.

Cromolyn sodium (Intal) is both an anti-inflammatory drug and has antihistamine properties that block asthma triggers such as allergens, cold, or exercise. Nedocromil (Tilade) is similar to cromolyn. A cromolyn nasal spray called NasalCrom has been approved for over-the-counter purchase, but only to relieve nasal congestion caused by allergies. Patients should not use it for self-medication without the advice of a doctor.

Candidates. Cromolyn is often used in children with allergic asthma, but it has also been an important treatment for exercise-induced asthma (EIA) in all age groups, for pregnant women, and possibly for preventing allergic asthma in adults as well as children. Both cromolyn and nedocromil appear to be useful for patients with aspirin-induced asthma. These drugs do not effectively treat asthma once an attack is underway. They also have very little long-term benefits on lung function compared to inhaled corticosteroids.

Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). These drugs are proving to be effective for long-term prevention of asthma, including exercise-induced asthma and aspirin (or NSAID)-induced asthma. Most studies to date still report better success with inhaled corticosteroids than with the leukotriene-antagonists. Their anti-inflammatory actions are different from those of steroids, however, and combinations of the two drugs are being tried. A 2002 analysis of 13 studies, however, reported only modest benefits when anti-leukotrienes were added to corticosteroids. The combination did improve asthma control in some of the studies, but they did not reduce corticosteroid use. (In all but one of these studies the subjects were adults.)

Of some concern are reports of Churg-Strauss syndrome in a few people taking zafirlukast or montelukast. Churg-Strauss syndrome is very rare, but it causes blood vessel inflammation in the lungs and can be life threatening. Oral steroids quickly resolve the problem. Usually the syndrome has occurred in patients who were tapering off steroids and changing over to the leukotrienes-antagonists. Some experts believe that, in such cases, the steroids may simply have masked the presence of the disorder, which then developed when the steroid drugs were withdrawn. Symptoms include severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

Theophylline. Theophylline (Theo-Dur, Theolair, Slo-Phyllin, Slo-bid, Constant-T, Respbid) relaxes the muscles around the bronchioles and also stimulates breathing. One study reported that it may also have anti-inflammatory qualities even in low doses. Available in tablet, liquid, and injectable forms, some theophylline sustained-release tablets and capsules have a long duration of action and can, therefore, be taken once or twice a day with good results.

If theophylline is not taken exactly as prescribed, an overdose can easily occur. Toxicity can cause nausea, vomiting, headache, insomnia, and, in rare cases, disturbances in heart rhythm and convulsions. Contact a doctor immediately if any of these side effects occur.

The risks for these adverse effects are small if the drug is taken exactly as prescribed, but the following precautions should be noted:

Chronic smokers metabolize theophylline much more quickly and require higher doses of the drug than nonsmokers; prolonged-release versions are helpful for such people.
Too much caffeine can increase the concentration of this drug and the amount of time it stays in the body.
Theophylline also interacts with many other drugs that are taken for other common medical conditions, including asthma. Exercise caution when using beta2-agonists and theophylline together.
No one with a peptic ulcer should take theophylline. The elderly and anyone with heart disease, liver disease, hypertension, seizure disorders, or heart failure, should take theophylline with caution. Of special note, people with heart conditions who take theophylline orally face an increased risk for sudden death from heart-related causes.

However, about 1 in 1,000 patients who take omalizumab develop anaphylaxis (a life-threatening allergic reaction). In 2007 the FDA requested the manufacturers of omalizumab put a “boxed warning” on the medicine’s label emphasizing the drug’s risk for anaphylaxis. The boxed warning notes that patients can develop anaphylaxis after any dose of omalizumab, even if they had no reaction to a first dose. Anaphylaxis may occur up to 24 hours after the dose is given.

The FDA recommends that health care providers observe patients for at least 2 hours after an injection. Patients should also carry emergency self-treatment for anaphylaxis (such as an Epi-Pen) and know how to administer it. With an Epi-Pen, or similar auto-injector device, patients can quickly give themselves a life-saving dose of epinephrine.

Anaphylaxis symptoms include:

Difficulty breathing
Chest tightness
Dizziness
Fainting
Itching and hives
Swelling of the mouth and throat

Other Treatments

Various drugs are being investigated for asthma treatment. Some of these drugs have anti-inflammatory effects, which may help reduce dependence on corticosteroids. For example, etanercept (Enbrel), which blocks the inflammatory protein called tumor necrosis factor alpha, is being investigated for patients whose asthma has not responded to other drugs. The humanized monoclonal antibody daclizumab has also improved asthma control in patients with treatment-resistant asthma, as well as patients with moderate to severe chronic persistent asthma. Certain antibiotics, such as clarithromycin (Biaxin), may improve lung function in patients with asthma who show evidence of infection with the bacterial organisms Mycoplasma or Chlamydiapneumoniae. Dapsone, a drug known as a sulfone, is also under investigation.

Alternative therapies are being widely used by children, adolescents, and adults with asthma. In one study, nearly half of asthma or allergy sufferers resorted to alternative treatments. To date, however, evidence does not support any value from most alternative therapies, including high-dose vitamins, urine injections, homeopathic remedies, and most herbal remedies.

Relaxation and Stress-Reduction Techniques. Patients report benefits from many stress reduction techniques, such as acupuncture, hypnosis, breathing relaxation techniques, massage therapy, and meditation practices.

Acupuncture, hypnosis and biofeedback are all alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

The Buteyko Breathing Method. The Buteyko breathing method is an experimental approach designed to increase levels of carbon dioxide in the body. To do this, patients are trained to reduce their volume of breath and to avoid hyperventilation (over-breathing). Some studies have reported that patients using this method reduce their use of medications and improve their quality of life. The system originated in Australia and is not yet widely available in the U.S.

Probiotics. Probiotics are beneficial bacteria that may help protect against allergies and asthma. Antibiotic over-use and modern hygiene may specifically be reducing these helpful organisms. Probiotics can be obtained in active yogurt cultures and in supplements, which are being studied for protection.

Herbal Remedies. There have been few rigorous studies on herbal remedies for asthma. Butterbur (also known as Petasites hybridus, butter dock, blatterdock, bog rhubarb, and exwort) is one traditional herbal remedy used for treating seasonal allergies and asthma. In a 2002 study, it appeared as effective and less sedating than a commonly prescribed antihistamine for treating seasonal allergies over a 2-week period, but there has been little research on its effect on asthma.

Manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

Managing Asthma

Avoidance or control of the triggers that lead to asthma attacks is as much a priority as treatment of the disease.

Controlling Pets. Patients who already have pets and are not allergic to them probably have a low risk for developing allergies. If pets trigger asthma, however, they should be kept outside. If this isn't possible, they should at least be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens, which can even be carried on clothing; dogs usually present fewer problems. Washing animals once a week can reduce allergens. Dry shampoos, such as Allerpet, are now available for both cats and dogs that remove allergens from skin and fur and are easier to administer than wet shampoos.

Controlling for Dust. Spray furniture polish is very effective for reducing both dust and allergens. Air cleaners, filters for air conditioners, and vacuum cleaners with High Efficiency Particle Arresting (HEPA) filters can help remove particles and small allergens found indoors. Neither vacuuming nor the use of anti-mite carpet shampoo, however, is effective in removing mites in house dust. In fact, vacuuming stirs up both mites and cat allergens. If possible, avoid carpets and rugs.

A HEPA (High Efficiency Particle Arresting) filter can remove the majority of harmful particles, including mold spores, dust, dust mites, pet dander and other irritating allergens from the air. Along with other methods to reduce allergens, such as frequent dusting, the use of a HEPA filtration system can be a helpful aid in controlling the amount of allergens circulating in the air. HEPA filters can be found in most air purifiers, which are usually small and portable.

Reducing Humidity in the House. Although warm, moist air from vaporizers can greatly ease and moderate asthma attacks, living in a damp house is counterproductive. Dust mites thrive in humidity and damp houses increase the risk for mold, so on-going humidifiers can be unuseful. If they are used, humidity levels should not exceed 40% and they should be cleaned daily with a vinegar solution.

Gas Stoves, Kerosene, and Cooking. People with asthma should choose electric ovens rather than gas, which release nitrogen dioxide, a substance that can aggravate asthma symptoms. Even smoky cooking can worsen asthma. Kerosene (used in space heaters and lamps) may also produce allergic reactions.

Exterminating Pests (Cockroaches and Mice). Use a professional exterminator to eliminate cockroaches. (One study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves.) Exterminate mice and attempt to remove all dust, which might contain mouse urine and dander.

Avoiding Smoking and Cigarette Smoke. Cigarette smoke can accelerate the decline in lung function related to asthma. Even exposure to secondhand smoke can double the risk of asthma-related emergency room visits. In one study, it was the most frequently cited trigger of asthma symptoms. Everyone should quit smoking and encourage others around them to quit. [For help in quitting, see In-Depth Report # 41: Smoking.]

Click the icon to see an image of common asthma triggers.

Avoiding Outdoor Allergens. The following are some recommendations for avoiding allergens outside:

Avoid scheduling camping and hiking trips during times of high pollen count (generally, May and June for grass pollen and mid-August to October for ragweed).
Avoid strenuous activity when ozone levels are highest, which usually occur in early afternoon, particularly on hot hazy summer days. Levels are lowest in early morning and at dusk.
Asthma attacks are often higher during thunderstorms. It is not clear why. Some evidence points to a build-up of ozone that accompanies such storms. One study suggested that changing airflow patterns bring a sudden downdraft of air containing concentrations of pollens, small particles and allergens.
Patients who are allergic to mold should avoid barns, hay, raking leaves, and mowing grass. Exposure to automobile fumes may worsen asthma. Fungi in car air conditioners can also be a problem.

Click the icon to see an image of fungus.

Reducing Exposure to Air Pollution. A number of studies have linked air pollution to asthma. An important 2000 study found a strong association between higher mortality rates from heart and lung diseases and high levels of specific pollutants (ozone, carbon monoxide, sulfur dioxide, and nitrogen dioxide). Some experts point out that asthma rates in North America have increased over recent years while the prevalence of many common air pollutants have declined. Nevertheless, evidence strongly suggests that air pollution can worsen existing asthma and patients should take precautions if they are exposed to polluted air.

A number of studies have estimated that between 2 - 26% of adult-asthma cases are related to work history. Some experts encourage doctors to suspect occupational factors in all cases of adult-onset asthma. Although workers who have allergies, who smoke, or both are at higher risk than others, any worker exposed to occupational triggers may be at risk for asthma.

Work-related asthma is one of two types:

Work-aggravated asthma, in which existing asthma symptoms are triggered by irritants at the workplace
Occupational asthma, which is new-onset asthma strongly associated with conditions at work

Occupational asthma is further categorized as:

Nonlatent (symptoms occur right after exposure to an irritant, usually high concentrations of gas, fumes, dust, or chemicals)
Latent (symptoms develop after prolonged exposure to substances in the workplace)

Occupational Triggers. Over 250 substances have been identified as potential occupational triggers of asthma, and the list is growing. A few of these chemicals and substances include:

Isocyanates used in the manufacture of polyurethane, paints, steel, and electronics
Trimellitic anhydrides (TMA) used in many plastics and epoxies
Western red cedar, oak, redwood, and mahogany
Metal salts (platinum, nickel, and chrome) and metal working fluids
Vegetable dusts (soybeans, grains, flour, cotton, and gums)
Biologic organisms (Bacillus subtilis, pancreatic enzymes)
Xylanase used in the baking industry
Pharmaceuticals (penicillin, phenylglycine acid chloride)
Glutaraldehyde used to sterilize medical equipment
Red dye made from the cochineal insect
Diacetyl, the main chemical in artificial butter flavoring used in popcorn

Workers in these industries and others, including farmers, hairdressers, and those who work in the garment industries are at risk for asthma.

Preventing Occupational Asthma. In people whose asthma is caused by workplace conditions, improved ventilation or face masks may help.

Sometimes, however, even low levels of chemical substances can trigger an asthma attack. In such cases, leaving the job is the only way to prevent the condition from getting worse. Because such a step can be emotionally and financially threatening, workers should be sure that occupational substances are the cause of the asthma by having a complete check-up by a lung specialist.

If the diagnosis of occupational asthma is certain, patients should obtain advice on available compensation plans for disability. The effects of workplace asthma can be permanent. However, in one study, 70% of people with asthma experienced significant improvement in symptoms after leaving the job.

Immunotherapy ("allergy shots") may help reduce asthma symptoms, and the use of asthma medications, in patients with known allergies. They may also help prevent the development of asthma in children with allergies. Immunotherapy poses some risk for severe allergic reactions, however, especially for children with poorly controlled asthma.

[See In-Depth Report #77: Allergic rhinitis; and Report #5: Asthma in children and adolescents.]

Preventing and Treating Respiratory Infections. Respiratory infections, including the common cold, can act with allergies to worsen asthma. People with asthma should try to minimize their risk for respiratory tract infections. Washing hands is a very simple but effective preventive measure.

Patients with asthma should ask their doctors about the flu vaccine and also whether they should receive the vaccination against pneumococcal pneumonia.

Zanamivir, a new drug used for treating influenza, is considered safe for patients with asthma 12 years of age or older. In one study, patients with asthma who were treated with zanamivir experienced fewer flu symptoms and had improved lung function. [See In-Depth Report #94: Colds and influenza.]

Managing Hormonal-Related Asthma. Women who suspect that menstrual-related changes may influence asthma severity should keep a diary recording their menstrual dates and times of asthma attacks. In some cases, adjusting medications in anticipation of menstruation may help prevent attacks. Some small studies have suggested that hormonal drugs called gonadotropin-releasing hormone (GnRH) analogues may help women with severe premenstrual asthma. Such drugs reduce or suppress estrogen levels, however, and can have severe side effects. More research is needed to determine if the disadvantages outweigh the benefits.

Weight Loss. People who have asthma and who are overweight may help reduce asthma symptoms with weight loss.

Vitamin D. There may be an association between a lack of vitamin D and asthma. Some research suggests that children are less likely to develop asthma at a young age if their mothers consume a high intake of vitamin D during pregnancy. Vitamin D is available from dietary sources or vitamin supplements.

Fish Oil. Omega-3 fatty acids, found in cold water oily fish and in supplements (preferably DHA-EPA, which are the important compounds in fish oil) have anti-inflammatory effects. Some evidence suggests they may be helpful for people with asthma, although it is weak.

Caffeine. Caffeine has properties that are similar to theophylline, a drug used to treat asthma. A major analysis of studies reported that caffeine improved lung function for up to 4 hours after consumption. (People who are going to have their lung function tested should avoid drinking coffee, tea, or other caffeinated beverages for at least 4 hours beforehand.)

Alcohol. In adults, some research suggests that alcohol intake may influence allergy severity. One study found that as little as one drink a day is enough to worsen dust mite allergies.

Role of Food Allergies. Although 67% of people with asthma believe their symptoms are aggravated by food allergies, studies indicate that this belief may be true in only 5% of cases. The primary suspects are monosodium glutamate, or MSG (found in some canned soups, cheese, and certain vegetables), and sulfites (preservatives in wine and foods that include processed frozen potatoes and tuna). Contrary to what many people believe, dairy products do not appear to worsen asthma symptoms in people who are not already allergic to them.

Asthma is no reason to avoid exercise. Historically, about 10% of Olympic athletes have asthma. Some studies indicate that long-term exercise even helps control asthma and reduce hospitalization. Patients should consult their doctors before embarking on any exercise program, however. Uncontrolled asthma can be dangerous and, in rare cases, can be fatal for athletes, even some with mild asthma. Use of the inhaler is extremely important.

People who enjoy running should probably choose an indoor track to avoid pollutants. Swimming is excellent for people with asthma. Yoga practice, which uses both stretching, breathing, and meditation techniques, may have particular benefits. One study reported that two-thirds of patients who practiced yoga regularly were able to reduce or stop taking their asthma medications.

Exercise-induced asthma is a limited condition that has specific recommendations.

People with asthma have no higher rate of anxiety or depression than the general population. However, such emotions interact with the effects of asthma and its treatments in important ways:

Negative emotions can discourage compliance with medication and the ability to cope
Poor control of asthma symptoms, in turn, increases the risk for negative emotions
Stress and depression have been associated with more severe symptoms and even an increased risk of fatal asthma attacks

Some evidence suggests that stress reduction techniques, a positive attitude and relaxation techniques can be very helpful in the long-term management of asthma. [See In-Depth Report #31: Stress.]

Resources

www.lungusa.org -- The American Lung Association
www.acaai.org -- American College of Allergy, Asthma & Immunology
www.aaaai.org -- American Academy of Allergy, Asthma & Immunology
www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
http://asthma.nationaljewish.org -- National Jewish Medical and Research Center
www.aafa.org -- Asthma and Allergy Foundation of America
www.aarc.org -- American Association for Respiratory Care

References

Glassroth J. The role of long-acting ß-agonists in the management of asthma: Analysis, meta-analysis, and more analysis. Ann Intern Med 2006 Jun 20; 144:936-7.

Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006 May 15;173(10):1091-7.

Review Date:
3/27/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Allergic rhinitis

FitSugar — Wed, 08 Oct 2008 17:35:27 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Prognosis
Diagnosis
Treatment
Other Treatments
Decongestants
Antihistamines
Corticosteroids
Immunotherapy
Prevention
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

Ciclesonide (Omanaris), a corticosteroid nasal spray, has been approved for treatment of seasonal and perennial allergic rhinitis (hay fever) in adults and children age 12 years and older.

FDA Drug Warnings

The antihistamine promethazine (Phenergan) should not be given to children younger than age 2 because it may cause serious breathing problems.
Omalizumab (Xolair) may cause a life-threatening allergic reaction (anaphylaxis). This drug is used to treat allergy-related asthma, but is also being investigated as an allergy treatment.

Cough and Cold Medicines for Children

In 2007, the FDA began reviewing the safety and effectiveness of cough and cold medicines for children. These medicines contain antihistamines, decongestants, expectorants, and cough suppressants. The FDA is particularly concerned about the use of these medicines in children younger than 2 years of age. Overdoses can cause serious heart problems and death. However, many experts are concerned that the currently recommended dosages are themselves not safe.

Immunotherapy (Allergy Shots)

Immunotherapy is safe and effective for patients with allergic rhinitis, particularly those who have not been helped by other treatments, indicates a 2007 review in the Cochrane Database.
An experimental DNA-based ragweed vaccine is showing promise in early clinical trials. In a 2006 pilot study published in the New England Journal of Medicine, six weekly injections of the vaccine helped improve symptoms with benefits lasting into the following ragweed season.

Allergic Rhinitis and Sleep

Allergic rhinitis can cause sleep disorders and interfere with sleep quality, indicates a 2006 study in the Archives of Internal Medicine. In the study of nearly 600 patients with allergic rhinitis, patients with severe allergic rhinitis experienced worse sleep problems than those with mild allergic rhinitis.

Allergic Rhinitis and Parkinson’s Disease

Allergic rhinitis may be associated with the later development of the neurological disorder Parkinson’s disease, suggests a 2006 study in Neurology. Both conditions are associated with an inflammatory response.

Introduction

The nose is separated into two passages by a wall of cartilage called the septum. The nasal passages are lined with a membrane that produces a clear liquid called mucus. Mucus is a one of the body's defense systems:

The mucus traps small particles and bacteria, which may enter the nose as a person breathes.
The trapped bacteria usually do not cause harm in healthy individuals.
However, the bacteria can lead to a daily cycle of congestion and decongestion.
When one side of the nose is congested, air passes through the open (decongested) side. The sides alternate between being wide-open and partly or completely blocked.

If the congestion becomes severe or other changes occur that irritate the nasal passage, rhinitis develops. To be diagnosed with rhinitis, the patient must experience at least two of the following symptoms for an hour or more on most days:

Runny nose
Obstruction in the nasal passage
Nasal itching
Sneezing

Click the icon to see an image showing symptoms of allergic rhinitis.

These symptoms may occur as a result of colds or environmental irritants, such as allergens, cigarette smoke, chemicals, changes in temperature, stress, exercise, or other factors.

Infectious Rhinitis. If symptoms last less than 6 weeks, the condition is referred to as acute rhinitis and is usually caused by a cold or infection, or temporary overexposure to environmental chemicals or pollutants. [See In-Depth Report #94: Colds and the flu.]

Chronic Rhinitis. When rhinitis lasts for a longer period, the condition is called chronic rhinitis. Allergies are often the cause, but structural problems or chronic infections could also be to blame.

Aging Process. The elderly are at risk for chronic rhinitis as the mucous membranes become dry with age. In addition, the cartilage supporting the nasal passages weakens, causing changes in airflow. In such cases, therapy involves avoiding possible allergens and airborne irritants as well as measures to keep the nasal passages moist. Decongestants are not helpful.

Irritative Rhinitis. Irritative rhinitis is caused by an overreaction to irritants, such as cigarette smoke, dozens of other air pollutants, strong odors, alcoholic beverages, and exposure to cold. The nasal passages become red and engorged. This reaction is not the same as an allergic reaction, although both are associated with increased numbers of white blood cells called eosinophils.

Vasomotor Rhinitis. Vasomotor rhinitis, also sometimes called idiopathic or irritant rhinitis, is congestion and stuffy nose that is produced by the changes in blood vessels and nerve cells in the nasal passages. It occurs in response to irritants, including smoke, environmental toxins, changes in temperature and humidity, stress, and even sexual arousal. This over-reaction is not associated with any immune response. The biologic causes are unknown. Some research has found an association between vasomotor rhinitis and gastroesophageal reflux disorder (GERD, a common cause of heartburn), which some experts think may be due to a common defect in the nervous system that controls muscle action. Symptoms of vasomotor rhinitis are similar to most of those caused by allergies. Usually, however, they are more severe and occur predominantly on one side of the nose.

Foreign Objects. Blockage in young children is very often caused by foreign objects that they have pushed up their nose. If they are left in place, they may eventually cause infection and nasal discharge, (usually in one side of the nose), which may be yellow or green and foul smelling.

Blockage in the Nose from Polyps or Structural Abnormalities. A number of conditions may block the nasal passages. Surgery may be helpful for certain cases.

Polyps. These are soft, gray, fluid-filled sacs that develop off stalk-like structures on the mucus membrane. They impede mucus drainage and restrict airflow. Polyps usually develop from sinus infections that cause overgrowth of the mucus membrane in the nose. They do not regress on their own and may multiply and cause considerable obstruction.
Deviated Septum. A common structural abnormality that causes rhinitis is a deviated septum. The septum is the inner wall of cartilage and bone that separates the two sides of the nose. When deviated, it is not straight but shifted to one side, usually the left.
Other Causes of Blockage. Rarely, cleft palates, overgrowth of bones in the nose, or tumors cause rhinitis.

Nonallergic Rhinitis in Children. Chronic nasal congestion in children often accompanies a susceptibility to ear, sinus, or adenoid infections. Adenoids are spongy tissue masses located between ends of the nasal passages and the soft tissue in the back of the throat. Enlarged adenoids may also cause ear problems. The bacteria that cause these other infections, however, are not usually the cause of this chronic rhinitis.

Medications and Illegal Drugs. A number of drugs can cause rhinitis or worsen it in people with conditions such as deviated septum, allergies, or vasomotor rhinitis:

Overuse of decongestant sprays used to treat nasal congestion can, over time (3 - 5 days) cause inflammation in the nasal passages and worsen rhinitis.
Many people with allergies and asthma are sensitive to common painkillers known as nonsteroidal anti-inflammatory drugs (NSAIDs). These include aspirin, ibuprofen (Motrin, Advil, Nuprin, Rufen), and naproxen (Aleve), among many others. Aspirin and products containing aspirin can even cause life-threatening asthma attacks in some highly susceptible individuals. NSAIDs vary, however, and some patients may not have a reaction to all of them. For minor pain, acetaminophen (Tylenol), which is not an NSAID, is usually recommended for patients with intolerance to NSAIDs. A pharmacist should be consulted if the ingredients of any over-the-counter preparations are not known.
Other medications that may cause rhinitis include oral contraceptives, hormone replacement therapy, anti-anxiety drugs (particularly alprazolam), some antidepressants, and some blood pressure medications, including beta-blockers and vasodilators.
Sniffing cocaine damages nasal passages and can cause chronic rhinitis.

Estrogen in Women. Elevated levels of estrogen appear to increase mucus production and swelling in the nasal passages and can cause congestion. This effect is most apparent in women during pregnancy. In such cases the condition usually clears up after delivery. Oral contraceptives and hormone replacement therapies that contain estrogen have also been associated with nasal congestion in some women.

Medical Conditions. Hypothyroidism is associated with chronic rhinitis. People with certain genetic or other medical conditions that specifically affect the mucous membranes are at also risk, although rhinitis in such people is apt to be only one of many more serious conditions, including chronic sinusitis and respiratory problems. Wegener's granulomatosis, for example, is a serious but very rare illness that causes long-term swelling and tumor-like masses in air passages.

Rare genetic disorders that cause chronic rhinitis include the following:

Cystic fibrosis, in which the mucus is very thick.
Kartagener's syndrome. With this condition the body's major internal organs are located in the mirror-image position of their normal location. In addition, the body's cilia (hair-like-projections on many body tissues that help to move mucus and other fluids) are impaired or motionless.

In both disorders, mucus build-up also produces an environment favorable to infection-causing organisms.

Click the icon to see an image of a deviated septum.

Click the icon to see an image of the adenoids.

Causes

The allergic process, called atopy, and its connection to asthma is not completely understood. It involves various airborne allergens or other triggers that set off a cascade of events in the immune system leading to inflammation and hyperreactivity in the airways.

The conductor in an orchestra of immune factors that contribute to allergies and asthma appears to be a category of white blood cells known as helper T cells, in particular a subgroup called Th2 cells.
Th2 cells overproduce interleukins (ILs), immune factors that are molecular members of a family called cytokines, which are involved in the inflammatory process.

Interleukins 4, 9, and 13 may be responsible for a first-phase asthma attack. These interleukins stimulate the production and release of antibody groups known as immunoglobulin E (IgE). People with both asthma and allergies appear to have a genetic predisposition for overproducing IgE.
During an allergic attack, these IgE antibodies bind to special cells in the immune system called mast cells, which are generally concentrated in the lungs, skin, and mucous membranes. This bond triggers the release of a number of active chemicals, importantly potent molecules known as leukotrienes. These chemicals cause airway spasms, overproduce mucus, and activate nerve endings in the airway lining.
Another cytokine, interleukin 5, appears to contribute to a late-phase inflammatory response. This interleukin attracts white blood cells known as eosinophils. These cells accumulate and remain in the airways after the first attack. They persist for weeks and mediate the release of other damaging particles that remain in the airways.

One theory blames the dramatic increase in asthma and allergies on the reductions in childhood infections that have occurred with modern hygiene and antibiotic use. The basic theory rests on the idea that infections stimulate production of specific immune factors called Th1 cells. As these cells build up, they replace other immune factors called Th2 cells, which react to allergens -- a less serious threat to the body. Without infections to stimulate the production of the Th1 infection fighters, the Th2 allergen fighters are not replaced, and they persist at high levels, making the growing child more susceptible to allergies and asthma.

A number of different studies support this theory:

Some studies suggest that being part of a large family or attending day care increases the risk for early respiratory infections but reduces the risk of childhood asthma. The occasional cold, then, may be protective.
In a 2002 study, researchers measured levels of bacterial byproducts called endotoxins in the mattress dust of 812 children. Those with the highest levels had an 80% lower rate in allergies and asthma.
Another study further found a strong association between allergy development and the absence of certain beneficial bacteria (called probiotics) in infants' intestines. Infants who were born in more hygienic environments tended to lack these bacteria. Antibiotic overuse and modern hygiene may reduce these helpful organisms. (Probiotics are available in active yogurt cultures and in supplements, which are being studied for protection.)

According to many studies, the standard vaccinations against serious childhood infections pose no risk for developing asthma or hay fever. Some studies have even reported lower risk for asthma and allergies in the second and third years after vaccinations.

Some evidence suggests that the increase in allergies and asthma may be due to overexposure to indoor allergens. These may include wall-to-wall carpeting, cats, and mold produced by dampness in homes. Children who spend hours indoor each day may become overexposed to indoor allergens. This exposure is intensified by the recent trend of making homes more energy-efficient, which may result in more dust mites being trapped inside. However, other studies suggest that early exposure to allergens may actually prevent the development of allergies in children.

Seasonal allergic rhinitis occurs only during periods of intense airborne pollen or spores. It is commonly, although inaccurately, called hay fever or rose fever, depending on whether it occurs in the late summer or spring. No fever accompanies this condition, and the allergic response is not dependent on either hay or roses. In general, triggers of seasonal allergy in the U.S. include:

Ragweed. Ragweed is the most dominant cause of allergic rhinitis in the U.S., affecting about 75% of allergy sufferers. One plant can release 1 million pollen grains a day. Ragweed occurs everywhere in the U.S., although it is less common in western coastal states, southern Florida, northern Maine, Alaska, and Hawaii. The effects of ragweed in the northern states are first felt in middle to late August and last until the first frost. Ragweed allergies tend to be most severe before midday.
Grasses. Grasses affect people in mid-May to late June. Grass allergies are experienced more in the late afternoon.
Tree Pollen. Small pollen grains from certain trees usually produce symptoms in late March and early April.
Mold Spores. Mold spores that grow on dead leaves and release spores into the air are common allergens throughout the spring, summer and fall. Mold spores may peak on dry windy afternoons or on damp or rainy days in the early morning.

Click the icon to see an animation about allergies.

Major weather changes, such as El Nino, can affect the timing of allergy seasons. For example, in 1998, when the effects of El Nino were very strong, allergy attacks were markedly increased, and maximum tree pollen counts occurred 2 - 4 weeks earlier and mold counts 2 - 3 months earlier than the previous year.

Allergens in the House. Allergens in the house can trigger attacks in people with year-long allergic rhinitis, called perennial rhinitis. Household allergens may include the following:

House dust and mites. Dust mites, specifically mite feces, are coated with enzymes that contain a powerful allergen.
Cockroaches
Pet dander
Molds growing on wallpaper, house plants, carpeting, and upholstery

However, some studies are suggest that early exposure to some of these allergens, including dust mites and pets, may prevent allergies from developing in the first place in children.

Fossil Fuels. There may be an association between traffic-related air pollution and allergic rhinitis. Some experts believe that refined fossil fuels, such as diesel fuel and particularly kerosene, are important triggers for allergic rhinitis. In people who already have allergies or asthma, exposure to such fossil fuels may worsen symptoms.

Symptoms

The general symptoms of rhinitis are congestion, runny nose, and postnasal drip, in which mucous drips into the throat from the back of the nasal passage, especially when lying on the back. Symptoms may vary depending on the cause of rhinitis. Symptoms of influenza and sinusitis must also be differentiated from allergies and colds.

Symptoms of allergic rhinitis occur in two phases, early and late.

Early Phase Symptoms. The early phase occurs within minutes of exposure to the allergens and includes:

Runny nose
Frequent or repetitive sneezing
Itching in the nose, eyes, throat, or roof of the mouth

Late-Phase Symptoms. The late phase occurs 4 - 8 hours later and may include one or more of these symptoms:

Nasal congestion and possibly plugged ears. Children may push their nose upward with the palm of their hand or twitch their nose rabbit-like to clear the obstruction.
Fatigue.
Mental changes can include irritability, a slight decrease in attention span, worsened memory, and slower thinking.
Other common physical symptoms include a decreased sense of smell, plugged ears, sinus headache, postnasal drip or some combination. In severe allergies, dark circles may develop under the eye. The lower eyelid may be puffy and lined with creases.

Risk Factors

Allergic rhinitis affects between 20 - 40 million Americans of all ages. As with asthma and many upper respiratory infections, the incidence in allergic rhinitis is increasing. Allergies most often appear first in childhood, and allergic rhinitis is the most common chronic condition in childhood, although it can develop at any age. About 20% of allergic rhinitis cases are due to seasonal allergies, 40% to perennial (chronic) rhinitis, and the rest are mixed.

Genetic factors are the major determinants of allergies.

If both parents have an allergy, the child's risk is 75%.
If one parent is allergic, the child's risk is 50%.

Having other allergies increases the risk for allergic rhinitis. Here are some examples:

Young children who have eczema (an allergic skin reaction) have a later risk for allergic rhinitis and asthma. In fact, a family history of eczema increases the risk.
Food allergies are associated with allergic rhinitis and asthma. (Early feeding patterns, time of weaning, and introduction of solid food do not appear to affect this risk.)
Asthma, especially in patients who develop it as adults, may increase allergic sensitivity to ragweed and other allergens. Patients who have asthma and a genetic tendency towards allergies (atopy) are also at risk for rhinitis.

Birth Month. Some studies report a higher risk of allergies and asthma in children born in winter months and lower risk in those born during the summer.

Breastfeeding. Some researchers suggest that the dramatic increase in asthma and allergies may be due to fewer women breastfeeding their infants. In a number of studies, breastfeeding has been associated with a lower risk for allergies and asthma -- at least until age 2. Breastfeeding can also help prevent other upper respiratory infections. The American Academy of Pediatrics recommends feeding infants exclusively breast milk for the first 6 months of life.

Prognosis

Seasonal allergic rhinitis tends to diminish as a person ages. The earlier the symptoms start, the greater the chances for improvement. People who develop hay fever in early childhood tend not to have the allergy in adulthood. In one study, over half of allergic subjects reported that by 40 years of age their symptoms had decreased, and a quarter were symptom-free. In some cases, allergies go into remission for years and then return later in life. People who develop allergies after age 20, however, tend to continue to have hay fever at least into middle age.

People with allergic rhinitis may be at higher risk for other allergies, including potentially serious food or latex allergies.

Although allergic rhinitis is not considered a serious condition, it nonetheless can interfere with many important aspects of life. A 2006 survey of nasal allergy sufferers reported that symptoms made patients feel tired (80%), miserable (65%), irritable (62%), and interfered with work performance (52%).

People with allergic rhinitis, particularly those with perennial allergic rhinitis, may experience sleep disorders and daytime fatigue. Often they attribute this to medication, but studies suggest congestion may be the culprit in these symptoms. In addition, a 2002 study indicated that patients with seasonal allergies experience hundreds of brief, subtle awakenings, called "microarousals," each night. In such cases, people are not aware that they wake up, but such events can cause fatigue the next day. A 2006 study of nearly 600 patients with allergic rhinitis found that sleep disorders and poor sleep quality were prevalent. Patients who had severe allergic rhinitis had worse sleep problems than those with mild allergic rhinitis.

Asthma and allergies often coexist, and the allergic response plays a strong role in childhood asthma. About 70 - 85% of children with asthma have allergies. Aggressive treatment of allergies in children with asthma can lower the risk for asthma attacks. Treating allergies in children may also help prevent the onset of asthma.

Any chronic rhinitis, whether allergic or nonallergic, can cause swelling in the turbinate, which may become persistent (turbinate hypertrophy). The turbinate is a tiny shelf-like bony structure that protrudes in the nasal passageways. It helps warm, humidify, and clean the air that passes over it. If turbinate hypertrophy develops, it causes persistent nasal congestion and, sometimes, pressure and headache in the middle of the face and forehead. This condition requires surgery.

Children with severe allergies may have a higher risk for behavioral problems than those without allergies. Some research suggests that allergic rhinitis is responsible for 2 million missed school days each year.
There have been reports that 30 - 45% of people with allergic rhinitis also suffer from ear infections (otitis media).
Chronic nasal obstruction from year-round allergies can affect a child's appearance. If a child can only breathe through the mouth, the continual force of air passing through the oral cavity can change facial development. Such changes may include an elongated face and an overbite from teeth coming in at an abnormal angle.
Chronic rhinitis can cause headaches and also affect a child's sleep, concentration, hearing, appetite, and growth.

Depression. Some evidence has linked depression with allergies. A 2002 study, for example, found that people with depression reported a higher rate of allergic disorders (71%) compared to nondepressed individuals (43%). During allergy season, patients with allergies were more likely to experience mood changes, including sadness, lethargy, and mental fatigue, than at other times. Some evidence suggests that specific immune factors in the allergic response can cause depressive symptoms. Other research indicates that both may have a common cause.

Parkinson’s Disease. A 2006 study suggested that allergic rhinitis may be associated with the later development of the neurological disorder Parkinson’s disease. The researchers think that the inflammatory response may be the link between the two conditions. However, there is not yet any evidence that treating allergic rhinitis can prevent Parkinson’s disease.

Chronic Fatigue Syndrome (CFS). Some, although not all, studies have reported that a majority of patients with CFS also have allergies to foods, pollen, metals (such as nickel or mercury), or other substances. One theory is that allergens, like viral infections, may trigger a harmful overreaction of the immune system that can cause fatigue, joint aches, and fever as well as hormone and brain chemical disturbances. (However, most people with allergies do not have CFS.)

Diagnosis

To determine the cause of allergic rhinitis, the doctor will ask a number of questions about:

Time of day and year of rhinitis episodes. Rhinitis that appears seasonally is typically due to pollens and outdoor allergens. If symptoms occur throughout the year, the doctor will suspect perennial allergic or non-allergic rhinitis.
Family history of allergies.
History of medical problems.
In women, if they are pregnant or taking drugs that contain estrogen (oral contraceptives, hormone replacement therapy).
Use of other medications including decongestants, which can cause a rebound effect.
Pets.
Any additional unusual symptoms. As examples, bloody nasal discharge and obstruction in only one nasal passage could suggest a tumor. Fatigue, sensitivity to cold, weight gain, and depression may be signs of hypothyroidism.

The doctor will examine the inside of the nose with an instrument called a speculum. This is a painless examination allowing the doctor to check for redness and other signs of inflammation. The doctor will also usually check the eyes, ears, and chest.

A skin test is a simple method for detecting common allergens. Patients are usually tested for a panel of common allergens. Skin tests are rarely needed to diagnose mild seasonal allergic rhinitis, since the cause is usually obvious. The skin test is not appropriate for children younger than age 3.

The procedure is as follows:

Patients should not take antihistamines for at least 12 - 72 hours before the test. Otherwise an allergic reaction may not show up.
Small amounts of suspected allergens are applied to the skin with a needle prick or scratch or are injected a few cells deep into the skin. The injection test may be more sensitive than the standard prick test.
If an allergy is present, a hive (a swollen reddened area) forms within about 20 minutes.

The test is not completely accurate. For instance, a 2001 study reported that testing detected allergies in less than half of children with rhinitis. Furthermore, about 15 - 20% of people may have a skin reaction without actually having an allergy.

Nasal Smear. The doctor may take a nasal smear. The nasal secretion is examined microscopically for factors that might indicate a cause, such as increased numbers of white blood cells, indicating infection, or high counts of eosinophils. High eosinophil counts indicate an allergic condition, but low counts do not rule out allergic rhinitis.

Tests for IgE. Blood tests for IgE immunoglobulin production may also be performed. One test is called the radioallergosorbent Test (RAST), used to detect increased levels of allergen-specific IgE in response to particular allergens. Blood tests for IgE may be less accurate than skin tests. They should be performed only on patients who cannot undergo skin testing or when skin test results are uncertain.

In people with chronic rhinitis, the doctor may also check for sinusitis. Imaging tests may be useful if other tests are ambiguous.

A test called transillumination, in which a doctor shines a bright light against the patient's cheek or forehead, is an inexpensive method for checking for abnormalities in the sinus cavities, although it is not highly accurate.
CT scans may be useful for some cases of sinusitis.

Click the icon to see an image of a CT scan.

In certain cases of chronic or unresponsive seasonal rhinitis, a doctor may use endoscopy to examine for any irregularities in the nose structure. Endoscopy uses a tube inserted through the nose that contains a miniature camera to view the passageways.

Treatment

If rhinitis is caused by non-allergic conditions, particularly if there are accompanying symptoms indicating a serious problem, the doctor should treat any underlying disorders. If rhinitis is caused by medications, such as decongestants, the patient may need to stop taking them or find alternatives.

Patients with chronic allergic rhinitis may require daily medications. Patients with severe seasonal allergies should start medications a few weeks before the pollen season and continue taking them until the season is over. Effective medications include:

Drugs that reduce the inflammatory response are important for preventing severe allergic rhinitis. Nasal corticosteroids (commonly called steroids) are now considered to be the most effective measure for preventing allergy attacks. Other anti-inflammatory drugs include leukotriene-antagonists and nasal cromolyn.
Antihistamine tablets relieve sneezing and itching and can prevent nasal congestion before an allergy attack. Many brands are available by prescription and over-the-counter.
Immunotherapy ("allergy shots") may be considered for patients with severe seasonal allergies that do not respond to treatment. It may also prevent asthma and the development of new allergies in children. Many experts now recommend immunotherapy for people with both asthma and allergies. Newer immunotherapeutic approaches using specially designed antibodies and vaccines are also showing promise.

All drug treatments have side effects, some very unpleasant and, in rare cases, serious. Patients may need to try different drugs until they find one that relieves symptoms without producing excessively distressing side effects.

Because seasonal allergies generally last only a few weeks, most doctors do not recommend the more potent prescription treatments for children. It is important for parents to determine if the child is actually under severe distress and that the parent is not simply responding to their own anxiety when they hear the child snorting or snoring. Prescription drugs are required only in severe cases. However, in children with both asthma and allergies, treatments for allergic rhinitis may also improve asthmatic symptoms.

Treating Mild Allergy Attacks. Mild allergy attacks usually require little more than reducing exposure to allergens and using a nasal wash. Dozens of treatments are available for allergic rhinitis. Many are available over-the-counter, but some require a prescription. They include the following:

Nasal washes
Decongestants that relieve nasal congestion and itchy eyes
Decongestant/antihistamine combinations

Due to side effects, decongestants should not be used in children ages 14 years or younger. Also, overuse of nasal decongestions can actually worsen sinus congestion.

Treating Severe Allergic Rhinitis. Patients with chronic allergic rhinitis, particularly if they also have asthma, may require daily medications. These drugs include:

Antihistamines. The newer non-sedating antihistamines -- such as cetirizine (Zyrtec), loratadine (Claritin), fexofenadine (Allegra), or desloratadine (Clarinex) -- cause less drowsiness than older antihistamines, such as Benadryl. Some of the newer drugs, such as Zyrtec and Clarinex, may also relieve nasal congestion.
Anti-inflammatory drugs. Nasal corticosteroids are now considered to be the most effective measure for preventing allergy attacks. They are recommended for patients with very severe allergies that do not respond to antihistamines.
Leukotriene-antagonists and nasal cromolyn may be beneficial in specific cases of allergies
Immunotherapy ("allergy shots") works well for many patients with severe allergies. It is also proving to reduce asthma symptoms and the use of asthma medications in patients with known allergies.

Itching and redness in the eyes sometimes respond to oral antihistamines. Eye drops, however, provide faster relief, and a combination of the two may be best. The following are eye drops for itchy eyes. Others are also available. Individual responses vary, and patients need to find which specific treatment works best for them.

Antihistamine eye drops: azelastine (Optivar), olopatadine (Patanol), ketotifen (Zaditor), levocabastine (Livostin) for relief of both nasal symptoms and itchy red eyes
Decongestant eye drops: phenylephrine (Allergan Relief), naphazoline (Naphcon, Opcon-A, VasoClear), tetrahydrozoline (Murine Plus, Visine)
Combination decongestant/antihistamine: Visine A.
Corticosteroids: loteprednol (Lotemax, Alrex), pemirolast (Alamast).

General Side Effects and Warning.

All eye drops can cause stinging, and some may result in headache and congestion.
No one should continue taking eye drops if they experience pain, changes in vision, worsened redness, or irritation, or if the condition lasts more than 3 days.
Do not touch the tip of the device to the eye or touch other surfaces with it. Replace the cap after using. Discard any solution that changes color or becomes cloudy.
People who have heart disease, high blood pressure, an enlarged prostate gland, or glaucoma should talk to their doctor before taking these types of eye drops.

Other Treatments

For mild allergic rhinitis, a nasal wash can be helpful for removing mucus from the nose. You can purchase a saline solution at a drug store or make one at home (one cup of warm water, half teaspoon salt, pinch of baking soda). Over-the-counter saline nasal sprays that contain benzalkonium chloride as a preservative may actually worsen symptoms and infection.

Simple method for administering a nasal wash:

Lean over the sink head down.
Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a time.
Spit the remaining solution out.
Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case the process is:

Lean over the sink head down.
Insert only the tip of the syringe into one nostril.
Gently squeeze the bulb several times to wash the nasal passage.
Then press the bulb firmly enough so that the solution passes into the mouth.
Repeat the process in the other nostril.

Nearly half of asthma or allergy sufferers resort to alternative treatments. To date, however, little evidence supports treatments such as high-dose vitamins, homeopathic remedies, and most herbal remedies. Some relaxation methods, such as massage therapy, may be beneficial in reducing stress related to allergy symptoms. According to research presented at a 2004 allergy conference, acupuncture is now the most popular alternative treatment among allergy sufferers. The following are examples of recent areas of research:

Acupuncture may provide symptom relief for persistent allergic rhinitis in children, according to results published in a 2004 pediatrics journal. The study compared the effects of active versus sham acupuncture. Larger trials are needed to confirm these results.
Butterbur (also known as Petasites hybridus, butter dock, blatterdock, bog rhubarb, and exwort) is a plant found in Europe, North American, and parts of Asia. It is a traditional herbal remedy used for seasonal allergies and asthma. In a 2002 study, it was as effective and less sedating than a commonly prescribed antihistamine for treating seasonal allergies over a 2-week period.
Probiotics are beneficial bacteria that may help protect against allergies and asthma. Probiotics are available in active yogurt cultures and in supplements, which are being studied for protection.

The following are special concerns for people with allergic rhinitis:

Grapeseed extract is sometimes touted as a natural antihistamine. A 2002 study, however, reported no benefits from it.
A 2002 study found no benefits with homeopathy immunotherapy for asthmatic patients allergic to dust mites.
Some patients have reported worse symptoms after drinking herbal teas, which may contain leaves or pollens the patient is sensitive to. Herbal remedies themselves can trigger an allergic reaction. For example, echinacea is of special concern. This herbal remedy actually boosts the immune system. People with nasal congestion may mistakenly take it because it is often used to treat colds. In the case of allergies, however, echinacea may worsen symptoms or even trigger them in people who haven't experienced them. People with autoimmune diseases or who have plant allergies should particularly avoid it.
A Chinese herbal cold and allergy remedy sold as Aller Relief contains trace amounts of aristolochic acid, a chemical that is toxic to the kidneys and a carcinogen. Products containing aristolochic acid have been associated with several reports of kidney failure in Europe. Of specific concern are studies suggesting that up to 30% of herbal patent remedies imported from China have been laced with potent pharmaceuticals such as phenacetin and steroids. Asian herbal remedies may also contain toxic metals.
Aromatherapy is often used for relaxation. Some of the exotic plant extracts in these formulas have been associated with a wide range of skin allergies.

Decongestants

For mild allergic rhinitis, a nasal wash can be helpful for removing mucus from the nose. Decongestants may help dry nasal congestion. They work by shrinking vessels in the nose. By reducing blockage, they decrease the risk of developing sinusitis caused by viruses or bacteria. Many over-the-counter decongestants are available, either in tablet form or as nasal or inhaled decongestants that are applied directly into the airways as sprays, drops, or vapors.

Nasal-delivery decongestants are applied directly into the nasal passages with a spray, gel, drops, or vapors. Nasal decongestants come in long-acting or short-acting forms. The effects of short-acting decongestants last about 4 hours; long-acting decongestants last 6 - 12 hours. The active ingredients in nasal decongestants include oxymetazoline, xylometazoline, and phenylephrine. Nasal forms work faster than oral decongestants and may not cause as much drowsiness. However, they can cause dependency and rebound.

Dependency and Rebound. The major hazard with nasal-delivery decongestants, particularly long-acting forms, is a cycle of dependency and rebound effects. The 12-hour brands pose a particular risk for this effect.

With prolonged use (more than 3 - 5 days), nasal decongestants lose effectiveness and can cause swelling in the nasal passages.
The patient then increases the frequency of the dose. As the congestion worsens, the patient may respond with even more frequent doses.
This causes dependency and increased nasal congestion.

Tips for Use. The following precautions are important for people taking nasal decongestants:

When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
Do not share droppers and inhalators with other people.
Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
Discard the medicine if it becomes cloudy or unclear.

Oral decongestants also come in many brands, which have similar ingredients. The most common active ingredient is pseudoephedrine (Sudafed, Actifed, Drixoral), sometimes in combination with an antihistamine. [The alternative decongestant, phenylpropanolamine (PPA) was taken off the market.] A small 2006 study reported that over-the-counter pseudoephedrine works just as well as the prescription drug montelukast (Singulair) in controlling allergic rhinitis symptoms. Patients in the study received a once-daily morning dose (240 mg) of ephedrine. Researchers suggest that taking pseudoephedrine in the morning, as opposed to later in the day or before bedtime, can help patients avoid side effects such as insomnia and nervousness.

Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants. These side effects include:

Agitation and nervousness
Drowsiness (particularly with oral decongestants and in combination with alcohol)
Changes in heart rate and blood pressure
Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives.

Individuals at Risk for Complications from Decongestants. People who may be at higher risk for complications are those with certain medical conditions, including disorders that make blood vessels highly susceptible to contraction. Such conditions include:

Heart disease
High blood pressure
Thyroid disease
Diabetes
Prostate problems that cause urinary difficulties
Migraines
Raynaud's phenomenon
High sensitivity to cold
Emphysema or chronic bronchitis. (Individuals with these conditions should particularly avoid high-potency, short-acting nasal decongestant.)
Medications that increase serotonin levels, such as certain antidepressants, anti-migraine drugs, diet pills, St. John's wort, and methamphetamine. The combination of these medicines and decongestants can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.

Anyone with these conditions should not use oral or nasal decongestants without a doctor's guidance. Other people who should not use decongestants without first consulting a doctor include:

Pregnant women
Children. The American College of Chest Physicians advises against the use of over-the-counter decongestants and other cold medications in children ages 14 years or younger. Children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. In 2007, the FDA began reviewing the safety and effectiveness of cough and cold remedies for children.

In 2000, the Food and Drug Administration (FDA) took action to ban oral decongestants containing phenylpropanolamine (PPA) from the U.S. market. This action was in response to reports of an increased risk of stroke in young women who took products containing this ingredient. All major brands that previously contained PPA have now substituted other active ingredients (usually pseudoephedrine) and are safe to use.

Anyone with old forms of decongestant should check the labels and discard them if they contain phenylpropanolamine.

Antihistamines

Histamine is one of the chemicals released when antibodies overreact to allergens. It is the cause of many symptoms of allergic rhinitis. Antihistamines can help relieve:

Itching, sneezing, and nasal discharge
Other allergy symptoms unrelated to rhinitis, including hives and some rashes
Nasal congestion, for some of the newer antihistamines, such as cetirizine (Zyrtec) and desloratadine (Clarinex)

If possible, patients should take antihistamines before an anticipated allergy attack.

Many antihistamines are available. They include short-acting and long-acting forms and are available as tablets, nasal-inhalers, eye drops, and syrups. Antihistamines are generally categorized as first- and second-generation. First-generation antihistamines may cause more side effects than newer second-generation ones.

There are some notes of caution when taking any antihistamine:

Antihistamines may thicken mucus secretions and can worsen bacterial rhinitis or sinusitis.
Antihistamines can lose their effectiveness over time, and a different one may need to be tried.

First-Generation Antihistamines Ingredients and Brand Names. The older, so-called first generation antihistamines include:

Diphenhydramine (Benadryl)
Carbinoxamine (Clistin)
Clemastine (Tavist)
Chlorpheniramine (Chlor-Trimeton). Some health professionals recommend this drug if antihistamines are required during pregnancy. It may be as effective as the second generation antihistamines and much less expensive.
Brompheniramine (Dimetane)
Promethazine (Phenergan). This antihistamine should never be used for children younger than age 2 because it may cause life-threatening breathing problems.

First-generation antihistamines contain compounds called anticholinergics, which tend to produce more side effects than second-generation antihistamines.

Side Effects

Drowsiness and impaired thinking
Dry mouth
Dizziness
Agitation
Insomnia or nightmares
Sore throat
Rapid heart beat and chest tightness (uncommon and should be reported)
Men with enlarged prostate glands may experience difficulty urinating

Drowsiness and First-Generation Antihistamines. Drowsiness is the most distressing side effect reported from first-generation antihistamines, and is potentially serious. It may pose a higher than average risk for work-related and automobile accidents than alcohol, narcotics, or prescription sedatives. However, some studies have not found any strong differences in sedation between the first- and second-generation antihistamines. Still, experts caution against the first-generation antihistamines for people most at risk from sedative effects, particularly elderly individuals. To reduce risks, take the antihistamine at home a few hours before bedtime, and do not combine it with alcohol or tranquilizers. Do not drive or operate heavy machinery.

The newer second-generation antihistamines do not contain anticholinergics, so they do not usually cause drowsiness to the extent that the first generation antihistamines do. They are sometimes referred to collectively as nonsedating antihistamines.

A major 2003 analysis reported that although Benadryl, the most common first-generation antihistamine, had a more negative effect on daily activities than the newer antihistamines, the differences were modest. Researchers in the study concluded that no clear distinction exists between the first- and second-generation antihistamines.

Brand Names. The second-generation drugs include:

Loratadine (Claritin). Claritin is available over-the-counter and is approved for children ages 2 and older. Desloratadine (Clarinex) is similar to Claritin but stronger and longer-lasting. It is available only by prescription.
Cetirizine (Zyrtec). Zyrtec is approved for both indoor and outdoor allergies. It is the only antihistamine to date approved for infants as young as 6 months. It is available over-the-counter.
Fexofenadine (Allegra) is also available over-the-counter.
Acrivastine (Semprex)
Ebastine, norastemizole, levocetirizine, and mizolastine are other second-generation antihistamines under investigation in the U.S. and Europe. Some may prove to be useful for specific populations.

For nonprescription antihistamines, some studies suggest that cetirizine (Zyrtec) is more effective than Allegra or Claritin in improving symptoms, including those in children. However, cetirizine can cause drowsiness when taken at high doses.

Zyrtec and Claritin are approved for children younger than 5 years, although most antihistamines appear to be safe in children. Zyrtec is the only antihistamine approved for both indoor and outdoor allergies and for infants as young as 6 months. Both are available in syrup form. Studies with Zyrtec have reported fewer symptoms in children allergic to dust mites, and one study reported that infants with allergies who were given Zyrtec were much less likely to develop asthma later on than untreated infants. Claritin, at this time, is generally the preferred drug for young people, however, because it has the least negative effect on concentration and learning. Women who are pregnant or nursing should avoid these medications unless recommended by a doctor.

Side Effects and Precautions

Common side effects include headache, dry mouth, and dry nose. (These are often only temporary and go away during treatment.)
Drowsiness occurs in about 10% of adults and between 2 - 4% of children.
Uncommon side effects include rapid heart beat and chest tightness. Tell your doctor if these effects occur.
Extended-release forms of Claritin and Zyrtec have other ingredients that can cause other symptoms, including nervousness, restlessness, and insomnia. Some patients taking Claritin-D 24 Hour Extended Release tablets have reported obstruction in the upper gastrointestinal tract, including difficulty swallowing.

Drug and Food Interactions. Two earlier second generation drugs, terfenadine (Seldane) and astemizole (Hismanal), in rare cases, caused dangerous heart rhythm abnormalities, particularly in high doses or in people who had liver disease. They also caused interactions with certain other medications and grapefruit juice. Both Seldane and Hismanal have been taken off the market. Allegra, Zyrtec, and Claritin do not appear to pose any of the dangers associated with Seldane.

Until more is known, however, anyone who takes a second-generation antihistamine should probably avoid or use with caution combinations with grapefruit juice or the drugs that caused problems with Seldane and Hismanal. Such medications include:

The antibiotics clarithromycin (Biaxin) and troleandomycin
Certain HIV protease inhibitors
Antidepressant serotonin-reuptake inhibitors (Prozac, Paxil, and Serzone)

Azelastine (Astelin) and levocabastine (Livostin) are available in nasal spray form. They can reduce nasal congestion as well as allergy symptoms. Both reduce symptoms, although azelastine may be more effective in some patients. Their disadvantages are a bitter taste, drowsiness, and expense. They are not as effective as steroid nasal sprays.

Many prescription and non-prescription products that combine antihistamines and decongestants are available. Combinations sold over-the-counter include Allerest, Sudafed Severe Cold Formula, Vicks DayQuil, Benadryl Allergy/Sinus, Contac Day/Night Allergy & Sinus. Prescription combinations include Claritin-D, Allegra D, and Zyrtec-D. Symptoms may improve within 60 minutes, with congestion clearing up first.

Corticosteroids

A number of drugs are available for reducing the inflammatory response in allergies. These drugs can help prevent an allergy attack from occurring.

Nasal-spray corticosteroids (commonly called steroids) are considered the most effective drugs for treating severe allergic rhinitis. Corticosteroids suppress important stress and other hormones in a region of the brain called the HPA axis. The suppression of these hormones blocks the inflammatory response that triggers an allergic attack. Steroids do not relieve symptoms immediately. It may take several hours before their effects are felt. Nasal spray steroids benefits include:

Reducing inflammation and mucus production
Improving night sleep and daytime alertness in patients with perennial allergic rhinitis
Treating polyps in the nasal passages

Comparison studies report that nasal steroid sprays work better than second generation antihistamines, such as loratadine (Claritin) and cetirizine (Zyrtec), and are possibly even more effective than allergy shots. They have no effect on itchy eyes, however.

Nasal-Spray Brands. Corticosteroids available in nasal spray form include:

Triamcinolone (Nasacort). Approved for children over age 6.
Mometasone furoate (Nasonex). Approved for use in patients age 3 and older.
Fluticasone (Flonase, Flounce, generic). Approved for children over age 4.
Beclomethasone (Beconase, Vancenase), flunisolide (Nasalide), and budesonide (Rhinocort). Approved for children over age 6.
Ciclesonide (Omnaris). Approved for patients age 12 and older.

Side Effects. Corticosteroids are powerful anti-inflammatory drugs. Although oral steroids can have many side effects, the nasal-spray form affects only local areas and has less risk for widespread side effects unless the drug is used excessively. Side effects of nasal steroids may include:

Dryness, burning, stinging in the nasal passage
Sneezing
Headaches and nosebleed (uncommon but should be reported to your doctor immediately)

Possible Long-Term Complications. All corticosteroids suppress stress hormones. This effect is known to produce some serious long-term complications in people who take oral steroids. Researchers have found far fewer concerns with nasal administration or inhaled forms, but there may be certain problems:

Effect on growth. The major concern for children is whether nasal steroids, like other forms of steroids, will adversely affect growth. Studies report either a temporary and slight (about half an inch) early effect on growth or no effect at all.
Effect on eyes. Glaucoma is a known side effect of oral steroids. Some ophthalmologists have observed higher pressure in the eye (a sign of glaucoma) in some patients taking nasal steroid sprays. (Studies have found no increased risk for cataracts in young people who have taken intranasal steroids). The eye pressure appears to return to normal after stopping the steroid, but periodic eye examinations are advised.
Use during pregnancy. Steroids appear to be safe during pregnancy, but pregnant women should talk to their doctor about other options before taking them.
Nasal passage injury. Steroid sprays may injure the nasal septum (the bony area that separates the nasal passage) if the spray is directed onto it. This complication is very rare.
Lower resistance to infection. People with any infectious disease or injury in the nose should not take these drugs until the disease or wound has been treated and cured.

Cromolyn serves as both an anti-inflammatory drug and a specific blocker for allergens. The standard cromolyn nasal spray (Nasalcrom) is not as effective as steroid nasal sprays but does work well for many people with mild allergies. It is one of the preferred first-line therapies for pregnant women with mild allergic rhinitis. It may take up to 3 weeks to experience full benefit.

Side Effects. Cromolyn has no major side effects, but minor ones include nasal congestion, coughing, sneezing, wheezing, nausea, nosebleeds, and dry throat. The spray can cause burning or irritation.

Leukotriene-antagonists are oral drugs that block leukotrienes, powerful immune system factors that are important in causing airway constriction and mucus production in allergy-related asthma. Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), zileuton (Ziflo), and pranlukast (Ultair, Onon). These drugs are mainly used to treat asthma. Montelukast was approved in 2003 to treat seasonal allergies, and in 2005 to treat indoor allergies.

Immunotherapy

Immunotherapy (commonly referred to as "allergy shots") is a safe and effective treatment for patients with allergies. It is based on the premise that people who receive injections of a specific allergen will lose sensitivity to that allergen. The most common allergens for which shots are given are house dust, cat dander, grass pollen, and mold.

Immunotherapy benefits include:

Targeting the specific allergen.
Reducing sensitivity in airways in the lungs as well as in the upper airways.
Preventing the development of new allergies in children.
Reducing asthma symptoms and the use of asthma medications in patients with known allergies. Research suggests it may also help prevent the development of asthma in children with allergies.

Candidates for Immunotherapy. Immunotherapy may be given to anyone over age 7 whose allergies are severe and who do not respond to medication. Many experts agree that immunotherapy should be considered as soon as possible for children with asthma and allergies. Immunotherapy is safe for pregnant women who are already receiving it, although half-strength doses are generally recommended, and it should not be started during pregnancy.

Individuals at Risk for Complications. People who should probably avoid immunotherapy include those who have:

An extreme response to skin tests (this may predict an allergic reaction).
Wheezing.
Uncontrolled severe asthma or lung disease.
Patients taking certain medications (such as beta-blockers).
The health status of anyone should be determined before starting treatment.

The major downside to immunotherapy is that it requires a prolonged course of weekly injections. The process generally includes:

Injections of diluted extracts of the allergen are given on a regular schedule, usually twice a week to weekly at first, then in increasing doses until a maintenance dose has been reached. It usually takes several months and may take up to 3 years to reach a maintenance dose.
At that time, intervals between shots can be 2 - 4 weeks, and the treatment is continued for another 3 - 5 years.
Patients can experience some relief within 3 - 6 months. If there is no benefit within 12 - 18 months, discontinue the shots.

After stopping immunotherapy, about a third of allergy sufferers no longer have any symptoms, a third have improved symptoms, and a third relapse.

The use of an injection series is effective, but patients often fail to comply with the regimens. Some other schedules and delivery methods are being investigated that might make the program easier and less distressing.

Rush Immunotherapy. Investigators are studying "rush immunotherapy," in which patients achieve the full maintenance dose with several shots a day over a period of 3 - 5 days. Rush therapy uses modifications that reduce the risk of severe reactions to excessive doses. Studies suggest that it is effective and safe, with few side effects other than itching. Patients must be monitored closely during this period, however, for severe reactions.

Oral Forms. Trials are underway to test oral forms of immunotherapy as an alternative to allergy shots. These methods include using a pill taken by mouth or a sublingual (under-the-tongue) tablet. Although oral and sublingual immunotherapy is prescribed in many countries in Europe and South America, it is not approved in the United States and is not considered accepted therapy at this time.

Injections for ragweed and, sometimes, dust mites have higher risks for side effects than other allergy shots. If complications or allergic reactions develop, they usually occur within 20 minutes, although some can develop up to 2 hours after the shot is given.

Side effects of immunotherapy include:

General itching, swelling, red eyes, hives, soreness at the injection site.
Less common side effects are low blood pressure, asthma worsening, or difficulty breathing. This is due to an extreme hypersensitivity response called anaphylaxis. It can also occur if excessive doses are given.
In rare cases, particularly because of excessive doses or if a patient has a serious lung problem, severe reactions can occur, which can be life threatening.
Premedicating patients with antihistamines and corticosteroids may help reduce the risk of reactions to immunotherapy, although this could mask early warning signs.

In a 10-year study, the incidence of any adverse effect was less than two-tenths of 1%, and the great majority of events were mild. The risk for a fatal response is estimated to be 1 in 63 million injections. (As a comparison, the risk for a fatal reaction to penicillin is much higher, 1 in 7.5 million injections.)

Vaccines. Of particular interest is the development of immunotherapeutic vaccines that use more specific targets to produce an insensitivity to allergens. One such vaccine uses a small protein from the allergen, which is injected into the patient. Other vaccines under investigation are those that use the allergen's genetic material (its DNA) to promote tolerance to the allergen. In a promising 2006 pilot study, patients who received 6 weekly injections of a DNA-based experimental ragweed vaccine had symptom reductions that lasted a year later into a second ragweed season. Researchers will be testing this vaccine in further clinical trials.

Monoclonal Antibodies. Monoclonal antibodies (MAb) are genetically-developed antibodies that are designed to target and attack very specific factors. A MAb known as omalizumab (Xolair) prevents the antibody immunoglobulin E (IgE) from triggering the inflammatory events that lead to allergies. Studies in recent years have suggested that omalizumab may help reduce symptoms and improve quality of life for patients with non-seasonal allergic rhinitis. A 2006 study suggested that treatment with omalizumab before and during ragweed allergy shots may help reduce immunotherapy side effects. The drug is currently approved for asthma. In 2007, the FDA warned that omalizumab may cause a life-threatening allergic reaction (anaphylaxis) in some patients.

Prevention

People with existing allergies should avoid irritants or allergens. These triggers include:

Pollen. This is the primary cause of allergic rhinitis.
Dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. These are the primary allergens inside the home.
Animal dander (flakes of skin) and hair from cats, house mice, and dogs. House mice are proving to be significant sources of allergens, particularly in urban children.
Molds.
Fungi.
Cockroaches are major asthma triggers and may reduce lung function even in people without a history of asthma.
Some research suggests that alcohol intake may influence allergy severity. One study found that as little as one drink a day is enough to worsen dust mite allergies.
Some studies suggest that early exposure to some of these allergens, including dust mites and pets, may actually prevent allergies from developing in children.

Controlling Pets. People who already have pets and are not allergic to them are probably at low risk for developing such allergies later on. When children are exposed to more than one dog or cat during their first year, they have a much lower risk for not only pet allergies but also seasonal allergies and asthma. (Pet exposure does not protect them from other allergens, notably dust mites and cockroaches).

In children who have an existing allergy to pets, however, the pets should be given away or kept outside. If this isn't possible, they should at least be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens, which can even be carried on clothing. Dogs usually present fewer problems. Washing animals once a week can reduce allergens. Dry shampoos, such as Allerpet, that remove allergens from skin and fur and are now available for both cats and dogs and are easier to use than wet shampoos.

For small children, stuffed animals might serve as a comforting replacement, although they might harbor dust mites. Putting stuffed animals in the freezer for 24 hours before washing them kills the dust mites. For best effect, this process should be done weekly.

Preventing Exposure to Cigarette and Cooking Smoke. Parents who smoke should quit. Studies show that exposure to second-hand smoke in the home increases the risk for asthma and asthma-related emergency room visits in children. [For help in quitting, see In-Depth Report # 41: Smoking.]

Controlling Dust. Spray furniture polish is very effective for reducing both dust and allergens. Air cleaners, filters for air conditioners, and vacuum cleaners with High Efficiency Particulate Air (HEPA) filters can help remove particles and small allergens found indoors. Neither vacuuming nor the use of anti-mite carpet shampoo, however, is effective in removing mites in house dust. Vacuuming actually stirs up both mites and cat allergens. People with these types of allergies should avoid having carpets or rugs in their homes.

Bedding and Curtains. Many experts recommend reducing exposure to dust mites by enclosing mattresses and pillows in semipermeable coverings. (Vinyl mattress covers limit airflow and may worsen, or even cause, asthma in children.) However, several 2005 studies suggested that such covers do not prevent allergies or asthma. Curtains should be replaced with shades or blinds and bedding washed using the highest water temperature setting.

Reducing Humidity in the House. Dust mites thrive in humidity, and damp houses increase the risk for mold. On-going humidifiers can worsen the problem. If they are used, humidity levels should not exceed 40%, and humidifiers should be cleaned daily with a vinegar solution.

Exterminating Pests (Cockroaches and Mice). Use professional exterminators to eliminate cockroaches. (One study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves.) Exterminate mice and attempt to remove all dust, which might contain mouse urine and dander.

Avoiding Outdoor Allergens. The following are some recommendations for avoiding allergens outside:

Start taking allergy medications 1 - 2 weeks before ragweed season begins. Be sure to take allergy medications before going outside. If regular medications do not work, ask your doctor about allergy shots.
Camping and hiking trips should not be scheduled during times of high pollen count (May and June for grass pollen and September to October for ragweed).
Patients who are allergic should avoid barns, hay, raking leaves, and mowing grass. (A mask can be worn during outdoor chores to help reduce pollen exposure.)
Sunglasses can help prevent pollen from getting into eyes.
After being outdoors, clean off pollen residue by bathing, washing hair and clothes, and using a nasal salt water rinse.

Some evidence suggests that people with allergic rhinitis and asthma may benefit from a diet rich in omega-3 fatty acids (found in fish, almonds, walnuts, pumpkin, and flax seeds) and fruits and vegetables (at least five servings a day). Some studies also suggest reducing sodium, trans fatty acids (hydrogenated fats found in commercial products and baked goods), and omega-6 fatty acids (found in most vegetable oils). Investigators are also studying probiotics -- so-called good bacteria, such as lactobacillus and bifidobacterium, which can be obtained in supplements.

Resources

www.aaaai.org -- American Academy of Allergy, Asthma & Immunology
www.acaai.org -- American College of Allergy, Asthma & Immunology
www.niaid.nih.gov -- National Institute of Allergy and Infectious Diseases
www.njc.org -- National Jewish Medical and Research Center
www.lungusa.org -- The American Lung Association

References

Bower JH, Maraganore DM, Peterson BJ, Ahlskog JE, Rocca WA. Immunologic diseases, anti-inflammatory drugs, and Parkinson disease: a case-control study. Neurology. 2006 Aug 8;67(3):494-6.

Calderon M, Alves B, Jacobson M, Hurwitz B, Sheikh A, Durham S. Allergen injection immunotherapy for seasonal allergic rhinitis. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD001936.

Creticos PS, Schroeder JT, Hamilton RG, Balcer-Whaley SL, Khattignavong AP, Lindblad R, et al. Immunotherapy with a ragweed-toll-like receptor 9 agonist vaccine for allergic rhinitis. N Engl J Med. 2006 Oct 5;355(14):1445-55.

Leger D, Annesi-Maesano I, Carat F, Rugina M, Chanal I, Pribil C, et al. Allergic rhinitis and its consequences on quality of sleep: An unexplored area. Arch Intern Med. 2006 Sep 18;166(16):1744-8.

Review Date:
3/22/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Sinusitis

FitSugar — Wed, 08 Oct 2008 17:35:28 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Symptoms
Complications
Diagnosis
Prevention
Treatment for Acute Sinusit...
Treatment for Chronic Sinus...
Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Restriction

In February 2007, the FDA announced that the antibiotic telithromycin (Ketek) should no longer be used for treatment of acute bacterial sinusitis. In June 2006, the FDA reported that several people had died of liver damage after taking this drug. Telithromycin is now only approved for treatment of community-acquired pneumonia.

Acute Sinusitis Treatment

Antibiotics are widely over-prescribed for acute sinusitis, according to a 2007 study. Researchers also reported that inhaled corticosteroids are frequently prescribed for acute sinusitis, despite little evidence for their efficacy. Most cases of acute sinusitis resolve on their own and do not require antibiotic treatment.

Allergic Fungal Sinusitis

Allergic fungal sinusitis should be considered a distinct form of chronic sinusitis, according to research presented at the 2007 annual meeting of the American Academy of Allergy, Asthma, & Immunolology. Researchers found that patients with allergic fungal sinusitis have an increased allergic and inflammatory response to fungi compared to patients with other types of chronic sinusitis.

Anti-Fungal Drugs

Allergic fungal sinusitis is currently treated with oral corticosteroids such as prednisone, but researchers are investigating whether anti-fungal drugs may help. The anti-fungal drug Amphotericin B (SinuNase) is currently in Phase III trials for patients with chronic sinusitis who have had sinus surgery but are still experiencing sinusitis symptoms. However, several 2006 studies indicated disappointing results.

Balloon Sinuplasty

Balloon sinuplasty is a relatively new procedure that uses a catheter-inserted balloon to gently open and drain nasal passages. In a study of 115 patients with chronic sinusitis, balloon sinuplasty achieved promising results, according to research presented at the 2007 meeting of the American Academy of Otolaryngology–Head and Neck Surgery Foundation. However, some experts believe that it is still too early to recommend this procedure for wide-scale use, especially until further large-scale clinical trials are conducted.

Introduction

The skull contains a number of air-filled spaces called sinuses. They perform the following functions:

Reduce the weight of the skull
Provide insulation for the skull
Provide resonance for the voice

Four pairs of sinuses, known as the paranasal air sinuses, connect to the nasal passages (the two airways running through the nose) and are those that are involved in sinusitis. These sinuses are the following:

Frontal sinuses (behind the forehead)
Maxillary sinuses (behind the cheekbones)
Ethmoid sinuses (between the eyes)
Sphenoid sinuses (behind the eyes)

Healthy sinuses are sterile and contain no bacteria. (The nasal passage, on the other hand, normally contains many bacteria that enter through the nostrils.) Maintaining sinus health depends on a cycle that involves a number of important factors and processes:

The sinuses are lined with a membrane that secretes mucus. Mucus drains down into the nasal passage from a small channel in each sinus. The mucous membranes must be intact and free of injury.
The mucus must be fluid in order to flow freely while being sticky enough to absorb pollutants and entrap bacteria.
The mucus must also contain sufficient amounts of bacteria-fighting substances, including immune factors called antibodies.
Small, hair-like projections called cilia must beat in unison to propel mucus outward, expelling bacteria and other particles.
The sinus passages must be open to allow mucus drainage and the circulation of air through the nasal passage.

Click the icon to see an image of an antibody.

The Disease Process. Sinusitis is an infection that occurs if one or more of the defense processes or factors are amiss, causing obstruction, and bacterial growth occurs in the paranasal sinuses. Among the many causes of such obstruction or congestion are the common cold, allergies, certain medical conditions, abnormalities in the nasal passage, and change in atmosphere. In any of these cases, sinusitis can develop as follows:

Mucus drainage and airflow are blocked.
Secretions build up, encouraging the growth of certain bacteria.
The resulting infection, swelling, and inflammation create further blockage, which may cause the sinuses to close up completely.

Forms of Sinusitis. Sinusitis is classified as acute, subacute, or chronic, or recurrent. The classification is based on how long symptoms last:

Acute: Less than 4 weeks
Subacute: 4 - 8 weeks
Chronic: 8 weeks or longer
Recurrent: 3 or more acute episodes in 1 year

Causes

Bacteria are the most common direct cause of acute sinusitis. (Other organisms might be the infecting cause in less common cases.) The ability of bacteria or other organisms to infect the sinuses, however, must first be set up by conditions that create a favorable environment in the sinus cavities. Sinusitis is most often an acute condition, which is self-limiting and treatable. In some cases, however, the inflammation in the sinuses persists or is chronic do begin with. The causes for such chronic sinusitis cases are sometimes unclear.

The typical process leading to acute sinusitis starts with a flu or cold virus. Viruses themselves do not usually cause sinusitis directly and are implicated in only about 10% of sinusitis cases. Instead, they set the stage by causing inflammation and congestion in the nasal passages (called rhinitis) that leads to obstruction in the sinuses. This creates a hospitable environment for bacterial growth, which is the direct cause of sinus infection. In fact, rhinitis is the precursor to sinusitis in so many cases that expert groups now refer to most cases of sinusitis as rhinosinusitis.

Rhinosinusitis tends to involve the following sinuses:

The maxillary sinuses (behind the cheekbones) are the most common sites.
The ethmoid sinuses (between the eyes) are the second most common sites affected by colds.
The frontal (behind the forehead) and sphenoid (behind the eyes) sinuses are involved in about a third of cold-related cases.

Nearly everyone with colds has inflamed sinuses. These inflammations are typically brief and mild, however, and most people with colds do not develop true sinusitis.

Chronic or recurrent acute sinusitis typically results from one of the following conditions:

Untreated acute sinusitis that results in damage to the mucous membranes
Chronic medical disorders that cause inflammation in the airways or persistent thickened stagnant mucus (such as diabetes, AIDS or other disorders of the immune system, hypothyroidism, cystic fibrosis, Kartagener's syndrome, and Wegener's granulomatosis)
Structural abnormalities
Allergic reaction to fungi

Chronic or recurrent acute sinusitis can be a lifelong condition.

The Role of Bacteria. The role of bacteria or other infectious organisms is complicated in chronic sinusitis. They may play a direct, an indirect, or, in some patients, no role at all. For example, one study reported the following for patients with chronic sinusitis who had not responded to antibiotics:

30% had no evidence of bacteria in their passageways.
20% had bacteria unrelated to infection.

Inflammatory Response, Allergies, and Asthma. The absence of bacterial organisms as a causal factor in many cases suggests that some instances of chronic sinusitis may be due to a continuing inflammatory condition. Such on-going inflammation may have been triggered immune factors that were produced in response to injuries from acute sinusitis. Many of the immune factors observed in people with chronic sinusitis resemble those that appear in allergic rhinitis, suggesting that sinusitis in some individuals is due to an allergic response.

Allergies, asthma, and sinusitis often overlap. Those with allergic rhinitis (so-called hay fever and rose fever) often have symptoms of sinusitis, and true sinusitis can develop as a result of the mucus blockage it causes. A causal association, however, has not been proved, and many experts believe allergies themselves rarely predispose to sinusitis. People with chronic sinusitis may also have an allergic reaction to fungal organisms.

Severe asthma (which is often associated with allergies) and chronic sinusitis often overlap, although the relationship is unclear. Between 53 - 75% of children with asthma caused by allergies have sinus abnormalities, and various studies have shown that between 17 - 30% of asthmatic patients develop true sinusitis. In fact, chronic sinusitis may actually be the cause of asthma in some cases.

Abnormalities of the Nasal Passage. Abnormalities in the nasal passage can cause blockage and thereby increase the risk for chronic sinusitis. Some abnormalities include:

Polyps (small benign growths) in the nasal passage block mucus drainage and restrict airflow. Polyps themselves may be consequences of previous sinus infections that caused overgrowth of the nasal membrane.
Enlarged adenoids can lead to sinusitis.

Adenoids are masses of tissue located high on the posterior wall of the pharynx. They are made up of lymphatic tissue, which trap and destroy pathogens in the air that enter the nasopharynx.

Cleft palate
Tumors
Deviated septum (a common structural abnormality in which the septum, the center section of the nose, is shifted to one side, usually the left)

Click the icon to see an image of a deviated septum.

The bacteria most commonly implicated in sinusitis include:

Streptococcus pneumoniae (also called pneumococcal pneumonia or pneumococci). This bacterium is found in between 20 - 43% of adults and children with sinusitis.
H. influenzae (a common bacterium associated with many upper respiratory infections). This bacterium colonizes nearly half of all children by age 2, and causes about 25% of sinusitis cases in this group. Studies have reported the presence of this bacterium in 22 - 35% of adult sinusitis patients.
Moraxella catarrhalis. Over 75% of all children harbor this bacterium, which causes about 25% of sinusitis cases.

Other possible bacterial culprits include:

Other streptococcal strains
Staphylococcus aureus

While fungi are an uncommon cause of sinusitis, the incidence of such infections is increasing. At least 5 - 10% of chronic rhinosinusitis patients may actually have allergic fungal sinusitis. At the 2007 meeting of the American Academy of Allergy, Asthma, & Immunology (AAAAI), experts presented evidence suggesting that allergic fungal sinusitis is a distinct form of chronic rhinosinusitis. Research indicates that allergic fungal sinusitis may provoke a distinct immune response. In the AAAAI study, patients with allergic fungal sinusitis showed increased antibody levels of immunoglobulin E (IgE) and immunoglobulin G (IgG) compared to patients with other types of chronic rhinosinusitis.

In earlier research from 2004, scientists from the U.S. National Institute of Allergy and Infectious Diseases exposed immune cells from patients with chronic sinusitis and healthy volunteers to four common types of fungi: Alternaria, Aspergillus, Penicillium, and Cladosporium. The study’s findings suggested that some people who suffer from chronic sinusitis have an extreme immune and inflammatory response to fungi and may benefit from anti-fungal treatment.

Fungi involved in sinusitis include:

Aspergillus is the most common cause of all forms of fungal sinusitis.
Other fungi include Curvularia, Bipolaris, Alternaria, Dreschslera, Cryptococcus, Candida, Sporothrix,Exserohilum, and Mucormycosis.
There have been a few reports of fungal sinusitis caused by Metarrhizium anisopliae, which is used in biological insect control.

There are four categories of fungal sinusitis:

Acute or invasive fungal sinusitis - This infection is most likely to affect people with diabetes and compromised immune systems.
Chronic or indolent fungal sinusitis - This form is generally found outside the U.S., most commonly in the Sudan and northern India.
Fungus ball (mycetoma) - This fungal sinusitis is noninvasive and occurs usually in one sinus, most often the maxillary sinus.
Allergic fungal sinusitis - This form typically occurs because of an allergy to the fungus Aspergillus (rather than being caused by the fungus itself). In such cases, a peanut butter-like fungal growth occurs in the sinus cavities that may cause nasal passage obstruction and the erosion of the bones.

Fungal infections can be very serious, and both chronic and acute fungal sinusitis require immediate treatment. Fungal ball is not invasive and is nearly always treatable.

Fungal infections should be suspected in people with sinusitis who also have diabetes, leukemia, AIDS, or other conditions that impair the immune system. Fungal infections can also occur in patients with healthy immune systems but they are far less common.

Risk Factors

Sinusitis is one of the most common diseases in the United States. According to the National Institute of Allergies and Infectious Diseases (NIAID), it affects an estimate 37 million Americans each year. However, a 2004 report in the Archives of Otolaryngology - Head and Neck Surgery suggests that sinusitis may not be as common as previously reported. The researchers found that accounts that rely solely on patient self-reporting may be exaggerated.

Everyone gets viral colds and flu, and most people develop symptoms in the upper respiratory tract (air passages in the head and neck) at some point. Over 85% of people with colds have inflamed sinuses. These inflammations are typically brief and mild, however, and only between 0.5 - 10% of people with colds develop true sinusitis. (One study suggested that nose blowing during a cold may transmit bacteria back into the sinuses and increase the risk for sinusitis.) Studies suggest that the following population groups have higher risks for sinusitis:

Young children and the elderly are at higher risk for more serious upper respiratory tract infections and for complications from them.
Women appear to be at higher risk than men.
People living in the Midwest and South have a higher incidence of sinusitis than those in the Northeast and West.
People in higher income and educational groups appear to have a greater risk than those in lower groups.
Caucasian and African Americans have a higher rate than Hispanic Americans.

Before the immune system matures, all infants are susceptible to respiratory infections, with a possible frequency of one cold every 1 - 2 months. Young children are prone to colds and may have 8 - 12 bouts every year. Smaller nasal and sinus passages also make children more vulnerable to upper respiratory tract infections than older children and adults. Ear infections such as otitis media are also associated with sinusitis. Nevertheless, true sinusitis is very rare in children under 9 years of age. Some experts believe it is greatly overdiagnosed in this population.

The elderly are at specific risk for sinusitis. Their nasal passages tend to dry out with age. In addition, the cartilage supporting the nasal passages weakens causing airflow changes. They also have diminished cough and gag reflexes and faltering immune systems and are at greater risk for serious respiratory infections than are young and middle-aged adults.

People with asthma, allergies or both are at higher risk for non-infectious inflammation in the sinuses. The risk for sinusitis is higher in patients with severe asthma. People with a combination of polyps in the nose, asthma, and sensitivity to aspirin (called Samter's or ASA triad) are specifically at very high risk for chronic or recurrent acute sinusitis.

Hospitalized patients are at higher risk for sinusitis, particularly those with:

Head injuries
Conditions requiring insertion of tubes through the nose
Antibiotics or steroids treatment
Breathing aided by mechanical ventilators. (Such patients may have a significantly higher risk for maxillary sinusitis. In fact, treating sinusitis in such patients may significantly reduce the risk for ventilator-associated pneumonia.)

A number of medical conditions put people at risk for chronic sinusitis. They include:

Diabetes
Gastroesophageal reflux disease
Nasal polyps or septal deviation
AIDS and other disorders of the immune system predispose the patient to sinusitis (fungal infections are especially risky)
Pregnancy -- may cause temporary congestion and symptoms of sinusitis
Hypothyroidism -- causes congestion that clears up when the condition is treated
Cystic fibrosis -- a genetic disorder in which the mucus is very thick and builds up
Kartagener's syndrome
Wegener's granulomatosis -- a serious but very rare illness that causes long-term swelling and tumor-like masses in air passages

Dental Problems. Anaerobic bacteria are associated with infections from dental problems or procedures, which precipitate about 10% of cases of sinusitis.

Changes in Atmospheric Pressure. People who experience changes in atmospheric pressure, such as while flying, climbing to high altitudes, or swimming, risk sinus blockage and therefore an increased chance of developing sinusitis. (Swimming increases the risk for sinusitis for other reasons, as well.)

Cigarette Smoke and Other Air Pollutants. Air pollution from industrial chemicals, cigarette smoke, or other pollutants can damage the cilia responsible for moving mucus through the sinuses. Whether air pollution is an important cause of sinusitis and, if so, which pollutants are critical factors is still not clear. Cigarette smoke, for example, poses a small but increased risk for sinusitis in adults. Second-hand smoke does not appear to have any significant effect on adult sinuses, although it does seem to pose a risk for sinusitis in children.

Symptoms

Symptoms Indicating a Bacterial Infection. Sinus symptoms are very common during a cold or the flu, but in most of these cases they are due to the effects of the infecting virus and resolve when the infection does. It is important to differentiate between inflamed sinuses associated with cold or flu virus and sinusitis caused by bacteria. With true acute bacterial sinusitis, the signs and symptoms typically have the following course:

Nasal congestion and discharge comes first and is typically thick with pus that is yellowish to yellow-green.
Pain in the teeth is increased by bending over. Symptoms may vary, however, depending on the sinuses involved.
Symptoms continue for 10 days or more after the start of a cold or flu.
They worsen after 5 - 7 days, or they return after initial improvement in a cold (called double sickening).

Other symptoms of acute sinusitis that usually occur in adults include:

Severe headache and pain or pressure in specific areas in the face -- eyes may be red, bulging or painful eyes if the sinus infection occurs around the eyes; in some cases, patients may also have double vision and even temporary vision loss.
A persistent cough (particularly during the day)
Fever
Fatigue (from lack of good rest)
Lack of response to decongestants or antihistamines

Sneezing, sore throat, and muscle aches may be present, but they are rarely caused by sinusitis itself. Muscle aches may be caused by fever, sore throat by post-nasal drip, and sneezing from cold or allergies.

Rare complications of sinusitis can produce additional symptoms, which may be severe or even life threatening.

Symptoms in Children. Children are most likely to develop infection in the ethmoid sinuses, located between the eyes. Children with sinusitis are also less likely to experience facial pain over the affected sinus and headache, which are the primary signs in adults. Symptoms of bacterial sinusitis may be less specific than in adults and include:

Persistent nasal discharge (of any type) and day time cough for more than 10 days, or
Severe symptoms last for at least 3 - 4 days in a row and include thick, greenish nasal discharge plus a fever of at least 102° F.

Other symptoms in children may include:

Irritability
Vomiting
Gagging on mucus
Cough

Recurrent acute and chronic sinusitis tend to take the following course:

Symptoms are more vague and generalized than acute sinusitis.
They last longer than 4 weeks. (Subacute sinusitis lasts longer than 4 weeks but less than 8 weeks. Chronic sinusitis lasts 8 weeks or longer.)
They occur throughout the year, even during nonallergy seasons.

Specifically symptoms may include:

Nasal congestion and obstruction
Chronic cough (day and night) -- research suggests that sinusitis is one of the main causes of chronic cough
Bad breath
Postnasal drip (which can cause repeated throat clearing)
Facial tenderness or pressure --patients do not usually experience facial pain unless the infection is in the frontal sinuses

Specific symptoms depend on the location of the infection:

Frontal sinusitis causes pain across the lower forehead.
The pain in maxillary sinusitis occurs over the cheeks and may travel to the teeth, and the hard palate in the mouth sometimes becomes swollen.
Ethmoid sinusitis causes pain behind the eyes and sometimes redness and tenderness in the area across the top of the nose.
Sphenoid sinusitis rarely occurs by itself; when it does, the pain may be experienced behind the eyes, across the forehead, or in the face.



ETHMOID SINUSITIS
Ethmoid sinuses are located between the eyes. They resemble a honeycomb and are vulnerable to obstruction. This is a common location for sinusitis in children.	Nasal congestion. Nasal discharge or postnasal drip. Pain or pressure around the inner corner of the eye or down one side of the nose. Headache in the temple or surrounding the eye. Symptoms worse when coughing, straining, or lying on the back and better when the head is upright. Fever. Symptoms of maxillary sinusitis often occur. Symptoms indicating medical emergency: Increasing severity of symptoms. Fever, swelling and drooping eyelid, loss of eye movement (possible orbital infection, which is in the eye socket). Fever, vision changes, pupil fixed or dilated. Symptoms spreading to both sides of face (may indicate blood clot).	Chronic nasal discharge, obstruction, and low-grade discomfort usually across the bridge of the nose. Symptoms worse in the late morning or when wearing glasses. Chronic sore throat and bad breath. Sinusitis also can recur in other sites.
ACUTE MAXILLARY SINUSITIS
Maxillary sinuses are located behind the cheek bones. They are present at birth and continue to develop as long as teeth erupt. Tooth roots, in some cases, can penetrate the floor of these sinuses.	Pain across the cheekbone, under or around the eye, or around the upper teeth; may occur on one or both sides of the face. Area over the cheekbone is tender and may be red or swollen. Possibly tooth pain. Symptoms are worse when the head is upright and improve when patient reclines. Nasal discharge or postnasal drip. Fever.	Discomfort or pressure below the eye. Chronic toothache. Symptoms become worse with colds, flu, or allergies. Discomfort increases during the day. Coughing increases at night.
FRONTAL SINUSITIS
Frontal sinuses are located on both sides of the forehead. These sinuses are late in developing, so infection here is uncommon in children.	Severe headache in the forehead. Fever (common but not always present). Symptoms are worse when lying on the back and when pressing against the area over the eye on the side closest to the nose. Symptoms are better when the head is upright. Nasal discharge or postnasal drip. Symptoms indicating medical emergency: Increasing severity of symptoms, particularly severe headache, altered vision, mild personality or mental changes (may indicate spread of infection to brain). Fever, vision changes, fixed or dilated pupil. Symptoms spreading to both sides of face (may indicate blood clot). Headache, fever, along with a soft swelling over the bone (may indicate bone infection).	Persistent, low-grade headache in the forehead. History of physical injury or other damage to the sinus area.
SPHENOID SINUSITIS
Sphenoid sinuses are located behind the eyes. They usually are present by age 3 and are fully developed by age 12.	Deep headache with pain in many places, including the back and top of the head, across the forehead, and behind the eye. Fever. Symptoms are worse when lying on the back or bending forward. Nasal discharge or postnasal drip. Symptoms indicating medical emergency: Increasing severity of symptoms, particularly severe headache, altered vision, mild personality or mental changes (may indicate spread of infection to brain).	Low grade, general headache (although not always present).

Complications

Bacterial sinusitis is nearly always harmless (although uncomfortable and sometimes even very painful). If an episode becomes severe, antibiotics generally eliminate further problems. In rare cases, however, sinusitis can be very serious.

Osteomyelitis. Adolescent males with acute frontal sinusitis are at particular risk for severe problems. One important complication is infection of the bones (osteomyelitis) of the forehead. In such cases, the patient usually experiences headache, fever, and a soft swelling over the bone known as Pott's puffy tumor.

Infection of the Eye Socket. Infection of the eye socket, or orbital infection, which causes swelling and subsequent drooping of the eyelid, is a rare but serious complication of ethmoid sinusitis. In these cases, the patient loses movement in the eye, and pressure on the optic nerve can lead to vision loss, which is sometimes permanent. Fever and severe illness are usually present.

Blood Clot. Another danger, although rare, from ethmoid or frontal sinusitis are blood clots. If a blood clot forms in the sinus area around the front and top of the face, symptoms are similar to orbital infection. In addition, the pupil may be fixed and dilated. Although symptoms usually begin on one side of the head, the process usually spreads to both sides.

Widespread Infection. The most dangerous complication of sinusitis, particularly frontal and sphenoid sinusitis, is the spread of infection by anaerobic bacteria to the brain, either through the bones or blood vessels. Abscesses, meningitis, and other life-threatening conditions may result. In such cases, the patient may experience mild personality changes, headache, altered consciousness, visual problems, and, finally, seizures, coma, and death.

Chronic and acute fungal sinusitis caused by the fungi Aspergillus and mucormycosis is difficult to treat and potentially lethal, particularly in people with diabetes and compromised immune systems. Mucormycosis is particularly dangerous if it is not treated quickly. Fungal ball (mycetoma) is not invasive and is nearly always treatable with surgery. Recurrence is rare.

The relationship between sinusitis and asthma is unclear. A number of theories have been proposed for a causal or shared association between sinusitis and asthma. Some include the following:

Stimulation of nerve pathways, inflammation, and overproduction of mucus in the nasal passages and sinus cavities may eventually affect the airways in the lung, causing them to hyperreact.
Breathing through the mouth when the sinuses are blocked allows in large particles that would other wise be filtered by the nasal defense system. Such particles could trigger allergic responses in the lungs that can trigger asthma in susceptible people.
Air breathed through the mouth is colder than air warmed in the nasal passages. Cold air is a known trigger of asthma.
Both may share similar immune abnormalities that cause inflammation in the airways in the lungs and sinuses.

Successful treatment of both allergic rhinitis and chronic sinusitis in children who also have asthma may reduce symptoms of asthma. It is particularly important to treat any coexisting bacterial sinusitis in people with asthma. They might not respond to asthma treatments unless the infection is cleared up first.

Pain and other symptoms of chronic sinusitis can have significant effects on the quality of life. This condition can cause emotional distress, impair normal activity, and reduce attendance at work or school. According to the American Academy of Allergy, Asthma, and Immunology, the average sinusitis patient misses about 4 work days a year. In fact, a 2003 study placed sinusitis in the top 10 medical conditions that most adversely affect American employers. In addition, some people may lose their sense of smell. Surgery or medical treatments can help restore this sense.

Diagnosis

Patients who have sinusitis symptoms that do not clear up within a few days, are severe, or are accompanied by high fever or acute illness should see a doctor. However, that only one-half to two-thirds of patients with such symptoms actually have sinusitis. Some experts complain that too many patients are diagnosed with true sinusitis and given unnecessary antibiotics when their symptoms would actually resolve easily in days with over-the-counter medications or no drugs at all. Others believe that true sinusitis is often mistakenly diagnosed as an allergy and not treated, which could lead to serious illness.

The first goal in diagnosing sinusitis is to rule out other possible causes of symptoms, and then determine:

The site where the infection has occurred
Whether the condition is acute or chronic
The organism causing the infection (if possible)

Ruling Out Sinus Symptoms Due to Cold or Flu Viruses. It is often difficult to tell when a viral infection converts to a bacterial infection. Studies have found that between 40 - 85% of patients with the common cold show signs of inflamed sinuses on x-rays or CT scans. A cold, however, unlike sinusitis, typically clears up without treatment within a week. (Only about 0.5 - 2% of adults with viral colds or flus actually develop bacterial infections.) In general, the doctor should suspect a bacterial infection under the following circumstances:

If sinus symptoms persist for 10 days or longer after a cold or flu, or
If symptoms become worse after 5 - 7 days

Ruling Out Allergies. Symptoms of both sinusitis and allergic rhinitis include nasal obstruction and congestion. The conditions often occur together. People with allergies and no sinus infection may have:

Thin, clear, and runny nasal discharge
Itchy nose, eyes, or throat (do not occur with bacterial sinusitis)
Recurrent sneezing
Symptoms of allergies appear only during exposure to allergens

Ruling Out Migraine and Other Headaches. Many primary headaches, particularly migraine or cluster, may closely resemble sinus headache. In fact, results presented at a 2004 meeting of the American Headache Society suggest that 90% of people who thought they had a sinus headache actually had migraines. Migraine and sinus headaches may even coexist in many cases. Sinus headaches are usually more generalized than migraines, but it is often difficult to tell them apart, particularly if headache is the only symptom of sinusitis. The following symptoms suggest a migraine rather than a sinus headache:

The headache is recurrent
It has a significant impact on daily activities
The headache does not get worse over time

Ruling Out Neuralgia. In some cases, headache that persists after successful treatment of chronic sinusitis may be due to neuralgia (nerve-related pain) in the face. This condition requires specific drugs, such as tricyclic antidepressants or carbamazepine. Trials using such drugs may identify patients with neuralgia and help avoid unnecessary invasive treatments for chronic sinusitis.

Ruling Out Other Conditions. A number of other conditions can mimic sinusitis. They include:

Dental problems
A foreign object in the nasal passage
Temporal arteritis (headache caused by inflamed arteries in the head and neck)
Persistent upper respiratory tract infections
Chronic fatigue syndrome (CFS) or fibromyalgia. However, researchers reported in the Archives of Internal Medicine that there may be a link between CFS and sinusitis. In the study, patients with unexplained chronic fatigue were nine times more likely to suffer sinus problems than those without fatigue.
Temporomandibular disorders (problems in the joints and muscles of the jaw hinges)
Vasomotor rhinitis, a condition in which the nasal passages become congested in response to irritants or stress. It often occurs in pregnant women.

Medical History. The patient should describe all symptoms such as nasal discharge and specific pain in the face and head, including eye and tooth pain.

After assessing symptoms, the doctor should take a thorough medical history of the patient:

Any history of allergies or headaches
Recent upper respiratory infection (colds, flus, infection)
History of sinusitis episodes that is unresponsive to antibiotic treatment. (In such cases, the doctor will usually diagnose chronic or recurrent acute sinusitis and refer the patient to a specialist for more advanced testing.)
Exposure to cigarette smoke or other environmental pollutants
Recent travel
Recent dental procedures, particularly if there is pain toward the back of the mouth
Medications being taken (particularly decongestants)
Any known structural abnormalities in the nose and face
Injury to the head or face
History of medical conditions, such as chronic fatigue syndrome or fibromyalgia, which can produce tender areas in the face or sinus regions and nonspecific symptoms of ill health
Any family history of allergies, immune disorders, cystic fibrosis, or immotile cilia syndrome
In small children with sinusitis, whether they attend a day care center or nursery school

The doctor will press the forehead and cheekbones to check for tenderness and check for other signs of sinusitis, including yellow to yellow-green nasal discharge. The doctor will also check the inside of the nasal passages using a device with a bright light to check the mucus and look for any structural abnormalities.

In some cases, tests may be used to detect that presence of immune factors in sinus tissues that would suggest persistent inflammation. Such findings would strongly suggest a chronic or allergic condition. In 2005, a new laboratory test became available for diagnosing chronic sinusitis. The CRS Fungal Profile tests mucus samples for eosinophil major basic protein (a protein involved in allergic and inflammatory reactions) and a type of fungi.

Nasal endoscopy, or rhinoscopy, is now used for diagnosing chronic and recurrent acute sinusitis and for differentiating between allergies and true acute sinusitis. It involves the insertion of a flexible tube into the nasal passage and the use of a fiberoptic light that enables the doctor to see inside the sinuses. Endoscopy allows detection of even very small abnormalities in the sinuses. It can determine whether surgery is necessary and if medications are having any effect. Bacterial cultures can also be taken from samples removed using endoscopy. (Endoscopy is also used for treating sinusitis.)

Computer Tomography. Computed tomography (CT) scanning is the best method for viewing the paranasal sinuses. There is little relationship, however, between symptoms in most patients and findings of abnormalities on a CT scan. CT scans are recommended for acute sinusitis only if there is a severe infection, complications, or a high risk for complications. CT scans are useful for diagnosing chronic or recurrent acute sinusitis and for surgeons as a guide during surgery. They show inflammation and swelling and the extent of the infection, including that in deep hidden air chambers missed by x-rays and nasal endoscopy. Often, they can detect the presence of fungal infections.

X-Rays. Until the availability of endoscopy and CT scans, x-rays were commonly used. They are not as accurate, however as these procedure in identifying abnormalities in the sinuses. For example, more than one x-ray is needed for diagnosing frontal and sphenoid sinusitis. X-rays do not detect ethmoid sinusitis at all, which can be the primary site of an infection that has spread to the maxillary or frontal sinuses.

Magnetic Resonance Imaging. MRI is not as effective as CT in defining the paranasal anatomy and therefore is not typically used to image the sinuses for suspected sinusitis. MRI is also more expensive than CT. However, it can help rule out fungal sinusitis and may help differentiate between inflammatory disease, malignant tumors, and complications within the skull. It may also be useful for showing soft tissue involvement.

Transillumination is a procedure aimed at visualizing maxillary and frontal sinuses. First the doctor shines a bright light against the patient's cheek or forehead in a completely darkened room. If the sinuses are clear, the doctor will observe a glow on the hard palate of the open mouth or in the areas of the cheek where the sinus passages are located. It is fast, safe, and inexpensive, but it is useful only in adults and only to rule out any problems. It has largely been supplanted by more accurate diagnostic techniques.

Sinus puncture with bacterial culture is the gold standard for diagnosing a bacterial sinus infection. It is invasive, however, and is performed only when antibiotics have not worked. Sinus puncture involves using a needle to withdraw a small amount of fluid from the sinuses. It requires a local anesthetic and is performed by a specialist. The fluid is then cultured to determine what type of bacteria is causing sinusitis.

Prevention

The best way to prevent sinusitis is to avoid colds and influenza. If you are unable to avoid them, the next best way to prevent sinusitis is to effectively treat colds and influenza.

Colds and flu are spread primarily when an infected person coughs or sneezes near someone else. A very common method for transmitting a cold is by shaking hands. Everyone should always wash their hands before eating and after going outside. Ordinary soap is sufficient. Waterless hand cleaners that contain an alcohol-based gel are also effective for every day use and may even kill cold viruses. (They are less effective, however, if extreme hygiene is required. In such cases, alcohol-based rinses are needed.) Antibacterial soaps add little protection, particularly against viruses. In fact, one study suggests that common liquid dish washing soaps are up to 100 times more effective than antibacterial soaps in killing respiratory syncytial virus (RSV), which is known to cause pneumonia. Wiping surfaces with a solution that contains one part bleach to 10 parts water is very effective in killing viruses.

Colds are not caused by insufficiently warm clothes or by going outside with wet hair. A 2002 study reported, however, that in older adults cold temperatures can thicken the blood and may increase the risk for respiratory infections and even circulatory and heart problems.

Foods Containing Lactobacilli (Good Bacteria). Researchers are studying the possible protective value of certain strains of lactobacilli bacteria found in the intestines. Some of these strains, particularly acidophilus, are used to make yogurt. According to one study, milk containing the strain lactobacilli GG helped reduce respiratory infections in children attending day care by 10 - 20%.

Vitamins. Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies in 2002 on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems.

Studies on vitamin E specifically have been largely negative. A 2002 study, in fact, reported a higher incidence and greater severity of respiratory infections in older adults who took 200 mg of vitamin E daily.

Breastfeeding. Evidence suggests that women who breastfeed reduce the risk of respiratory infections in their children. The American Academy of Pediatrics recommends that babies be fed exclusively breastmilk for their first 6 months.

Low Stress and Active Social Life. More than one study has reported that people with low stress who also have an active social life have fewer colds than people who have high stress levels or those who have low stress and few social connections.

Zinc appears to have certain important effects on the immune system and it may have a direct effect on viruses. How it works is not entirely clear, however. Zinc preparations in lozenge or nasal gel form are now available as cold treatments. Studies are very mixed on the effects of zinc on colds.

A nasal gel (Zicam), which contains zinc gluconate, has shown some success, possibly because the gel sticks to the nasal passages long enough for the zinc to interact with the virus. In a 2003 study, for example, the nasal gel shortened the duration and severity of the cold compared to placebo when it was started within 14 - 48 hours of the onset of symptoms. The supports earlier studies reporting that it shortened the duration of a cold by about 2 days.
Zinc lozenges are showing mixed results. One 2000 study suggested that the use of zinc acetate lozenges may be more effective and have a better taste than other formulations, such as zinc gluconate. On the other hand, a 2002 study reported that zinc gluconate reduced cold duration significantly. To further confuse matters, the two zinc lozenge preparations were directly compared in a 2000 study, and neither was effective.

In any case, no one with an adequate diet and a healthy immune system should take zinc for prolonged periods for preventing colds. Long-term use of zinc (100 mg or higher daily) has been associated with heart problems, anemia, and other conditions.

Side Effects. Side effects of zinc include:

Dry mouth
Constipation
Nausea
Bad taste (possibly only with zinc gluconate lozenges)
Overdose may cause severe vomiting, dehydration, and restlessness. Call a doctor if any of these symptoms occur.
In rare cases, an allergic response may occur.

Food and Drug Interactions. Zinc may also interact with drugs or food:

Zinc may reduce absorption of certain antibiotics.
Foods high in calcium or phosphorus may reduce zinc absorption.
In high doses, and for long periods of time, zinc can cause copper deficiencies.

The following are special concerns for people taking natural remedies for sinusitis:

Echinacea is commonly taken to prevent onset and ease symptoms of cold or flu. However, a rigorous study published in 2005 in the New England Journal of Medicine determined that echinacea does not help to prevent or treat colds. In addition, allergic reactions have been reported. People with autoimmune diseases or plant allergies should particularly avoid this herbal remedy. Echinacea has also been associated with a reaction called erythema nodosum. This involves a rash, sometimes accompanied by fever, headache, muscle and joint aches, and sore throat.
Grapeseed extract is sometimes touted as a natural antihistamine. A 2002 study, however, reported no benefits from it.
Chinese herbal products containing aristolochic acid have been associated with several reports of kidney failure in Europe. Some studies suggest that up to 30% of herbal patent remedies imported from China are laced with potent pharmaceuticals such as phenacetin and steroids. Chinese herbal remedies can also contain toxic metals such as lead.

Vaccines against influenza use inactivated (not live) viruses. Because influenza viruses change from year to year, influenza vaccines are redesigned annually to match the anticipated viral strains. Experts recommend that people receive annual influenza vaccinations in October or November. People who should definitely be vaccinated include: all adults 65 years or older; children age 6 months - 5 years; other adults or children who are at high risk for developing serious medical complications from influenza; health care workers and others who care for individuals who are at high risk for influenza complications. [See In-Depth Report #94: Colds and influenza.]

The pneumococcal vaccine protects against S. pneumoniae (also called pneumococcal) bacteria, the most common cause of respiratory infections. There are two effective vaccines available, one called a 23-valent polysaccharide vaccine (Pneumovax, Pnu-Immune) for adults and a 7-valent conjugate vaccine (Prevnar or PCV7) for infants and young children. Experts are now recommending that more people, including healthy elderly people, be given the pneumococcal vaccine, particularly in light of the increase in antibiotic-resistant bacteria. [See In-Depth Report #64: Pneumonia.]

Treatment for Acute Sinusitis

The primary objectives for treatment of sinusitis are reduction of swelling, eradication of infection, draining of the sinuses, and ensuring that the sinuses remain open. Less than half of patients reporting symptoms of sinusitis need aggressive treatment. Home remedies can be very useful.

Home remedies that open and hydrate sinuses may, indeed, be the only treatment necessary for mild sinusitis that is not accompanied by signs of acute infection.

Drinking plenty of fluids and getting lots of rest when needed is still the best bit of advice to ease the discomforts of the common cold. Water is the best fluid and helps lubricate the mucous membranes. (There is no evidence that drinking milk will increase or worsen mucus, although milk is a food and should not serve as fluid replacement.)
Chicken soup does indeed help congestion and aches. The hot steam from the soup may be its chief advantage, although laboratory studies have actually reported that ingredients in the soup may have anti-inflammatory effects. In fact, any hot beverage may have similar soothing effects from steam. Ginger tea, fruit juice, and hot tea with honey and lemon may all be helpful.
Spicy foods that contain hot peppers or horseradish may help clear sinuses.
Inhaling steam 2 - 4 times a day is extremely helpful, costs nothing, and requires no expensive equipment. The patient should sit comfortably and lean over a bowl of boiling hot water (no one should ever inhale steam from water as it boils) while covering the head and the bowl with a towel so the steam remains under the cloth. The steam should be inhaled continuously for 10 minutes. A mentholated or other aromatic preparation may be added to the water. Long, steamy showers, vaporizers, and facial saunas are alternatives.

Many people take medications to reduce mild pain and fever. Adults most often choose aspirin, ibuprofen (Advil), or acetaminophen (Tylenol).

The following are recommendations for children:

Acetaminophen (Tylenol) or ibuprofen (usually Advil or Motrin) is the pain-reliever of choice in children. Most pediatricians advise such medications for children who run fevers over 101°F.
Aspirin and aspirin-containing products are virtually never recommended for children or adolescents. Reye syndrome, a very serious condition, has been associated with aspirin use in children who have flu symptoms or chicken pox.

Some studies suggest that these anti-fever drugs may actually reduce the body's immune response against cold and flu viruses and prolong symptoms. A 2000 study, for example, reported a longer flu duration in people who took aspirin or acetaminophen (although people still felt better). Nevertheless, most doctors strongly recommend lowering fevers in children, since high fevers can sometimes cause seizures.

A nasal wash can be helpful for removing mucus from the nose. A saline solution can be purchased at a drug store or made at home. (Mix 1 teaspoon of table salt with a pinch of baking soda in 2 cups of warm water.) The nasal wash should be performed several times a day. Researchers have reported that daily irrigation of the nasal passages with a hypertonic saline solution relieves sinusitis symptoms and also reduces antibiotic use and the occurrence of acute exacerbations. Patients in the study had 72% fewer sinus infections, a 69% improvement in breathing, and they reduced medication usage by more than half.

A simple method for administering a nasal wash is:

Lean over the sink head down.
Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a time.
Spit the remaining solution out.
Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case the process is:

Lean over the sink head down.
Insert only the tip of the syringe into one nostril.
Gently squeeze the bulb several times to wash the nasal passage.
Then press the bulb firmly enough so that the solution passes into the mouth.
The process should be repeated in the other nostril.

Decongestants are drugs that help reduce nasal congestion. They are available in a pill or nasal form. However, decongestants will not cure sinusitis. Nasal decongestants can actually worsen sinusitis by increasing sinus inflammation. Due to the lack of evidence for nasal decongestants’ benefits for sinusitis, the FDA has ruled that manufacturers of over-the-counter (OTC) nasal decongestant products remove from their labeling all references to sinusitis.

Your doctor may still recommend that you take either an OTC or prescription nasal decongestant to help relieve blockage symptoms associated with sinusitis. If you think you have sinusitis, it is important that you check with your doctor before taking a decongestant. Do not try to treat sinusitis by yourself.

Nasal Decongestants. Nasal decongestants come in long-acting or short-acting forms. The effects of short-acting decongestants last about 4 hours; long-acting decongestants last 6 - 12 hours. The active ingredients in nasal decongestants include oxymetazoline, xylometazoline, and phenylephrine.

Tips for Use. The following precautions are important for people taking nasal decongestants:

When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
Do not share droppers and inhalators with other people.
Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
Discard the medicine if it becomes cloudy or unclear.

Decongestants Taken by Mouth. Pseudoephedrine is the only decongestant taken by mouth that is currently available over-the-counter (OTC) in the United States. It decreases the volume of mucous in the nose, as well as within the Eustachian tubes. Many brands of OTC oral decongestants are available. A common brand is Sudafed. Oral decongestants such as Sudafed can also be helpful for relieving cough associated with postnasal drip.

Warning: Anyone with old forms of any decongestant should check the labels and discard them if they contain phenylpropanolamine. In November 2000, the FDA banned products, including decongestants, which contained phenylpropanolamine (PPA). This action was in response to a few reports of an increased risk of stroke. (Stroke tended to occur in people who took diet suppressants containing PPA rather than decongestants. In any case, serious events were still very rare.) All major brands that previously contained PPA have now substituted other active ingredients (usually pseudoephedrine) and are safe to use.

Side Effects of Decongestants. Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants and include:

Agitation and nervousness
Drowsiness (particularly with decongestants taken by mouth and in combination with alcohol)
Changes in heart rate and blood pressure
Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives

Heart disease
High blood pressure
Thyroid disease
Diabetes
Prostate problems that cause urinary difficulties
Migraines
Raynaud's phenomenon
High sensitivity to cold
Emphysema or chronic bronchitis. (Such individuals should particularly avoid high-potency short-acting nasal decongestant.)
People taking medications that increase serotonin levels, such as certain antidepressants, anti-migraine drugs, diet pills, St. John's wort, and methamphetamine. The combinations can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.

Anyone with these conditions should not use either oral or nasal decongestants without a doctor's guidance. Other groups who should not use these drugs without first consulting a doctor include:

Pregnant women
Children. The American College of Chest Physicians advises against the use of over-the-counter decongestants and other cold medications in children ages 14 years or younger. Children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. In 2007, the FDA began reviewing the safety and effectiveness of cough and cold remedies for children.

Older antihistamines such as diphenhydramine (Benadryl) are helpful in relieving cough when used alone or in combination with a decongestant.

Expectorants are drugs that cause mucus to be coughed up from the lungs. The most common type used is guaifenesin, which is found in many over-the-counter (OTC) cough syrups as well as prescription products. Expectorants used to be recommended for treatment of sinusitis-associated cough, but some recent guidelines advise against their use. According to the American College of Chest Physicians (ACCP), expectorants and cough suppressants do not help treat cough. The ACCP recommends that adults instead take a decongestant or antihistamine to relieve cough. The ACCP also recommends against OTC cold and cough medicine for children ages 14 years and younger. Parents should talk with their child’s pediatrician for advice on treating cough.

Overview on Antibiotics and Their Overuse. Sinusitis is the fifth most common diagnosis for antibiotic prescriptions. And, there is much evidence that antibiotics are inappropriately prescribed for many patients:

According to a 2007 study of recent treatment patterns for acute and chronic sinusitis, antibiotics are widely overused. The researchers noted that viruses (not bacteria) account for a large percentage of acute sinusitis cases and that most acute sinusitis cases clear up on their own. The study also indicated that inhaled corticosteroids are frequently prescribed for acute sinusitis despite a lack of evidence for their benefit.
A major analysis reported that antibiotics helped only 1 child in 8 who had persistent nasal discharge for at least 20 days. Even when antibiotics were helpful, benefits were modest in reducing duration of the infection. This study supports other research that has found no significant benefit from antibiotics for most children. In a 2001 study, for example, 87% of children improved regardless of their treatment.

The intense and widespread use of antibiotics -- not only for sinusitis but also for other upper respiratory tract infections -- is leading to a serious global problem, which is bacterial resistance to common antibiotics. For example, according to reports in 2002 and 2001, in Canada 15% of S. pneumoniae strains are resistant to penicillin; in the U.S. 30 - 40% are resistant; in Hong Kong 70 - 80% of strains no longer respond to penicillin. Furthermore, in the U.S. about 23% of S. pneumoniae are currently resistant to at least three antibiotics. High rates of resistance strains are even being observed in infants. In general, regions with the highest rate of resistance are those in which antibiotics are the most heavily prescribed. Encouraging studies are now reporting that inappropriate antibiotic prescriptions are on the decline.

When to Use Antibiotics. Because the majority of sinusitis cases resolve on their own, doctors generally wait 10 - 14 days before prescribing antibiotics. However, antibiotics may be prescribed sooner if severe symptoms develop. These symptoms include:

Fever
Facial pain or tenderness
Swelling around the eyes

Antibiotic Regimens

The standard first-line antibiotic treatment for acute bacterial sinusitis is a 10 - 14 day course of amoxicillin. Trimethoprim-sulfamethoxazole is an alternative choice.
If no change occurs within 3 - 5 days, the doctor may prescribe a different type of antibiotic such as amoxicillin-clavulanate, cephalosporin, or a macrolide.
If the patient does not respond after 21 - 28 days, broad-spectrum antibiotics such as amoxicillin-clavulanate, cefuroxime, or cefpodoxime may be used. Other choices include clarithromycin or azithromycin (macrolides) or levofloxacin (a fluoroquinolone).

Side Effects of Antibiotics. Most antibiotics have the following side effects (although specific antibiotics may have other side effects or fewer of the standard ones):

The most common side effect for nearly all antibiotics is gastrointestinal distress.
Antibiotics double the risk for vaginal infections in women. Taking supplements of acidophilus or eating yogurt with active cultures may help restore healthy bacteria that offset the risk for such infections.
Allergic reactions can also occur with all antibiotics but are most common with medications derived from penicillin or sulfa. These reactions can range from mild skin rashes to rare but severe, even life-threatening anaphylactic shock.
Certain drugs, including some over-the-counter medications, interact with antibiotics; patients should inform the doctor of all medications they are taking and of any drug allergies.

Beta-Lactams

The beta-lactam antibiotics share common chemical features and include penicillins and cephalosporins. Their primary action is to interfere with bacterial cell walls.

Penicillins. Amoxicillin (Amoxil, Polymox, Trimox, Wymox, or any generic formulation) has been the most widely prescribed antibiotic for acute sinusitis. This penicillin is both inexpensive and at one time was highly effective against the S. pneumoniae bacteria. Unfortunately, bacterial resistance to amoxicillin has increased significantly, both among S. pneumoniae and H. influenzae, and penicillin is no longer as reliable as it once was.

Amoxicillin-clavulanate (Augmentin) is a type of penicillin that works against a wide spectrum of bacteria. An extended release form has been approved for treating adults with sinusitis infections that have become resistant to penicillin.

Many people have a history of an allergic reaction to penicillin, but some evidence is suggesting that the allergy may not recur in a significant number of adults. Skin tests are available that could determine if some people previously allergic could use these important antibiotics.

Cephalosporins. These drugs are also effective against S. pneumoniae. They are often classed by generation:

First generation includes cephalexin (Keflex), cefadroxil (Duricef, Ultracef), and cephradine (Velosef).
Second generation include cefaclor (Ceclor), cefuroxime (Ceftin), cefprozil (Cefzil), and loracarbef (Lorabid).
Third generation include cefpodoxime (Vantin), cefdinir (Omnicef) cefditoren (Sprectracef), cefixime (Suprax), and ceftibuten (Cedex). Ceftriaxone (Rocephin) is an injected cephalosporin. These are effective against a wide range of bacteria.

The later-generation antibiotics cefpodoxime, cefdinir, and cefuroxime are good choices for penicillin-allergic patients with mild-to-moderate sinusitis who have been treated in the previous 4 - 6 weeks. Penems, a type of beta-lactam antibiotic, are also being investigated for sinusitis treatment.

Macrolides and Azalides

Macrolides are a class of antibiotics that are divided into different sub-groups. Azalides are one of those sub-groups. This type of antibiotic is often used to treat mild-to-moderate bacterial sinusitis in patients who are allergic to penicillin. Some of the most common macrolids/azalides are azithromycin (Zithromax), clarithromycin (Biaxin), and roxithromycin (Rulid). An extended-release form of azithromycin (Zmax) was approved in 2005 as a single dose treatment for mild-to-moderate acute bacterial sinusitis. These antibiotics are also effective against many strains of S. pneumoniae and M. catarrhalis, but macrolide-resistance rates doubled between 1995 - 1999 as the number of children treated with the antibiotics increased. Erythromycin is not effective against H. influenzae.

Macrolides have anti-inflammatory actions, which may have benefits for some patients with chronic sinusitis. Investigators are studying long-term low-dose macrolide treatments, which are not intended to eliminate bacteria, but to reduce inflammation. Studies suggest that this approach may be effective without increasing the risk for bacterial resistance.

Trimethoprim-Sulfamethoxazole

Trimethoprim-sulfamethoxazole (Bactrim, Cotrim, Septra) is another first-line antibiotic for sinusitis. It is less expensive than amoxicillin and particularly useful for patients with mild sinusitis who are allergic to penicillin. It is no longer effective, however against certain streptococcal strains. It should not be used in patients whose infections occurred after dental work or in patients allergic to sulfa drugs. Allergic reactions can be very serious.

Fluoroquinolones (Quinolones)

Fluoroquinolones (also simply called quinolones) interfere with the bacteria's genetic material so they cannot reproduce.

Newer generation fluoroquinolones, which include levofloxacin (Levaquin), sparfloxacin (Zagam), gatifloxacin (Tequin), and moxifloxacin (Avelox), are currently the most effective antibiotics against the common bacteria that cause sinusitis. They are recommended for adults with moderate sinusitis who have already been treated with antibiotics within 6 weeks or who are allergic to beta-lactam antibiotics.

Some of the newer fluoroquinolones only need to be taken once a day, which make compliance easier. Some, but not all, quinolones cause photosensitivity. S. pneumoniae strains resistant to the quinolones have been uncommon in the U.S. but their numbers are increasing. In fact, levofloxacin was the first drug approved specifically for penicillin-resistant S. pneumoniae. Unfortunately, studies are now finding resistance to this drug as well.

Lincosamide

Lincosamides prevent bacteria from reproducing. The most common lincosamide is clindamycin (Cleocin). This antibiotic is useful against many S. pneumoniae bacteria but not against H. influenzae.

Tetracyclines

Tetracyclines inhibit bacterial growth. They include doxycycline, tetracycline, and minocycline. They can be effective against S. pneumoniae and M. catarrhalis, but bacteria that are resistant to penicillin are also often resistant to doxycycline. Tetracyclines have unique side effects among antibiotics, including skin reactions to sunlight, possible burning in the throat, and tooth discoloration.

Ketolides

In February 2007, the FDA withdrew approval of telithromycin (Ketek) for treatment of acute bacterial sinusitis. The agency decided that the serious risks of telithromycin outweigh its benefits for sinusitis treatment. The decision followed several 2006 reports of patient deaths due to severe liver damage. Telithromycin is now approved only for treatment of community-acquired pneumonia (CAP).

In 2003, research suggested that delivering medications directly to the sinus passages (instead of the bloodstream, like a pill might) significantly increases the amount of time chronic sinusitis patients remain infection free. The treatment, called nebulized antibiotic therapy, requires that patients inhale antibiotics in mist form to topically treat their sinusitis. The study showed that nebulization therapy increased the infection free period for some patients by almost 300% when compared to other treatments.

Patients who show signs that infection has spread beyond the nasal sinuses into the bone, brain, or other parts of the skull require emergency care. High dose antibiotics are administered intravenously, and emergency surgery is almost always necessary in such cases.

Severe Fungal Sinusitis. Sinusitis caused by severe fungal infections is a medical emergency. Treatment is aggressive surgery, and high-dose antifungal chemotherapy with a drug such as amphotericin B can be life saving. The use of oxygen administered at high pressure (hyperbaric oxygen) is showing promise as additional therapy for potentially deadly fungal infections.

Treatment for Chronic Sinusitis

Determining and Treating any Underlying Conditions. A thorough diagnostic work-up should be performed to rule out any underlying conditions, including but not limited to allergies, asthma, any immune problems, gastroesophageal reflux disorder, and structural problems in the nasal passages. If a primary trigger for chronic sinusitis can be identified, it should be treated or controlled if possible.

Initial Treatment of Sinusitis. For treatment of chronic sinusitis itself, some doctors recommend:

A wide spectrum antibiotic (one that can eliminate a wide range of bacteria) taken for at least 30 days.
Alternatively, an antibiotic that attacks anaerobic pathogens.
A corticosteroid nasal spray -- some doctors also recommend oral corticosteroids (such as prednisone) for patients who do not respond to nasal corticosteroids or for those patients who have nasal polyps. Prednisone is also used for patients who have allergic fungal sinusitis.
Saline nasal washes.
The expectorant guaifenesin with a decongestant taken by mouth.
Antihistamines.

If the condition dramatically improves between 1 - 2 months, then the antibiotics are stopped. The patient should continue with both the steroid and saline nasal solutions. If there is no improvement after this time, the surgery may be considered. For some people with chronic sinusitis, however, the condition is not curable, and the goal of treatment is to improve the quality of life.

Chronic sinusitis is often the result of damage to the mucous membrane from a past, untreated acute sinus infection. The aerobic and anaerobic bacteria present in chronic sinusitis are often different from those that cause the acute form. The role of antibiotic treatment for chronic sinusitis is controversial. Special types of antibiotics may be used, and treatment may be needed for a longer time.

Intravenous antibiotic therapy may be required for some patients with chronic sinusitis, particularly those with underlying medical disorders that can worsen the condition. They are typically administered 2 weeks before surgery and continued for about month afterward.

Some studies have reported good results in using antibiotics that are sprayed into the nasal passages using a nebulizer. In one study, patients preferred this method to either oral or intravenous treatments.

Benefits of Corticosteroid Nasal Sprays. Nasal-spray corticosteroids, most commonly called steroids, are effective drugs for treating allergic rhinitis. They also are proving to be very important in the treatment of chronic sinusitis and are sometimes used for acute sinusitis. Some studies have reported that, when combined with antibiotics, they speed recovery and improve healing rates of sinusitis compared to antibiotics alone. Nasal spray steroids are proving to be safe and have the following benefits:

They reduce inflammation and mucus production.
They improve night sleep and daytime alertness in patients with perennial allergic rhinitis.
They appear to be beneficial in treating polyps in the nasal passages.

Nasal-Spray Brands. Corticosteroids available in nasal spray form include:

Triamcinolone (Nasacort). Approved for children over age 6.
Mometasone furoate (Nasonex). Approved for use in patients as young as age 3.
Fluticasone (Flonase, Flounce). Approved for children over age 4.
Beclomethasone (Beconase, Vancenase), flunisolide (Nasalide), and budesonide (Rhinocort). Approved for children over age 6.

Side Effects. Corticosteroids are powerful anti-inflammatory drugs. Although oral steroids can have many side effects, the nasal-spray form affects only local areas, and the risk for wide spread side effects is very low unless the drug is used excessively.

Dryness, burning, stinging in the nasal passage
Sneezing
Headaches and nosebleed (these side effects are uncommon but should be reported to your doctor immediately)

Possible Long-Term Complications. Corticosteroids suppress stress hormones, which are known to produce some serious long-term complications in people who take oral steroids. Researchers have found far fewer concerns with nasal administration or inhaled forms, but there may be certain problems.

Effect on growth. The major concern for children is whether nasal steroids, like other forms of steroids, will adversely affect growth. Studies report either only a temporary and slight (about half an inch) early effect on growth or no effect at all.
Effect on eyes. Glaucoma is a known side effect of oral steroids. Some ophthalmologists have observed higher pressure in the eye (a sign of glaucoma) in some patients taking nasal steroid sprays. Studies have found no increased risk for cataracts in young people who have taken intranasal steroids. All the conditions resolve after stopping the steroid, although periodic eye examinations are advised.
Use during pregnancy. Steroids are most likely safe during pregnancy, but pregnant women should discuss all options carefully before taking them.
Nasal passage injury. Steroid sprays may injure the nasal septum (the bony area that separates the nasal passage) if the spray is directed onto it. This complication is very rare.
Lower resistance to infection. People with any infectious disease or injury in the nose should not take these drugs until the disease or wound has been treated and cured. People should avoid steroids if they have not been vaccinated or have had chicken pox or measles.
In some cases, people become insensitive to the effects of corticosteroids and they stop working.

Leukotriene-antagonists are oral drugs that block leukotrienes, powerful immune system factors that are important in causing airway constriction and mucus production in allergy-related asthma. Leukotriene-antagonists include zafirlukast (Accolate), montelukast (Singulair), (Ziflo), and pranlukast (Ultair, Onon). They may also be useful in certain cases of chronic sinusitis, including sinusitis due to polyps, when allergies are the cause, or in some cases when the cause is unknown.

Scientists are investigating whether antifungal drugs may help treat chronic sinusitis. One such drug, Amphotericin B (SinuNase), is currently in Phase III trials for patients who have had sinus surgery but are still experiencing recurrent sinusitis. Results from previous clinical trials have been mixed.

Patients often have various combinations of allergies, sinusitis, and asthma. Treating each condition is important for improving them all. In addition to decongestants, pain relievers, and expectorants, other remedies are available for people who suffer from nonbacterial sinusitis during allergy season.

Anti-Inflammatory Drugs. Nasal spray corticosteroids (commonly called steroids) are important for reducing the inflammatory response in the nasal passages and airways. They are important in the treatment of asthma and are now considered to be the most effective measure for preventing allergy attacks. Leukotriene-antagonists are also useful for sinusitis symptoms.
Antihistamines. Antihistamine tablets relieve sneezing and itching and can prevent nasal congestion before an allergy attack. Many brands are available by prescription and over the counter.
Immunotherapy. Immunotherapy, commonly referred to as "allergy shots," may be considered for patients with severe seasonal allergies that do not respond to treatment. Immunotherapy is the only treatment that affects the cause of allergies. In one year-long study using immunotherapy, over half of young patients participating experienced improvement in overall sinusitis symptoms, and nearly all felt better in general. Immunotherapy also may prevent asthma and the development of new allergies in children. Newer immunotherapeutic approaches using specially designed antibodies and vaccines are also showing promise.
All drug treatments have side effects, some very unpleasant and, in rare cases, serious. Patients may need to try different drugs until they find one that relieves symptoms without producing excessively distressing side effects.

Surgery

Surgery is used to unblock the sinuses when drug therapy is not effective or if there are other complications, such as structural abnormalities or fungal sinusitis.

The simplest surgical approach is the insertion of a drainage tube into the sinuses followed by an infusion of sterile water to flush them out.

In the past few years there has been a major advance in the surgical treatment with a minimally invasive technique called functional endoscopic sinus surgery (FESS). The procedure allows correction of obstructions, including any polyp and ventilation and drainage to aid healing.

Candidates for the Procedure.

FESS may be a good choice for people with chronic sinusitis associated with structural abnormalities. In one study, the best results were seen in people with polyps (but not those associated with ASA triad, the combination of polyps in the nose, asthma, and sensitivity to aspirin).
Several studies are finding it to be safe and effective in children with chronic sinusitis or whose sinuses have not developed. It does not have an adverse effect on facial growth.
Surgery may help patients with HIV who have chronic or recurrent sinusitis.
It may benefit appropriate candidates who have both sinusitis and asthma. One study suggested that lung function may improve afterward in some patients.

Surgery may not be as effective for patients with the ASA triad, fungus infections, or severe chronic sinusitis, although endoscopy is proving to be beneficial even for these conditions with the use of more powerful instruments.

Procedure. The surgery generally proceeds as follows:

Adults require only a local anesthetic for the procedure, though a general anesthetic is needed for children.
Before the procedure, a computed tomography (CT) scan is taken for use by the surgeon in planning the procedure and as a guide to the sinuses during surgery. Some doctors are now using a device called a depth of field image (DOFI) video enhancement screen that displays a holographic 3-D image. It allows the surgeon an excellent view of the sinus cavities and may prove to significantly reduce complications.
A flexible tube, a miniature camera, and a fiberoptic light source are inserted through a single small opening.
Instruments are then used to remove diseased bone or tissue and clear obstructions. For instance, shavers are used to gently remove soft tissue. Bone cutters are sometimes employed to open the floor of the frontal sinus and restore drainage (called the modified Lothrop procedure). Lasers are also being investigated to remove bone, coagulate the passageways, or clear obstructions.

Complications. Serious complications of FESS are very rare, but the following have been reported in a few cases:

Cerebrospinal fluid leak is the most common major complication, but it occurs in only 0.2% of cases and is usually easily repaired during surgery.
Other very rare complications include meningitis, hemorrhage, infection, or vision loss.
Patients can develop infections afterward that are very difficult to treat. Interesting studies are reporting good to excellent results in these patients by spraying antibiotics into the nasal passages using a nebulizer.

Postsurgical Care. Postsurgical care involves the following:

The patient will experience a dull ache around the nose and sinus cavity that can be treated with pain medication.
Following surgery, the patient should flush the sinuses twice daily with a saline or alkaline solution.
Antibiotics may be prescribed for several weeks until postnasal drip has stopped, and corticosteroid sprays and antihistamines may be needed.

Success Rates. It may take several months for the mucous membranes to completely recover, but between 85 - 90% of patients experience good to excellent symptomatic relief after surgery. Children may require a second procedure 2 - 3 weeks after the first surgery to remove crusty matter.

A high-pressure water jet (HPWJ) treatment that flushes diseased mucus that remains after FESS surgery is being investigated for those whose symptoms do not clear. One 2000 study found the procedure an effective therapy that may even be safe for children.

A new type of surgical procedure threads a small balloon through the sinus passages. As the balloon is gently opened, the sinus passages expand and drainage occurs. Some experts think that this procedure is only appropriate for select patients with sinusitis disease in the maxillary (behind cheek bones), frontal (behind the sides of the forehead), and sphenoid (behind the eyes) sinus regions. It may not work for patients with disease in the ethmoid (between the eyes) sinuses, even though this a common sinusitis location.

Endoscopy is now used in most cases of chronic sinusitis, but in severe cases, invasive surgery using conventional scalpel techniques to remove infected areas may be required. This may be the case with acute ethmoid sinusitis in which pus breaks through the sinus and threatens the eye, with very severe frontal sinusitis, with invasive fungal sinusitis, or when cancer is present in the sinuses.

Resources

www.entnet.org -- American Academy of Otolaryngology - Head and Neck Surgery
www.aaaai.org --American Academy of Allergy, Asthma, and Immunology
www.acaai.org --American College of Allergy, Asthma, and Immunology
www.niaid.nih.gov -- National Institute of Allergy and Infectious Disease
www.american-rhinologic.org -- American Rhinologic Society
www.cdc.gov/nip -- National Immunization Program

References

Brown CL, Bolger WE. Safety and feasibility of balloon catheter dilation of paranasal sinus ostia: a preliminary investigation. Ann Otol Rhinol Laryngol. 2006 Apr;115(4):293-9.

Clay KD, Hanson JS, Pope SD, Rissmiller RW, Purdum PP 3rd, Banks PM. Brief communication: severe hepatotoxicity of telithromycin: three case reports and literature review. Ann Intern Med. 2006 Mar 21;144(6):415-20.

Ebbens FA, Scadding GK, Badia L, Hellings PW, Jorissen M, Mullol J, et al. Amphotericin B nasal lavages: not a solution for patients with chronic rhinosinusitis. J Allergy Clin Immunol. 2006 Nov;118(5):1149-56.

Sharp HF, Denman D, Puumala S, Leopold DA. Treatment of acute and chronic rhinosinusitis in the United States, 1999-2002. Arch Otolaryngol Head Neck Surg. 2007 March;133(3):260-265.

Weschta M, Rimek D, Formanek M, Podbielski A, Riechelmann H. Effect of nasal antifungal therapy on nasal cell activation markers in chronic rhinosinusitis. Arch Otolaryngol Head Neck Surg. 2006 Jul;132(7):743-7.

Review Date:
3/23/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Skin wrinkles and blemishes

FitSugar — Wed, 08 Oct 2008 17:34:59 -0700

In This Report

Highlights
Introduction
Blemishes
Risk Factors
Prevention
Treatment
Resurfacing Treatments
Implant Procedures
Plastic Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Smoking and Skin Damage

The skin of smokers ages more rapidly than the skin of non-smokers, even in areas of the body not exposed to sunlight, according to a 2007 study. Women in the study who smoked also had much lower levels of vitamin E secretions in their skin. Vitamin E may protect the skin from sun damage.
There may be an association between smoking and higher frequency of a type of acne (noninflammatory acne) in adult women, according to a European study.

Antioxidants and Your Skin

A study in the Journal of Nutrition found that a combination of antioxidants and trace elements supplementation raises the risk of skin cancer in women, but not in men.

Ultraviolet Radiation

Overall, exposure to ultraviolet radiation from sunlight (radiation referred to as UVA or UVB) accounts for about 90% of the symptoms of premature skin aging.
UVB primarily affects the outer skin layers. It is most intense when sunlight is brightest. People receive slightly over 70% of their yearly UVB dose during the summer.
UVA penetrates more deeply and efficiently. The intensity of UVA rays is less dependent on the time of day and season of the year than that of UVB rays.

Vitamin D

A report analyzing studies of vitamin D supplementation found that people who take vitamin D supplements live longer than those who do not. People who avoid sunlight are at risk for vitamin D deficiency.

Introduction

As you age, your skin undergoes progressive changes:

The cells divide more slowly, and the inner layer of skin (the dermis) starts to thin. Fat cells beneath the dermis begin to shrink. In addition, the ability of the skin to repair itself decreases with age, so wounds heal more slowly. The thinning skin becomes vulnerable to injuries and damage.
The deeper layer of the skin, which provides scaffolding for the surface skin layers, loosens and unravels. Skin then loses its elasticity (ability to stretch). When pressed, it no longer springs back to its initial position. Instead, older skin sags and forms furrows.
The sweat- and oil-secreting glands atrophy (waste away), leaving the skin without a protective layer of water and fat. The skin's ability to stay moisturized then decreases, and it becomes dry and scaly.
Frown lines (those between the eyebrows) and crow's feet (lines that spread from the corners of the eyes) appear to develop because of permanent small muscle contractions. Habitual facial expressions also form characteristic lines.
Gravity makes the situation worse, contributing to the formation of jowls and drooping eyelids. Eyebrows, surprisingly, move up as a person ages, possibly pulled up by forehead wrinkles.

Wrinkles can have a profound impact on self-esteem. The stigma attached to looking old is evidenced by the more than $12 billion Americans spend each year on cosmetics to hide the signs of aging. Our society places a premium on youthfulness, and age discrimination in the workplace, although illegal, has stalled many people's careers. Indeed, the emotional consequences of aging explain in large part why the cosmetics industry and plastic surgeons thrive.

The sun is the most important cause of prematurely aging skin (a process called photoaging) and skin cancers. Overall, exposure to ultraviolet radiation from sunlight (radiation referred to as UVA or UVB) accounts for about 90% of the symptoms of premature skin aging. Most of these effects occur by age 20:

Even small amounts of UV radiation trigger the processes leading to skin wrinkles.
Long-term repetitive exposure to sunlight adds up, and likely is responsible for the vast majority of unwanted consequences of aging skin, including basal cell and squamous cell cancers.
Intense exposure to sunlight in early life is an important cause of melanoma, a particularly aggressive type of skin cancer.

Initial Damaging Effects of Sunlight. Ultraviolet radiation penetrates the layers of the skin. Both UVA and UVB rays cause damage leading to wrinkles, lower immunity against infection, aging skin disorders, and cancer. They appear to damage cells in different ways, however.

UVB is the main cause of sunburns, and primarily affects the outer skin layers. UVB is most intense at midday when sunlight is brightest. People receive slightly over 70% of their yearly UVB dose during the summer. We receive only 28% during the remainder of the year. Window glass filters out UVB.
UVA penetrates more deeply and efficiently. The intensity of UVA rays is less dependent on the time of day and season of the year than that of UVB rays. For example, you receive only about half of your yearly UVA dose during the summer months, with the balance spread over the rest of the year. Window glass does NOT filter out UVA.

Both UVA and UVB rays cause damage to the body, including genetic injury, wrinkles, aging skin disorders, and skin cancers. Exactly how they cause this damage is not yet fully understood.

Processes Leading to Wrinkles. Even small amounts of UV radiation trigger the processes that can cause wrinkles:

Sunlight damages collagen fibers (the major protein that gives structure to the skin). Sunlight also causes damage to elastin, a protein in the skin that normally maintains springiness and strength of tissue beneath the skin.
In response to this sun-induced elastin accumulation, the body produces large amounts of enzymes called metalloproteinases. One study indicated that when people with light to moderate skin color are exposed to sunlight for just 5 - 15 minutes, the metalloproteinase levels in their body remain high for about a week.
The normal function of these metalloproteinases is generally positive -- to remodel the sun-injured tissue by producing and repairing collagen. This is an imperfect process, however, and some of metalloproteinases produced by sunlight actually degrade (break down) collagen. The result is an uneven formation (matrix) of disorganized collagen fibers called solar scars. Repetition of this imperfect skin rebuilding causes wrinkles.
An important event in this process is the over-production of oxidants, also called free radicals. These are unstable molecules that are normally produced by chemical processes in the body, a process called oxidation. Environmental damage, however, causes an overproduction of oxidants. Excessive amounts of oxidants damage the body's cells and even alter their genetic material. Oxidation may contribute to wrinkling by activating the specific metalloproteinases that degrade connective tissue.

In addition to sunlight, other factors may hasten the formation of wrinkles:

Cigarette Smoke. Smoking produces oxygen-free radicals, which accelerate wrinkles and aging skin disorders, and increase the risk for non-melanoma skin cancers. Studies also suggest that smoking and subsequent oxidation produce higher levels of metalloproteinases, the enzymes associated with wrinkles.

Air Pollution. Ozone, a common air pollutant, may be a particular problem for the skin. One study reported that it might deplete the amount of vitamin E in the skin. This vitamin is an important antioxidant.

Rapid Weight Loss. If weight loss occurs too rapidly, the volume of fat cells that cushion the face are also decreased before chemicals in the skin can react. This not only makes a person look gaunt, but can cause the skin to sag.

Blemishes

This report covers three types of blemishes: Liver spots, purpura, and seborrheic keratoses (or warts).

Liver spots (known as lentigos, or sun-induced or pigmented lesions) are flat brown spots on the skin. They are almost universal signs of aging. Occurring most noticeably on the hands and face, these blemishes tend to enlarge and darken over time. The extent and severity of the spots are determined by a combination of skin type, sun exposure, and age. These spots are harmless, but should be distinguished from lentigo maligna, which is an early sign of melanoma.

Liver spots or age spots are a type of skin change that are associated with aging. The increased pigmentation may be brought on by exposure to sun, or other forms of ultraviolet light, or other unknown causes.

Treating Liver Spots. Liver spots do not require treatment, although some people are distressed by their appearance. Treatments may include the following:

Trichloroacetic acid (a chemical peel).
Tretinoin (Retin A) alone or in a combination with Mequinol (Solagé). Tretinoin is related to vitamin A, and is also effective in treating wrinkles.
Gentle freezing with liquid nitrogen (cryotherapy).
Laser treatment. Specific lasers, such as the Nd:YAG, are effective in eliminating 80% of liver spots in one treatment. It may be more effective than cryotherapy and have fewer side effects.
Bleaching creams -- these are commonly available but are not as satisfactory as peels, and high concentrations can sometimes cause permanent loss of skin color.

Purpura occurs when tiny capillaries (blood vessels) break and leak blood into the skin. In older people, the condition (called senile or actinic purpura) is usually caused by fragile blood vessels. The capillaries appear as flat purplish patches. These patches are called petechiae when they are smaller than 3 mm (about a tenth of an inch). When they are greater than 3 mm, they are referred to as ecchymoses. Patients typically complain of a rash, which may appear reddish at first but gradually change color, turning brown or purple.

Treatment. Although there is no specific treatment for purpura, patients are advised to avoid trauma, including vigorous rubbing of the skin, which may be sufficient to damage the capillaries. Emollients that soften the skin may be helpful. Some doctors also recommend vitamin C, but its effectiveness is unproven.

Seborrheic keratoses, (also called seborrheic warts), are among the most common skin disorders in older adults. Their cause or causes are unknown. They usually appear on the head, neck, or trunk and can range in size from 0.2 - 3 cm (a little over an inch). They are well defined and appear to be pasted onto the skin, but their appearance can vary widely:

They can be smooth with tiny, round, pearl-like formations embedded in them.
They can be rough and warty.
They can be brown or black.

Seborrheic keratoses sometimes look like melanoma, since they can have an irregular border, but they are always benign. A dermatologist can tell the difference between them, although experts warn that melanomas may "hide" among these benign lesions and go unnoticed without close inspection. In general, seborrheic keratoses have a uniform appearance while melanomas often have a smooth surface that varies in height, color density, and shading. In some cases, keratoses may cause itching or irritation. They can be easily removed with surgery or freezing. Vitamin D3 ointment is also showing promise in clinical trials.

Risk Factors

Exposure to Sun in Childhood. It is estimated that 50 - 80% of skin damage occurs in childhood and adolescence from intermittent, intense sun exposure that causes severe sunburns. In spite of this now well-known effect, many people still believe that a tan in children signifies health. And even though many parents are concerned about sun exposure, they still rely too much on sunscreen and not enough on protective clothing.

The Elderly. Most people over 70 have at least one skin disorder. Many have three or four. Everyone experiences skin changes as they age, but a long life is not the sole determinant of aging skin. Family history, genetics, and behavioral choices all have a profound impact on the onset of aging-skin symptoms.

Of all the risk factors for aging skin, exposure to UV radiation from sunlight is by far the most serious. Indeed, the vast majority of undesirable consequences of aging skin occur in individuals who are repetitively exposed to the sun, including the following:

Outdoor workers, such as farmers, fishermen, construction workers, and lifeguards
Outdoor enthusiasts
Sunbathers
People who regularly attend tanning salons or use tanning beds (One study indicated that regular use significantly increases the risk for non-melanoma skin cancers. Fair-skinned women under age 50 may be at particular risk.)

Experts have devised a classification system for skin phototypes (SPTs) based on the sensitivity to sunlight. It ranges from SPT I (lightest skin plus other factors) to IV (darkest skin). People with skin types I and II are at highest risk for photoaging skin diseases, including cancer. It should be noted, however, that premature aging from sunlight can affect people of all skin shades.


Skin Type	Tanning and Burning History
I	Always burns, never tans, sensitive to sun exposure
II	Burns easily, tans minimally
III	Burns moderately, tans gradually to light brown
IV	Burns minimally, always tans well to moderately brown
V	Rarely burns, tans profusely to dark
VI	Never burns, deeply pigmented, least sensitive

The common belief is that women are at greater risk for wrinkles than men. Some evidence suggests, however, that given the same risk factors, men and women in the same age groups have comparable risks for skin photoaging. In a French study, the evidence of moderate-to-severe photoaging was observed in the following:

Twenty two percent of women and 17% of men ages 45 - 49
Thirty six percent of women and 38% of men by age 54
Nearly half of both men and women by age 60

Some studies report that men are more likely to develop non-melanoma skin cancers.

Heavy smokers are almost five times more likely to have wrinkled facial skin than nonsmokers, according to one study. The skin of smokers in areas of their bodies not exposed to sunlight also seems to age more rapidly, compared to non-smokers in the same age group, according to a 2007 study. In fact, heavy smokers in their 40s often have facial wrinkles more like those of nonsmokers in their 60s.

Studies of identical twins have found smokers to have thinner skin (in some cases by as much as 40%), more severe wrinkles, and more gray hair than their non-smoking twins. Even worse, cigarette smokers are more prone to skin cancers, including squamous cell carcinoma and giant basal cell carcinomas. A European study found an association between smoking and higher frequency of a particular type of acne in adult women. The study also found that women who smoked had much lower levels of vitamin E secretions in their skin. Vitamin E is an antioxidant that may help protect the skin from sun damage. [See In-Depth Report #41: Smoking.]

Prevention

The best long-term prevention for overly wrinkled skin is a healthy lifestyle.

Eat Healthy. A diet with plenty of whole grains, fresh fruits and vegetables, and the use of healthy oils (such as olive oil) may protect against oxidative stress in the skin. One study reported that people over age 70 years had fewer wrinkles if they ate such foods. Diet played a role in improving skin regardless of whether the people in the study smoked or lived in sunny countries. Benefits from these foods may be due to high levels of anti-oxidants found in them.

Exercise. Daily exercise keeps blood flowing, which brings oxygen to the skin. Oxygen is an important ingredient for healthy skin.

Reduce Stress. Reducing stress and tension may have benefits on the skin.

Quit Smoking. Smoking not only increases wrinkles, but smokers have a risk for squamous cell cancers that is 50% higher than nonsmokers' risk. Smokers should quit smoking to prevent many health problems, not just unhealthy skin.

The following are some daily measures for skin protection:

Don't wash your face too often with tap water. (Once a day is enough.) It strips the skin of oil and moisture. In addition, chlorinated water, particularly at high temperatures, poses special risks for wrinkles.
Wash your face with a mild soap that contains moisturizers. Avoid alkaline soaps, especially with deodorant.
Pat the skin dry and immediately apply a water-based moisturizer.
Always apply sunscreen, even if going outdoors for short periods.
Avoid drinking alcohol within 3 hours of bedtime. Alcohol increases the risk for leaks in the capillaries, which allows more water in and causes sagging and puffiness. Capillary leakage increases when one is lying down.
Lie on the back when sleeping. This helps offset the effects of gravity.

One of the most important ways to prevent skin damage is to avoid episodes of excessive sun exposure. The following are some specific guidelines:

Use sunscreens that block out both UVA and UVB radiation. However, do not rely only on sunscreen for sun protection. Wear protective clothing and sunglasses in addition.
Avoid exposure particularly from 10 a.m. to 4 p.m., when sunlight pours down 80% of its daily UV dose.
Avoid reflective surfaces, such as water, sand, concrete, and white-painted areas. Clouds and haze are not protective and in some cases may intensify UVB rays.
Ultraviolet intensity depends on the angle of the sun, not heat or brightness. So the dangers are greater the closer to the summer-start date. For example, in the Northern Hemisphere, UV intensity in April (2 months before summer starts) is equal to that in August (2 months after summer begins).
The higher the altitude the quicker one sunburns. One study suggested, for example, that an average complexion burns in 6 minutes at an altitude of 11,000 feet at noon, compared with 25 minutes at sea level in a temperate climate.
Avoid sun lamps and tanning beds or salons. They provide mostly high-output UVA rays. Some experts believe that 15 - 30 minutes at a tanning salon is as dangerous as a day spent in the sun. People should not be misled by advertising claims of "safe" tanning or promotions offering unlimited tanning.

Sunscreens. The use of sunscreens is complex, and everyone should understand how and when to use them. The bottom line is not that people should avoid sunscreens or sunblocks, but that they should always use them in combination with other sun-protective measures.

Protective Clothing. Wearing sun-protective clothing is extremely important and protects even better than sunscreens. Special clothing is now available for blocking UV rays and is rated using SPF ratings or a system called the UPF (ultraviolet protection factor) index, with 50 UPF being the highest. (According to one study, this is a very reliable indicator of protection.) The clothing is expensive, however. The following are some tips for everyone:

Adults and children should wear hats with wide brims. Even wearing a hat, however, may not be fully protective against skin cancers on the head and neck.
People should look for loosely fitted, unbleached, tightly woven fabrics. The tighter the weave, the more protective the garment.
Washing clothes over and over improves UPF by drawing fabrics together during shrinkage. An easy way to assess protection is simply to hold the garment up to a window or lamp and see how much light comes through. The less the better.
Everyone over age 1 should wear sunglasses that block all UVA and UVB rays.

Chemical Tanners. Some research suggests that melanin and dihydroxyacetone (DHA), the active ingredients in many self-tanning lotions, may help filter out UVA and UVB radiation and are therefore protective against sun damage More research is underway. A preliminary study funded by the National Cancer Institute found that people who received numerous daily injections of melanotan-1 (MT-1) before going in the sun or a tanning bed tanned more quickly and showed fewer signs of sun-related damage. MT-1 is a synthetic version of the hormone melanin, which helps produce the skin's natural pigment (color).

In choosing a sunscreen, look at the ingredients. Preparations that help block UV radiation are sometimes classified as sunscreens or sunblocks, according to the substances they contain. In general, sunscreens contain organic formulas and sunblocks inorganic formulas. However, the term sunblock is used less and less as sunscreens increasingly contain both kinds of ingredients:

Organic formulas contain UV-filtering chemicals such as octocrylene, octyl salicylate, homosalate, and octyl methoxycinnamate (block UVB), avobenzone-Parsol 1789 (blocks UVA), cinoxate, ethylhexyl p-methoxycinnamate (blocks UVB and small amounts of UVA), oxybenzone, benzophenone-3 (blocks UVA/UVB). People should look for a wide-spectrum sunscreen that contains combinations of these ingredients and filter both UVA and UVB. Of note: para-amino benzoic acid (PABA), once a popular ingredient, is now used infrequently. PABA may actually break down in the presence of UV exposure and release harmful oxidants. In addition, many people have an allergic reaction to it. Some products contain PABA derivatives, such as padimate O or octyl dimethyl PABA. It is not known if they have the same effects.
The Food and Drug Administration approved Anthelios SX in July 2006. This new sunscreen prevents sunburn and protects against ultraviolet A and B rays. The product contains ecamsule, an ingredient not previously marketed in the United States.
Inorganic formulas contain the UV-blocking pigments zinc oxide or titanium dioxide. Zinc and titanium oxides lie on top of the skin and are not absorbed. They prevent nearly all UVA and UVB rays from reaching the skin. Older sunblocks are white, pasty, and unattractive, but current products use so-called microfine oxides, either zinc (Z-Cote) or titanium. They are transparent and nearly as protective as the older types. Microfine zinc oxide may be more protective and less pasty-colored than microfine titanium oxide.

Inexpensive products work as well as expensive ones with the same ingredients. Unfortunately, there are still no standards for sunscreens, and even those claiming UVA protection may offer very little. In one study, the average UVA protection from a wide range of brands was only 23%. In fact, the average protection of brands not making the claim was 37%!

Organic formulas and inorganic microfine oxides do not protect against visible light, which is a problem for people who have light-sensitive skin conditions, including actinic prurigo, porphyria, and chronic actinic dermatitis. Inorganic sunscreens that protect against visible light and are still cosmetically acceptable are now available in Europe, but not yet in the US.

Calculating the SPF. The sun protection factor (SPF) on all sunscreen labels is a ratio based on the amount of UVB (not UVA) radiation required to turn sunscreen- or sunblock-treated skin red compared to non-treated skin. For instance, people who sunburn in 5 minutes and who want to stay in the sun for 150 minutes might use an SPF 30. The formula would be: 30 (the SPF number) times 5 (minutes to burn) = 150 minutes in the sun.

Protection offered by sunscreens may be classified as follows:

Minimal: SPF 2 to 11.
Moderate: SPF 12 through 29.
High: 30+. (Although some sunscreens claim SPFs higher than 30, the added protection at such higher levels is insignificant.)

SPF Levels by Age Group. Certain groups should have higher or lower SPFs depending on age and other factors:

Although sunscreens are safe in most toddlers and children, they should not be the first and only lines of defense. In fact, experts are worrying that by relying too much on sunscreen and not providing other protective measures, parents may actually be increasing their children's risk for melanoma. All young children should be well covered with clothing, sunglasses, and hats as the first line of defense against sunburn. Children should be kept out of the sun during peak sunlight periods. Sunscreens should not be used on babies younger than 6 months without consulting a doctor.
Older children and adults (even those with darker skin) benefit from using SPFs of 15 and over. Some experts recommend that most people should use SPF 30 on the face and 15 on the body.
Adults who burn easily instead of tanning and anyone with risk factors for skin cancer should use at least SPF 30.

Timing and Amount of Application. You should apply sunscreen or sunblock liberally as follows:

Adults should include sunscreen with a daily skin regimen, even if going outdoors for only a short time.
Apply a large amount to all exposed areas, including ears and feet. To achieve protection as indicated by the sunscreen's SPF, experts recommend half a teaspoon each for the head, neck, and each arm and a teaspoon each for the chest area, the back, and each leg.
Apply initially 30 minutes before venturing outdoors for best results. (This allows time for the sunscreen to be absorbed. Then reapply every 15 - 30 minutes while being in the sunlight.
Also reapply each time after exercise or swimming. (Choose a waterproof or water-resistant formula even if activities don't include swimming. Waterproof formulas last for about 40 minutes in the water, whereas water-resistant formulas last half as long.)
Insect repellents reduce sunscreen SPFs by up to one-third. Use higher SPFs and very liberal application when applying both.

Possible Hazards of Sunscreens, Sun Avoidance, or Both. When used generously and appropriately, sunscreen products and sun avoidance help reduce the severity of many aging skin disorders, including squamous cell cancers. There are certain concerns, however.

Sunscreen Use May Not Protect Against Basal Cell and Melanoma Cancers and May Even Increase the Risk. Although sunscreens help prevent squamous cell carcinomas and other skin disorders, sunscreens do not appear to provide protection against melanoma and some basal cell cancers. In fact, some studies have reported a higher association with sunscreen use and these skin malignancies, though not all studies report such negative results.

The reasons for this possible increased risk are unclear, though some theories include the following:

Until recently, many sunscreens blocked only or mostly UVB rays and not UVA, the more deeply penetrating rays now known to be especially dangerous. Past studies may not have reflected the effects of the broad-spectrum sunscreens now available, which block both UVA and UVB.
People who apply sunscreens may feel safe and stay out longer during high sun-exposure hours than is safe. Even if a person doesn't sunburn, UVA rays can still penetrate the skin and do harm.
People may not put on enough sunscreen. According to a 2002 study, people generally apply only 20 - 60% of the recommended amount, which can provide significantly less protection than the given SPF. (Of note, a 2003 study reported that when applied at the recommended amount, a broad-screen sunscreen prevents DNA damage from UV exposure. However, omitting it even once resulted in significant cell injury.)

Sunscreen Use May Increase the Risk for Health Problems Related to Sunlight Deficiencies. There is some major concern that underexposure to sunlight, due to the use of sunscreens or sun-avoidance measures, may produce other health problems, such as the following:

Vitamin D Deficiency. Vitamin D is found in only a few foods, such as fortified dairy products and fish, but it is produced in the skin in response to UVB sunlight. A medical literature review published in the journal Nutrition and Cancer reported that UVB rays may outshine dietary supplements for building the body's vitamin D reserves. Without an appropriate mix of diet and supplements, vigorous sun protection measures may increase a person's risk for developing vitamin D deficiency. Vitamin D is important for prevention of rickets, osteoporosis, and some cancers, including melanoma. People who need to avoid sunlight and whose diet is low in foods that contain vitamin D should check with their doctor about taking supplements. People with darker skin are at higher risk for deficiencies from sun protection than those with whiter skin. Note: vitamin D is toxic in high doses. Most doctors recommend 200 IU a day (for young adults) to 600 IU a day (above age 70). Doses up to 2,000 IU a day are considered safe. A report analyzing studies of vitamin D supplementation found that people who take vitamin D supplements live longer than those who do not. The researchers looked at 18 studies. They found that participants who received vitamin D supplements were, on average, 7% less likely to die during the study they were in, compared with those receiving "sugar pills."
Other Cancers. Although sunlight is implicated in skin cancers, it is also associated with lower risks for breast, prostate, ovarian, and colon cancers. Some protection against these cancers may be related to vitamin D production by sunlight.
Depression. Many people suffer from SAD (seasonal affective disorder), a form of depression that generally occurs in winter and is associated with exposure to less sunlight.

The bottom line is that some sunlight is important and even necessary for a healthful and high-quality life. Adults may benefit from daily moderate tanning (20 - 30 maximum minutes of exposure during lower-risk hours) over several days to slowly build up pigment in the skin.

Treatment

An increasing number of dermatology patients are looking for a way to improve the appearance of their skin. As a result, more and more products have become available to treat skin wrinkles and blemishes. From vitamins and supplements to exfoliants and chemical peels -- the options can be overwhelming. In some cases, more than one approach may be needed.

Antioxidants are substances that hunt oxygen-free radicals, the unstable particles that can damage cells. Free radicals may also cause sun damage and even skin cancers. Exposure to sunlight depletes antioxidants in the skin, and therefore they must be replaced.

Antioxidant ointments, creams, and lotions ("topical products") may help reduce the risk of wrinkles and protect against sun damage. Unlike sunscreens, they build up in the skin and are not washed away, so the protection may last. Selenium, coenzyme Q10 (CoQ10), and alpha-lipoic acid are types of antioxidants that come in topical form. Many are proving to be very beneficial for the skin.

Vitamin A. Vitamin A is important for skin health. UV radiation produces vitamin A deficiencies in the skin. Topical products containing natural forms of vitamin A (retinol, retinaldehyde) or vitamin A-related products called retinoids (tretinoin, tazarotene) may help repair skin damage due to sunburn and natural aging.

Tretinoin (Retin-A). Tretinoin (known commercially as Retin-A) is the only topical agent approved for treating photoaging and is available in prescription form (Avita, Renova, Differin). The June 2004 issue of Dermatology Surgery reported that tretinoin (0.25% concentration) was an effective and well-tolerated treatment for photodamaged facial skin. This drug produces a rosy glow and reduces fine and large wrinkles, liver spots, and surface roughness. It also may help prevent more serious effects of ultraviolet radiation. Patients may apply tretinoin to the face, neck, chest, hands, and forearms, and should do so at least twice a week. Noticeable improvement takes 2 - 6 months. Because Retin-A increases a person's sensitivity to the sun, patients should apply just a tiny amount at bedtime, and wear sunblock during the day. Patients should also avoid overexposure to the sun. Almost all patients experience redness, scaling, burning, and itching after 2 or 3 days that can last up to 3 months. In women who experience irritation, a daytime moisturizer or low-dose corticosteroid cream, such as 1% hydrocortisone, may help. There is some concern that overuse of high-dose tretinoin may cause excessive skin thinness over time. Studies now suggest that low concentrations (as low as .02%) of tretinoin can produce significant improvements in wrinkles and skin color, with less irritation than the higher doses.
Retinol. Retinol, a natural form of vitamin A, could not, until recently, be used in skin products because it was unstable and easily broken down by UV radiation. Stable preparations are now sold over the counter. In the right concentrations, retinol may be as effective as tretinoin, and studies indicate that it has fewer side effects. An animal study suggests that adding antioxidant creams (such as those containing vitamins C or E) may offer added protection against degradation of retinol, but not tretinoin. The Food and Drug Administration warns that over-the-counter retinol skin products are unregulated. The amount of active ingredients is unknown, and some preparations, in fact, may contain almost no retinol.
Tazarotene. Tazarotene (Tazorac, Zorac, Avage) is a retinoid used for acne and psoriasis. It has now been approved for treating wrinkles, skin discoloration, and blemishes due to photoaging. One short-term study suggested that it may be as effective as tretinoin and even slightly better at high doses. At such high doses, however, it can cause very severe irritation. Redness and peeling may be reduced by administering tretinoin first to get the skin acclimated. A randomized study of 562 patients with facial photodamage found that a daily application of tazarotene 0.1% cream resulted in a minimum 1 grade improvement in fine and coarse wrinkling, uneven skin color, pore size, skin roughness, and overall photodamage. More research is needed to determine if it produces any long-lasting significant benefits.

Warning: Pregnant women and those who may become pregnant should avoid any vitamin A derivative (a product related to vitamin A). For example, oral tretinoin causes birth defects, and women should avoid even topical Retin-A when pregnant or trying to conceive.

Vitamin C. Vitamin C, or ascorbic acid, is a very potent antioxidant. Most studies on the effects of antioxidants on the skin have used this vitamin. In laboratory studies, large amounts of vitamin C reduced skin swelling and protected immune factors from sunlight. It may even promote collagen production. Vitamin C by itself is unstable, but products that solve the delivery problem are now available (such as Cellex-C, Avon's Anew Formula C Treatment Capsules, Physician Elite, and others). More research is needed.

Antioxidants Under Investigation for Skin Care. Other antioxidants are also being investigated for their value in skin protection. Most available brands, however, contain very low concentrations of these antioxidants. In addition, they are also not well absorbed and have a short-term effect. New delivery techniques, however, may prove to offset some of these problems.

Vitamin E. Studies suggest that topical vitamin E, particularly alpha tocopherol cream (a form of vitamin E), decreased skin roughness, length of facial lines, and wrinkle depth. Studies on mice have also reported reductions in UV-induced skin cancer with its use.
Both green and black tea may provide some protection against skin cancers and photoaging. There is also some evidence that pomegranate and soy extracts may help rejuvenate aging skin.
Aloe, ginger, grape seed extract, and coral extracts contain antioxidants and are promoted as being healthy for the skin, although evidence of their effects on wrinkles is weak.

A small study found that taking vitamin C and E supplements by mouth -- at the same time -- may help reduce sunburn, although it doesn't work as well as sunscreen. Taking the vitamins separately did not have any effect. Vitamin C and E are also antioxidants.

One of the basic methods for improving skin and eliminating small wrinkles is exfoliation (also called resurfacing), which is the removal of the top layer of skin to allow regrowth of new skin. Methods for doing this run from simple scrubs to special creams to intensive peeling treatments, including laser resurfacing. People with darker skin are at particularly higher risk for scarring or discoloration with the more powerful exfoliation methods.

Abrasive Scrubs. Scrub gently with a mildly abrasive material and a soap that contains salicylic acid to remove old skin so that new skin can grow. The motion should be perpendicular to the wrinkles. Use textured material or cleansing grains with microbeads. Organic materials, such as loofahs or sea sponges, may harbor bacteria. Avoid cleansing grains that contain pulverized walnut shells and apricot seeds, which can scratch skin on a microscopic level. Cleansing grains with microbeads don't have sharp edges and remove skin without cutting it. Exfoliation using scrubs, however, can worsen certain conditions, such as acne, sensitive skin, or broken blood vessels.

Topical Alpha Hydroxy Acid and Similar Substances. Alpha hydroxy acids (AHA) ease the shedding of dead skin cells and may even stimulate the production of collagen and elastin. Their natural forms are:

Lactic acid (milk)
Glycolic acid (sugar cane)
Malic acid (found in apples and pears)
Citric acid (oranges and lemons)
Tartaric acids (grapes)

Most alpha hydroxy acid products contain glycolic acid. Skin care products are also made from polyhydroxy acids (PHAs) and beta hydroxy acids (BHAs). Research suggests that PHA products may cause less skin irritation than AHA or BHA products.

Acid concentrations in over-the-counter AHA preparations are 2 - 10%. One clinical study suggested that 8% concentrations showed modest skin improvement Some examples include Avon's Anew Intensive Treatment (8% glycolic), Pond's Age Defying Complex (8%), Elizabeth Arden's Alpha-Ceramid Intensive Skin Treatment (3 - 7.5%), and BioMedic's home product (10%). Prescription strength creams contain at least 12% glycolic acid, and glycolic acid peels of 30 - 70% concentration may be administered in a doctor's office at weekly or monthly intervals.

Response to AHA varies, and the treatment is not without risk, particularly in high-concentration products. Side effects from over-the-counter creams, prescription products, and professional AHA peels can include burns, itching, pain, and possibly scarring. Studies also suggest that AHA may increase susceptibility to sun damage, even at concentrations as low as 4%. Such effects can persist up to a week after a person stops using the product. Experts advise that people purchase products with AHA concentrations of 10% or less. Chemical peels of up to 60% are available without prescription on the Internet. Such concentrations are not recommended, except under a doctor's supervision. If any adverse effects occur, stop using the product immediately. Always avoid sunlight or use proper sun protection when using these products.

Copper Peptides. Certain copper-containing compounds may protect skin and help repair it. Note: copper is a toxic metal. When using products containing copper, buy only those that contain peptides (small protein fragments) that bind to copper. Most studies have been conducted on the copper peptide glycyl-l-histidyl-l-lysine:copper (II) or GHK-Cu. It is currently used in a number of products (such as CP Serum, Neutrogena's Visibly Firm, ProCyte's Neova).

Furfuryladenine. Furfuryladenine (Kinetin, Kinerase) is a naturally occurring growth hormone found in plant and animal DNA. It has antioxidant and anti-aging properties. Some small laboratory studies suggest that furfuryladenine may delay the onset and decrease the effects of aging on skin. However, there are no well-conducted human studies to support this suggestion.

Vitamin K. Microsponge-based vitamin K is said to clear bruises spider veins, and other small blood vessel damage. Vitamin K is important for blood clotting.

Moisturizers help prevent dryness, bruising, and tearing. They have no effect on wrinkles by themselves. Moisturizers should be applied while the skin is still damp. These products retain skin moisture in various ways:

Occlusives, such as petroleum jelly, prevent water from evaporating.
Humectants, including glycerin, act by pulling water up to the surface of the skin from deep tissues. People with oily skin generally should use the humectant type.
More powerful compounds, such as monolaurin (Glylorin), contain mixtures of fatty molecules (lipids), which may help restore the skin's natural barriers against moisture loss and damage.

Most moisturizers contain combinations of these compounds. They usually have other ingredients as well, such as alpha hydroxy acids, sunscreens, collagen, and keratin. Collagen and keratin leave a protein film and temporarily stretch the skin. They range widely in price, and a major consumer organization found little difference in general between the more and less expensive products.

The skin under the eyes is very thin and does not produce as much of the protective oils that keep skin soft and supple. Manufacturers market their under-eye gels as being able to reduce puffiness and dark circles. The creams typically work in one of two ways:

By temporarily constricting blood vessels to prevent the build-up of fluids
By firming the skin with an invisible film

Never rub the creams under the eyes, as this may cause more wrinkles to form. Instead, apply these products with a light tapping motion to stimulate the skin.

Cosmetics, if properly applied, can be surprisingly effective in camouflaging the signs of aging skin, including wrinkles and age spots. Moreover, they offer additional benefits by retarding water loss and providing a physical barrier to UV radiation. However, as women age, less is more.

Here are some suggestions for older women:

Moisturizers. Apply moisturizers before foundation. If reddish discoloration is extensive or the skin is sallow, tinted moisturizers may be helpful and can be worn alone or under foundation.

Foundations. Caking on make-up will cause cracks at the wrinkle lines and only increase the appearance of aging. Try to cover large areas of the face with a moderate-coverage foundation that has a matte or semi-matte finish. Facial powder reflects light and thus minimizes wrinkles, but people with dry skin should avoid it.

Correcting Color. When blemishes are especially prominent, applying color correctors under the foundation can be very effective:

Green neutralizers mask red lesions.
Yellow will camouflage dark circles and bruises.
Mauve (a purplish-pink color) helps neutralize sallow skin or yellowish blemishes.
A white, pearled base helps to minimize wrinkles.

Blushes. Blushes and color washes can help conceal the spidery network of dilated capillaries on the nose and cheeks. Powder blushes are preferred because they blend easily on top of foundation.

Eyes. Powder eye shadows applied on top of a moisturizer are better than cream-based shadows. Light-colored shadow, applied along the upper eyelid crease and above the iris (the colored part of the eye) is best for offsetting the appearance of deep-set eyes. You should then apply a slightly deeper shade of the same color to the lower part of the eyelid, and draw it out to the corner.

Lips. A lip-setting cream or facial foundation should be applied before lipstick to help prevent it from bleeding into surrounding wrinkles. Try using a stiff bristle brush instead of a lip pencil. The brush will help keep the lipstick on and prevent bleeding. (Some women use the pencil itself for the full lip, which gives color but appears natural.) Some make-up artists recommend cream lipsticks instead of matte.

The Food and Drug Administration (FDA) does not regulate herbal remedies and dietary supplements. In other words, the manufacturers and distributors of such products do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been numerous reported cases of serious and even deadly side effects from herbal products.

Overexposure to sunlight can damage skin. The following natural remedies may cause extra sensitivity to light (photosensitivity):

St. John's wort (Hypericum perforatum) is a popular herbal remedy for depression. People who are sensitive to light should not use it. A case report suggests that St. John's wort may cause skin reactions in patients who have laser treatment.
Kava (Piper methysticum) is an herb used to calm nerves and reduce stress. In addition to photosensitivity, it can cause liver damage.
Yohimbe (Pausinystalia yohimbe) is used to treat erectile dysfunction. Both the herb and the pharmaceutical drug (yohimbine) can cause sensitivity to light.
Essential oils in many botanical aromatherapy products can trigger photosensitivity. Avoid citrus oils (grapefruit, lemon, lime, and orange) as well as bergamot, cumin, ginger, and angelica root oils.

Resurfacing Treatments

There are many choices for skin resurfacing (also called exfoliation), and the patient must consider several different factors that affect the choice. Resurfacing can achieve the following:

Removal of abnormal tissue and rough skin
Stimulation of new skin growth
Stimulation of collagen and elastin production

In addition to determining the skill of the surgeon and the safety of the procedure, the patient must discuss the desired depth of the resurfacing and the capability of each procedure to reach this depth safely. All resurfacing procedures require a healing period afterward, during which the skin is red and sensitive. The deeper the procedure, the higher the risk for complications, including delayed healing, infection, loss of pigment (skin color), and scarring.

If you make the decision to pursue intensive treatments, consider the following factors, among others, and discuss them with your dermatologist or plastic surgeon:

The ability of the procedure to safely reduce wrinkles
The ease and safety record of the procedure
The skill of the doctor
The length of recovery
Possible complications
How long the benefits will last

A person's age also helps determine the procedure:

For people in their 30s, a simple chemical peel is sufficient.
After age 40, people may benefit from collagen or fat implants.
At age 50 and over, plastic surgeons recommend laser resurfacing and customized treatments for individual needs.

In older individuals, combination procedures may be beneficial. Some examples include the following:

Laser surgery may be used for deep lines (such as those around the mouth) and chemical peels used over the rest of the face.
For enhancing the eye by correcting droopy eyelids, bags, and a "sinking" brow, combinations of eyelift (blepharoplasty), Botox, and laser resurfacing may be used.

Chemical peels, also known as chemosurgery, help restore wrinkled, lightly scarred, or blemished facial skin. Much like chemical paint strippers, chemical peels strip off the top layers of skin, and new, younger-looking skin grows back. The procedure is very effective for the upper lip but cannot be performed around the eyes. Partial peels are often done in conjunction with a face-lift. Combinations of the topical antioxidants, such as tretinoin and vitamin C, along with a chemical peel, may be particularly effective.

The Procedure.

A dermatologist applies chemicals to the skin. They include trichloroacetic acid, high concentrations of alpha hydroxy or beta hydroxy acids, or combinations of all three.
In some cases, tretinoin or alpha hydroxy is applied 4 - 6 weeks before, and starting one day after, the peel. Such treatments can enhance the effects of a peel and reduce the risk of discoloration in people at risk for this complication. Tretinoin is being tested as a chemical peel.
A crust or scab generally forms within 24 hours after surgery. You can remove this scab by gently cleansing with soap and water.
The skin takes 6 - 7 days to heal.
After the scab disappears, the visible skin is deep red but gradually lightens as it regenerates.

Complications. Complications include white heads, cold sores, infection, scarring, numbness, and permanent discoloration, particularly in people with darker skin. Refinement of chemical peel techniques are now permitting doctors to reach deeper skin, improvements which make it easier to apply peels to non-facial skin and to individuals with darker skin.

Dermabrasion affects deeper layers of skin than chemical peels, and may be useful for removing disfiguring marks, such as deep acne scars or deep wrinkles. As with chemical peels, it is effective for wrinkles on the upper lip and chin, and cannot be used around the eyes. Some doctors prefer dermabrasion to lasers for skin surfacing of people with darker skin colors.

Standard Dermabrasion. Standard dermabrasion uses a rotating brush that removes the top layers of a person's skin. As with chemical peels, dermabrasion selectively strips away the upper layers of skin, leaving the underlying skin layers exposed. Similar to chemical peels, after the procedure, the treated skin oozes and forms a scab, a reaction that looks and feels uncomfortable, but only temporary. Postoperative care is similar for both procedures.

Microdermabrasion. A gentler variation called microdermabrasion uses very tiny crystals to polish the skin and a vacuum technique to remove them. It has largely replaced the older dermabrasion, and, in fact, was the fourth most common non-surgical cosmetic procedure performed in 2005, with over a million done. Results are similar to light chemical peels. Patients can have this procedure done on their lunch hour and return to work. Only mild redness occurs after treatment, although for best results five or six repetitive treatments are needed every 1 - 2 weeks. To date, overall patient satisfaction has been very high.

Lasers are currently the most effective exfoliation tools for eliminating wrinkles. Their unique advantages over other resurfacing methods are their ability to tighten the skin. A successful procedure can make patients look 10 - 20 years younger, and the results can last up to 10 years.

The procedure is most beneficial for the following areas:

It is best around the mouth and eyes. Recent evidence suggests CO₂ lasers may be even better than dermabrasion for the upper lip.
It is slightly less beneficial for the area around the nose.

Used alone, current laser therapy does not eliminate crow's feet, broken blood vessels, or dark circles under the eye. The evidence of the effects of lasers on acne scars is incomplete.

Standard laser dermabrasion is too harsh for thinner skin layers, such as on the neck. Newer and gentler laser techniques, however, stimulate collagen without removing skin layers, and may prove to be useful for necklines.

The Laser Resurfacing Procedure. In general the procedure works in the following way:

Laser pulses penetrate the skin quickly, vaporizing water and surface skin without damaging the deeper layers, allowing new top skin to grow.
In addition, the laser delivers enough heat to shorten collagen fibers, restoring some elasticity to the skin.

Choice of Lasers. The lasers used depend on skin type and severity of the condition. Some of the more common laser types are:

The carbon dioxide (CO₂) laser. This is the most powerful laser treatment and is used for deep wrinkles and skin imperfections. People who have had silicone injections should not have CO₂ procedures, which can burn and scar the skin over the implanted area.
The erbium: YAG (Er:YAG). This laser is gentler than the CO₂ laser, and is effective for mild wrinkles and for providing a smooth skin texture. It has a shorter recovery time. Some experts have even found the YAG laser as effective in removing deep wrinkles as CO₂ when used to sufficient depth. A variable pulse YAG laser can shift between pulses that destroy skin tissue to those that heat the skin. This process effectively resurfaces the skin with fewer side effects than CO₂ laser therapy.
Pulsed dye laser. Pulsed dye laser uses yellow light, which is easily absorbed by hemoglobin, the molecule that gives blood its red color. Pulsed dye laser treatments are used to treat skin blemishes that are due to blood vessel abnormalities, such as port-wine stains.

A gentle laser procedure called non-ablative laser resurfacing (NLite), also called photorejuvenation, is now approved for the treatment of all facial wrinkles. The procedure uses light energy to gently stimulate new collagen, and possibly elastin production, without removing the skin tissue itself. Its effects are less pronounced than those of other laser procedures. However, because it does not injure the external layers of skin, it can be used on delicate skin areas, such as the neck and around the eyes. It also causes very little irritation afterward.

Some surgeons are using combination techniques that employ more than one laser technology in one session, to achieve different effects. For example, one combination technique uses CO₂, YAG, pulsed-dye laser, and one other laser technology to both improve wrinkles and clear under-eye dark circles and acne scarring. Pretreatment with botulinum (Botox) injections before laser resurfacing significantly improved the treatment of crow's feet in one study.

Post-Procedure Recovery. The procedure itself is relatively painless, but the redness and irritation that occur during the healing process can be severe. Non-ablative laser resurfacing does not have the same severe after-effects as other laser treatments. For 8 - 9 days, the face looks skinned and swollen, and requires continuous moisturizing. Some doctors suggest that people with very sensitive skin, who cannot tolerate the necessary medications and lubricants, should avoid laser resurfacing. Redness and sensitivity can persist for 1 - 4 months. The patient must stay out of the sun as much as possible during this time, and should always avoid sunbathing and damaging their skin again. Early research suggests that silicone dressings may reduce post-procedure pain and crusting.

Complications. Scarring and infections can occur in about 1% of procedures. The risk of complications depends on the experience of the surgeon. People with a history of herpes simplex may experience flare-ups of fever, facial pain, and flu-like symptoms for 5 or 6 days after the procedure. In addition, people with darker skin may wish to avoid the procedure, because it can cause unpredictable and dramatic lightening of the skin.

A new skin rejuvenation technology, called Plasma Skin Resurfacing, or Portrait Plasma, was introduced in February 2005. The technology uses plasma energy (heat and light energy) to rejuvenate the skin from the deeper layers outwards. While new skin regenerates, the outer layers of the skin act as a natural bandage. When the outer layers peel off in the week after treatment, the new skin emerges. The process prevents or minimizes the raw appearance that follows laser treatments. This system uses radio waves to "excite" nitrogen gas, resulting in the release of energy. According to the manufacturer, skin regeneration using the Portrait Plasma system is rapid, and satisfaction with the procedure appears high. Long-term follow-up studies are not available yet for this new method. In 2006, the Food and Drug Administration approved this method for the treatment of wrinkles on other areas of the body, besides the face.

Cold Ablation. Cold ablation, called coblation for short, delivers saline (salt water) to the skin, through which a cool electric current is passed. A subsequent reaction heats and vaporizes the top shallow layer of skin. The procedure is very specific and appears to minimize any damage to other areas of the skin.

Radiofrequency Resurfacing. A promising technique uses low radiowave energy to resurface the skin. Preliminary research indicates that this procedure may eventually be as effective as laser surgery in reducing severe wrinkles around the eyes and mouth, with minimal pain and a shorter recovery time. In one study, one radiofrequency treatment with only a skin anesthetic resulted in tighter facial skin for 14 out of 15 patients within 12 weeks. All but one patient returned to normal activity immediately afterward. A small clinical trial published in Dermatology Surgery found that a noninvasive radiofrequency technique called NARF safely and effectively improved drooping lower eyelids.

Intense Pulsed Light. Intense pulsed light (IPL) uses filters to deliver different wavelengths of light. Doctors use it to treat a number of photoaging skin problems, and it appears to have long-term effects. Typically, four to six treatments are performed over a four-month period. Each treatment takes 15 - 20 minutes. Unlike laser light, which uses one color wavelength (such as green or red), intense pulsed light starts with a full spectrum of light. It then allows the doctor to selectively block off specific wavelengths, depending on how shallow or deep the procedure should go. IPL machines are less expensive and safer than lasers.

Implant Procedures

Implants, also called injectable fillers, are becoming a common means of erasing wrinkles and folds. Several materials are being used for deep wrinkles, depression under the eyes, lip enhancements, and acne scars.

After being banned from the market in 1992, silicone is making a comeback in research settings as a potential permanent wrinkle eraser. Scientists are looking into a new microdroplet technique (the use of very small drops) combined with purified silicone as a way to eliminate any danger. The past problems with silicone occurred when it was mixed with a foreign substance, like mineral oil, or when it was injected in large doses.

Most implants to date, however, are not completely satisfactory. Collagen implants and biologic fillers from animal, bacterial, or human sources do not provide long-lasting benefits. Synthetic fillers are permanent but may cause an allergic reaction, which can lead to chronic problems. Such reactions are rare, but they can be painful and unattractive.

The U.S. Food and Drug Administration (FDA) approved the Juvéderm product line in June 2006. Juvéderm is an injectable treatment of moderate-to-severe facial wrinkles and folds. Juvéderm products are gels made from hyaluronic acid. They are injected into the face. Doctors report good results after a single treatment with Juvéderm, and the results last for at least 6 months.


Name and Material Used	Procedure	Specific Areas Affected	Benefits	Drawbacks
Collagen implants. Collagen is the protein that forms the structures in the body (such as skin, bones, cartilage). The implant procedure has typically used bovine (cow) collagen. A form of human collagen (CosmoDerm, CosmoPlast) has now been approved.	Injected into target wrinkles with needle and syringe. Several weeks after injection, cow collagen breaks down and is replaced by newly created human collagen.	Wrinkles around the eyes and mouth. It is used to give lips greater fullness.	Very simple with faster recovery than many other implant techniques.	Wrinkles form again, and require repeat treatments 3 - 12 months later. Rarely, severe allergic reactions occur. Should not be used by children, pregnant women, and people with a history of autoimmune disease.
Microlipoinjection. Fat tissue from the patient's own thigh or abdomen.	Injected into target wrinkles with needle and syringe.	Deep wrinkles around the nose and mouth, folds in the forehead, and wrinkles on the hands.	No allergic or immune reaction because substance is patient's own fat.	Body eventually absorbs the fat, resulting in a need for multiple injections. Some studies suggest that 70% of the fat may still be in place after at least a year.
Gore-Tex. Highly porous (full of tiny holes) and inert (not chemically active) synthetic material.	Requires some surgery. Tiny patches are inserted under the skin to fill out wrinkles. Skin cells and blood vessels pass through the porous material easily, reducing the risk of severe irritation.	Deep wrinkles.	Material does not break down.	Possible scarring from surgical procedure. Allergic reactions are rare but can occur even with chemically inactive materials.
Artecoll. Contains PMMA, or polymethylmethacrylate, an inert substance, enclosed in tiny droplets of natural collagen.	Material is injected. Body absorbs collagen. PMMA remains and stimulates new collagen growth.	Deep wrinkles.	Although part of the implant is a natural collagen implant, it does not degrade as quickly as a full collagen implant.	Repeat treatments may still be needed. Possible allergic reaction.
Hyaluronic acid. Natural (non-animal) substance acts like a molecular sponge to absorb water. The FDA approved Restylane in 2003, Captiva, Hylaform-Plus, and Hylaform in 2004, and Juvéderm in 2006.	Gel is injected under the skin.	Moderate-to-severe wrinkles.	Low risk for allergic reaction. May last longer than cow collagen.	Repeat treatments needed.
Poly-L-lactic acid. Synthetic polymer. Approved in US as Sculpta. Approved in other countries as New-Fill.	Material is injected under the skin.	Approved in U.S. only for patients with facial fat loss due to HIV. Approved in other countries for wrinkles.	Low risk of allergies. Treatment effects can last 18 - 24 months.	Doctors require special training.

The popularity of Botox injections has skyrocketed in the United States. Between 2004 and 2005, the number of procedures performed jumped 16 percent. Botox injection was the number one non-surgical cosmetic procedure in 2005, with more than 3.2 million injections. Botulinum, the deadly toxin found in uncooked foods, is also a powerful muscle-relaxant. Tiny amounts of a purified form (Botox) are injected into wrinkles to relax the surrounding muscles. It may benefit forehead and frown lines, crow's feet, lower eyelids, lines on the side of the nose, and the area between the upper lip and the nose. It is also useful for treating involuntary muscle movements that can occur after a face-lift.

The injections need to be repeated every few months, since the effects wear off. The treatment decreases the ability to frown or squint and may cause the corners of the mouth to turn down. When used for areas around eyes, it produces a rounder appearance afterward, which patients should be aware of before they undertake the procedure.

The drug does not cross the blood-brain barrier, and, to date, the only side effects are temporary muscle weakness near the injection site. Although there have been some reports that Botox can reduce migraine and tension headaches, Botox also causes headaches in about 1% of cases. In some cases, the headaches can be very severe and long lasting (from 8 days to a month). Some researchers suggest that either a contaminated batch of Botox or a specific injection technique may be the cause, but additional investigation is needed.

Plastic Surgery

In 2005, there were over 2.1 million cosmetic surgeries, up 1% from the year before. Most of these surgeries were liposuction and breast surgeries. However, over 200,000 each of eyelid and nose surgeries were performed. Facial plastic surgeries range from being fairly minimal, such as a brow lift, to a full face-lift.

Several face-lift procedures (called rhytidectomies) are available. Face-lifts can provide individuals with a more youthful look. The degree of improvement, however, depends on many factors, including age, bone structure, skin type, and personal habits, such as smoking and sunbathing.

The Procedure. When a face-lift is a relatively simple procedure, it can take about 2 hours under local anesthetic in a doctor's office. Complicated face-lifts are done under general anesthesia in a hospital and can take 3 - 6 hours. The face-lift procedure may be one of the following:

Superficial musculoaponeurotic system (SMAS) is the most common face-lift procedure. The surgeon makes an incision at the hairline and separates the skin from the underlying tissue and muscles. The muscles are tightened and excess fat and tissue, such as fat under the chin and neck, are removed.
The endoscopic subperiosteal or subgaleal face-lift is a less invasive surgical technique. The surgeon raises facial structures rather than cutting away flaps of skin. Only a few half-inch incisions are made, and scarring is minimal. Not all individuals are candidates for this procedure, however.

Neither SMAS nor the endoscopic version is effective for the middle part of the face, particularly the deep lines (naso-labial folds) that run down from the nose beside the mouth. Some time after the SMAS face-lift, the upper face begins to age again while the lower area keeps its shape, causing the face to look imbalanced. Researchers are looking at other approaches, such as one called composite face-lift, that lift most muscles in the face.

Recovery Process. Recovery normally lasts from several weeks to several months. Swelling and discoloration are common. Some patients report tingling or numbing sensations after surgery. These sensations generally decrease as damaged nerves regenerate.

Complications. A face-lift is not without risks. A postsurgical hematoma is a collection of blood that can occur after a face-lift. In one study, major hematomas occurred in 2.2% of patients and minor hematomas in 6.65% of patients. They generally develop within 2 weeks of the surgery and require draining. Even minor hematomas need fast treatment to prevent greater complications. Such complications can include infection, changes in skin color, fluid buildup, and prolonged recovery time.

Other less common complications may include the following:

Infection
Excessive bleeding
Imbalanced facial muscles
Delayed healing
Scarring
Permanent injury to the nerves that control facial movements

These complications are rare, particularly with a skilled surgeon, but the more complex the face-lifts, the greater the risk.

Blepharoplasty. Blepharoplasty is the primary surgical procedure for eye lifts. Results usually last 5 -10 years. Although simple, it has potential complications, including permanent difficulty in closing the eyes or making a stern expression. Newer techniques, however, are preventing this complication. Assuming the surgeon is experienced, laser surgery is now preferred to the standard surgical scalpel approach. Laser surgery reduces bleeding and bruising, and both the operation and recovery are faster. Temporary blurred or double vision is common. More serious complications include infection, bleeding, dry eyes, difficulty in closing the eyes, and pulling down of the lower lids. Rare cases of blindness have been reported.

Transconjunctival Upper Blepharoplasty. An innovative procedure called transconjunctival upper blepharoplasty removes fat from the membrane that lines the eyelids (the conjunctiva) and is an effective technique for treating both the upper and lower eyelids. Unlike traditional blepharoplasty, this procedure does not cause scarring in the nasal area. In patients who have scars from previous surgeries, transconjunctival removal of fat can also make existing scars less obvious. Long-term side effects and effectiveness of this procedure have not been studied.

Laser Liposculpture and Platysma Resurfacing. A procedure called laser neck and jowl liposculpture and platysma resurfacing may prove to be an alternative to face-lifts. The procedure requires only a one-inch incision under the chin and removing excess fat. After the fat is removed, the surgeon tightens the platysma, the thin muscular sheet under the skin of the neck, which improves the shape of the neck. Only local anesthetic is needed, and the patient can return to normal activities in 2 days. The patient's skin should be elastic enough to be able to reform without sagging.

Resources

www.aad.org -- American Academy of Dermatology
www.asds.net -- American Society for Dermatologic Surgery
www.plasticsurgery.org -- American Society of Plastic and Reconstructive Surgeons
www.surgery.org -- American Society for Aesthetic Plastic Surgery
www.skincarephysicians.com/agingskinnet -- Aging Skin Net

References

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Edison BL, Green BA, Wildnauer RH, Sigler ML. A polyhydroxy acid skin care regimen provides antiaging effects comparable to an alpha-hydroxyacid regimen. Cutis. 2004;73(2 Suppl):14-17.

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Review Date:
10/23/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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