Asthma in Adults

March 2000

WHAT IS ASTHMA?
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 passes into the lungs through progressively smaller airways called bronchioles. The lungs contain millions of bronchioles, all leading to alveoli, microscopic sacs where oxygen and carbon dioxide are exchanged. Asthma is a chronic condition in which these airways undergo changes when stimulated by allergens or other environmental triggers that cause patients to cough, wheeze, and experience shortness of breath (dyspnea). Asthma appears to have two primary stages: hyperreactivity (also called hyperresponsiveness) and the inflammatory response.

Hyperreactive Response
In the hyperreactive response, smooth muscles in the airways constrict and narrow excessively in response to inhaled allergens or other irritants. It should be noted that the airways in everyone's lungs respond by constricting when exposed to allergens or irritants, but people without asthma are able to breathe in deeply to relax the airways and rid the lungs of the irritant. When asthmatics try to take those same deep breaths, their airways do not relax and the patients 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.

Inflammatory Response
The hyperreactive stage is followed by the inflammatory response, in which 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, 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. 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.

WHAT CAUSES ASTHMA?

Asthma has dramatically risen worldwide over the past decades and experts are puzzling over the cause of this phenomenon. The mechanisms that cause asthma are complex and vary among population groups and even individuals. Many asthma sufferers also have allergies, and researchers are investigating the events that occur in both these conditions. Not all people with allergies have asthma, however, and not all cases of asthma can be explained by allergic response. Other contributing causes are being investigated. Asthma is most likely a result of genetic susceptibility, which probably involves several genes, and various environmental triggers, such as infections, dietary patterns, air pollution, and allergens.

Immune Factors Involved in the Allergic Response

In people who have asthma caused by an allergic response, various airborne allergens or other triggers set off a cascade of events in the immune system that lead to inflammation and hyperreactivity in the airways. The process is not completely understood, but the conductor in this orchestra of immune factors appears to be a group of white blood cells known as helper T-cells. Subgroups called TH2-cells overproduce interleukins (ILs), a subgroup of immune factors known as cytokines, which are powerful agents of the inflammatory process. Of special interest are IL4, IL 5, IL 9, and IL 13. Interleukin 4 and 9, for example, stimulate the production and release of a group of antibodies known as immunoglobulin E (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. If this happens, a number of active chemicals (importantly those known as leukotrienes) are released that collectively produce a first-phase asthma attack by causing spasms in the airways and producing mucus and activating nerve endings in the airway lining. Another cytokine, interleukin 5, appears to attract white blood cells known as eosinophils, which accumulate and remain in the airways after the first attack for weeks and mediate the release of other damaging particles that cause a late-phase inflammatory response. Over the course of years, the repetition of these processes can cause structural and functional changes in lung tissue that contribute to the development of chronic asthma.

Genetic Factors
About one third of all persons with asthma share the problem with another member of their immediate family. Genetic factors appear to play a more important role than environmental factors or allergies in such families. The condition may be more likely to be passed to children from the mother than from the father. One study reported, however, that the risk of having an asthmatic child was six times higher if both parents had a history of asthma than if just one had the disease. One study found that specific genetic regions increase the risks for asthma in different ethnic populations, including African Americans, Hispanics, and Caucasians. Although specific genes for asthma have not yet been identified, research is progressing toward this goal.

Exercise-Induced Asthma
About 40% to 90% of asthma cases are exercise-induced asthma (EIA), in which exercise triggers coughing, wheezing, or shortness of breath. It occurs most often in children and young adults and during intense exercise in cold dry air. EIA is triggered only by exercise and is distinct from ordinary allergic asthma in that it does not produce a longterm increase in airway activity (as allergic asthma does) so people who only have EIA do not require long-term maintenance therapy. (Some people, however, have both types.) There is some evidence that patients with EIA may also experience an asthmatic response hours after physical activity; more research is needed to confirm this. It should be noted that asthma is no reason to avoid exercise. About 10% of US athletes who participated in the 1996 Olympics were asthmatic. (Similar results were reported in the 1984 Olympics.) Some studies are indicating that long-term exercise may help control asthma and reduce hospitalization. The warm-up and cool-down periods, which are important for any exercise regimen, may also help reduce the risk of exerciseinduced asthma (EIA). People who enjoy running should probably choose an indoor track to avoid pollutants. Swimming is excellent for people with asthma. Patients should consult their physicians before embarking on an exercise program.

Hormones
Hormones or changes in hormone levels appear to play a role in the severity of asthma in women. Between 30% and 40% of women with asthma experience fluctuations in severity that are associated with their menstrual cycle. One study indicated that such women tend to be older, have had asthma longer, and have more severe asthma than those whose asthma is not related to their periods. Their severe asthma attacks are likely to occur three days before and four days into the menstrual period. Oral contraceptives may help such asthma sufferers by leveling out hormonal changes. However, in postmenopausal women, hormone replacement therapy, both with and without progesterone, poses twice the risk for late-onset asthma. During pregnancy, one-third of asthmatic women suffer more from the condition, one-third suffer less, and the other third experience no difference in severity. One interesting study suggests that expectant asthmatic mothers carrying a female baby tend to have more severe symptoms than do those who are bearing a male.

Contributing Medical Conditions

Infections. The organisms Chlamydia pneumoniae, Mycoplasma pneumoniae, adenovirus, and the respiratory syncytial virus are major causes of respiratory infections and are becoming important suspects in many cases of severe adult asthma. (Serious respiratory infections that occur in early childhood probably do not play a role in asthma that develops in adulthood.) In one study, patients whose asthma was initiated after

infections also had a more severe condition than those whose asthma was due to other causes, but asthma caused by infections did not last as long (5.6 years compared to 13.3 years). Rhinovirus, or the common cold virus, can exacerbate asthma attacks and has been reported to be the most common infectious agent 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. Gastroesophageal reflux disease (GERD), the cause of heartburn, is common in many asthmatic patients. A constellation of irritable bowel syndrome, asthma, and gastroesophageal reflux disease also occurs in some people. GERD may cause asthma by spilling acid into the airways, which triggers a hyperreactive response. GERD may be suspected in patients who do not respond to asthma treatments, whose asthma attacks follow episodes of heartburn, or whose attacks are worse after eating or exercise. People with asthma associated with GERD may be at risk for long-term erosion of the esophagus. [ See Well-Connected, 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% and 30% of asthmatic patients develop true sinusitis. The presence of sinusitis, however, does not appear to increase the severity of asthma.

WHO GETS ASTHMA?

General Risk Factors
Asthma affects 5% to 10% of the worlds population and is increasing globally, in both industrialized and nonindustrialized nations. More than 17 million Americans have asthma, and the number of cases increased by 75% between 1980 and 1994. Other respiratory diseases, sinusitis, and ear infections are also on the rise, suggesting that airborne or environmental factors may be at work that affect all of these conditions, including asthma. Asthma occurs before the age of 15 more often in males, but after puberty it may be more common in girls. One study suggested that women are almost twice as likely as men to suffer from acute asthma. In addition, women may be at much greater risk of death from asthma than men. About 90% of US deaths from asthma occur among the elderly, the majority of whom are women. Research indicates that like many other diseases, asthma is significantly underdiagnosed and undertreated in the elderly.

Ethnicity and Socioeconomic Factors

In addition to the elderly, the population group at highest risk for severe asthma and death are the urban poor. About 6.1% of African-Americans have asthma compared to

5% of whites. African-Americans are also three times as likely as whites to die of the disease. A number of studies indicate that these higher rates are more likely to be due to socioeconomic differences, particularly to lower literacy levels or living in the city, rather than any genetic factors. To confound matters, however, regardless of socioeconomic factors, asthma rates and hospitalizations are dramatically higher in New York Puerto Ricans than in Hispanic-Americans who live in Los Angeles or the Southwest, indicating that other factors are also involved.

WHAT ARE THE SYMPTOMS OF ASTHMA?

After exposure to asthma triggers, symptoms rarely develop abruptly but progress over a period of hours or days. In some cases, the airways have become seriously obstructed by the time the patient even calls the doctor. Asthma is usually worse at night, and attacks often occur between 2 and 4 AM. Asthma occurs primarily at night in as many as 75% of asthma patients. This night time propensity is due to a number of reasons: chemical and temperature changes in the body during the night increase inflammation and narrowing of the airways, delayed allergic responses can occur from exposure to allergens during the day, and toward the early morning, the effect of inhaled medications may wear off and trigger an attack. Some evidence suggests that conditions relating to sleep itself, such as sleep apnea or sleeping on ones back, may play a role in the worsening of asthma at night; further research is needed. The classic symptoms of an asthma attack are coughing, wheezing, and shortness of breath (dyspnea). Wheezing when breathing out is virtually 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. Irritation of the nose and throat, thirst, and the need to urinate are common symptoms and may occur before an asthma attack begins. Some people first experience chest tightness or pain or a nonproductive cough that is not associated with wheezing. Chest pain, in fact, occurs in about three quarters of patients; it can be very severe and its intensity is unrelated to the severity of the asthma attack itself. The neck muscles may tighten and talking may become difficult or impossible. The end of an attack is often marked by a cough that produces a 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.) Asthma symptoms vary in severity from occasional mild bouts of breathlessness to daily wheezing that persists despite taking large doses of medication. Without effective treatment during an attack, exhaustion may worsen respiratory function, and in rare cases, a life-threatening situation can occur. 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, and the patient may begin to lose consciousness.

HOW SERIOUS IS ASTHMA?

Complications of Asthma
According to the Centers for Disease Control, deaths from asthma increased from 1,800 in 1978 to a current, and presumably stable rate of about 5,400 deaths annually. Most deaths from asthma occur in elderly adults and are preventable. It is very rare for a person who is receiving proper treatment to die of asthma. Many individuals with asthma and even some physicians, however, underestimate the severity of this disease. According to one 1999 study, almost half of fatal or near-fatal attacks progress to a severe state within a few minutes. It is difficult even for many close family members and physicians to predict the risk of such episodes, possibly due to unrecognized factors such as the patient's psychological state or poor adherence to therapy. One study reported that people at high risk for fatal or near-fatal asthma attacks had poor awareness of their own reduced ability to breathe and therefore were slow in seeking help. Even when it is not life threatening, asthma is debilitating and frightening. Sleeplessness is a common problem. Studies indicate that between 80% and 93% of asthmatics 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.

Long-Term Outlook
Asthma is usually chronic, although it occasionally goes into long periods of remission. In one study, 72% of men and 86% of women had asthmatic symptoms fifteen years after an initial diagnosis. Only 19% of these people, however, were still seeing a doctor and only 32% used any maintenance medication. Asthma is categorized as mild intermittent, mild persistent, moderate persistent, and severe persistent. 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 severe persistent cases (about 10%), however, the structure of the walls of the airways changes, which leads to progressive and irreversible problems in lung function, even in aggressively treated patients. Studies show that lung function declines much faster than average in asthmatics, particularly in those who smoke and in those with excessive mucus production (an indicator of poor treatment control). People who develop occupational asthma may experience asthmatic symptoms for years, even after avoiding the harmful agents, although improvement occurs over time in most people who leave such jobs. A 1999 study indicates that over 60% of patients with occupational asthma suffer permanent impairment to some degree even after leaving their jobs.

Asthma and Pregnancy

Asthma in pregnant women puts them at slightly higher risk for complications, particularly hemorrhage (which is still very uncommon) and places their babies at risk for lower birth weight and breathing disorders. Fortunately, studies indicate that most asthma drugs are safe to take during pregnancy.

WHAT TESTS MAY BE REQUIRED TO DIAGNOSE ASTHMA?

Medical History
When asthma is suspected, the patient should describe for the physician any pattern related to the symptoms and possible precipitating factors, including whether symptoms are more frequent during the spring or fall (allergy seasons) and whether exercise, a respiratory infection, or exposure to cold air has ever triggered an attack. The patient should report any occupational or long-term exposure to chemicals and any family history of asthma or allergic disorders, such as eczema, hives, or hay fever. 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.

Ruling Out Other Diseases

A number of disorders may cause some or all of the symptoms of asthma. Asthma, chronic bronchitis, and emphysema all affect the lungs in similar ways and, in fact, may all be present in the same person. Unlike the other two conditions, however, asthma usually first appears in patients less than 30 years old and is not revealed by abnormal chest x-rays. Other diseases that must be considered during diagnosis are upper respiratory tract infections, pulmonary embolism, cancer, heart failure, tumors, psychosomatic illnesses, and certain rare disorders. Panic disorder can coincide with asthma or be confused with it.

Pulmonary Function Tests

If symptoms and a patient's history are indicative of asthma, the physician will usually perform 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 physician will determine several values: (1) the vital capacity (VC), which is the maximum volume of air that can be inhaled or exhaled; (2) the peak expiratory flow rate (PEFR), which is the maximum flow rate that can be

generated during a forced exhalation; (3) and the forced expiratory volume (FEV1), which is the maximum volume of air expired in one second. During an attack, narrowing of the airways will decrease the PEFR and FEV1. If these measurements indicate that some degree of airway obstruction is present, the doctor may administer a bronchodilator (a drug that opens the air passages) and then take measurements again; a reversal of the obstruction confirms a diagnosis of asthma. If there are no signs of airflow obstruction but asthma is still suspected, the doctor may perform a challenge test by administering a drug (histamine or methacholine), which usually increases airway resistance in people with asthma and not in those without asthma. The challenge test is not always accurate, particularly in patients whose only asthmatic symptom is persistent coughing. It may be quite useful in ruling out occupational asthma. Another method for inducing airway resistance is to administer cold air. Although this so-called cold air hyperventilation test is very accurate for ruling out asthma, it is not sensitive enough to accurately identify adults who actually are asthmatic.

Laboratory Tests
The patient may be given skin or blood allergy tests, particularly if a specific allergen or occupational agent 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. 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, and examination of the patients sputum for eosinophils, white blood cells that in high levels are associated with severe allergic asthma. Measurements showing decreased levels of exhaled nitric oxide or higher levels of hydrogen peroxide may indicate uncontrolled asthma and provide methods for gauging the effectiveness of treatment.

WHAT ARE THE GENERAL GUIDELINES FOR TREATING ASTHMA?

Avoiding allergens, following appropriate drug treatments, and home monitoring are key elements in preventing dangerous asthma attacks and hospitalization. Drug treatments are now categorized by their ability to (1) control long-term persistent inflammation or (2) relieve acute asthma symptoms. The primary drugs used to control inflammation are corticosteroids (commonly called steroids), leukotriene-antagonists, and cromolyn. Generally, the drugs that relieve symptoms are bronchodilators, which open the airways during an asthma attack; they include short-acting beta-adrenergic agonists (beta2-agonists), theophylline, and certain anticholinergic agents. (Long-acting beta2-agonists are not used for acute attacks but are proving to be effective for prevention.) For moderate to severe asthma, controlling inflammation is as important as relieving symptoms. Unfortunately, simply coping with asthma rather than controlling it is a common and serious error. Only a third of asthma sufferers know that uncontrolled asthma can lead to permanent lung damage and more than half do not know the difference between drugs that help prevent asthma attacks and those that

only provide symptom relief.

Emergency Treatment for an Acute Attack

An acute attack may require hospitalization during which beta2-agonists are administered with a nebulizer (a device that administers the drug in a fine spray) or with hourly administration of inhaled beta2-agonists. A corticosteroid may be administered if the patient does not respond to other treatments. Oxygen is usually given, though one study found that giving 100% oxygen to very ill asthmatic patients might be harmful. A 1999 study has found that a mixture of helium and oxygen (heliox) reduces airway obstruction within 20 minutes, and may prove to be an effective bridge until corticosteroids take effect. Investigators are looking for treatments to help prevent relapse after leaving the hospital. One small 1999 study suggested that adding an inhaled corticosteroid, such as budesonide, with oral corticosteroids following discharge reduced the incidence of worsening symptoms afterward. Others have found that a single injection of triamcinolone (another steroid) shortly before discharge from the hospital may be effective. Unfortunately, according to one study, almost one in four adolescents who are hospitalized due to uncontrollable asthma show insensitivity to steroid treatment. Of some promise is a report that the use of intravenous immunoglobulin along with steroids may be effective in such patients.

Treating Asthma at Home

Treating Acute Symptoms. Generally, on a day-to-day basis, the drugs that relieve symptoms are bronchodilators; these medications open the airways during an asthma attack. They include the class of drugs known as short-acting beta-adrenergic agonists (beta2-agonists), theophylline, and certain anticholinergic agents. (Long-acting beta2agonists, while not anti-inflammatory agents, are being used for prevention rather than treatment of attacks.) Beta2-agonists provide no protection against hospital readmissions. Maintenance Therapy. A number of drugs may be required for preventing asthma attacks on an ongoing basis. Corticosteroids (commonly called steroids) are the standard agents used to reduce the inflammatory response in moderate to severe asthma. Long-acting beta2-agonists (salmeterol, formoterol) have no effect on inflammation but are beneficial for prevention of exercise-induced asthma and for asthma attacks during the night in patients with mild asthma. They may be used in combination with steroids. Newer antiinflammatory drugs known as leukotrienes-antagonists are also proving to be effective alone or in combination with steroids. Combining such drugs with steroids may be very effective in reducing both severe and mild symptoms, improving lung function, and reducing the need for high doses of steroids. Such combination regimens can be complicated, however, and compliance rates are low. In starting maintenance therapy for patients with moderate to severe asthma, experts debate whether a so-called step-up or step-down approach is best. With a step-up approach, the patient is started at low doses of medication and given increasing doses

until symptoms improve. With the step-down approach, the patient is treated very aggressively at first, usually with high-dose corticosteroids, and then medication is reduced to the lowest effective dose. British guidelines recommend the step-down approach, but two different studies comparing an initial regimen of a high-dose corticosteroid (800 mcg of budesonide) compared to lower doses had opposite results, with one finding an advantage and the other no benefits starting with the high dose. There were some differences in the studies, however, and more research is needed for clarification. One 1999 study found that monitoring the patient for signs of airway inflammation and administering treatments based on the severity of airway hyperresponsiveness, rather than using a stepped approach, led to far greater control of asthma and alleviation of airway inflammation. Proper use of medications, in any case, is crucial for safe and effective treatment. Studies are finding that a significant number of moderate or severely asthmatic patients overuse their inhaled beta-agonists and underuse their corticosteroid medications. Because so many patients suffer most attacks during the night, experts now question the standard practice of administering long-acting medications evenly over 24 hour periods, calling instead for more medication to be delivered during the night compared to during daytime activity. Drug Administration Methods. Some asthma drugs may be taken orally but most are inhaled. The standard device has been the metered-dose inhaler (MDI), which allows precise doses to be delivered directly to the lungs. These 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. Standard MDIs use ozonedepleting chlorofluorocarbons as propellants, but alternatives that deliver a powdered form of medications directly into the lungs and do not threaten the environment are now available. Such devices include Rotahaler, Spiros, Spinhaler, Turbuhaler, Diskhaler, and many others. They are proving to be as effective as the older devices and have other advantages, including a better taste. As with the MDI, training is needed to use them properly. Monitoring. 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 physician or emergency room visit to control symptoms. Physicians recommend that patients with even mild asthma monitor their own conditions. A peak flow meter is the standard monitoring device. Some recommend taking readings two or three times a day, although for mild to moderate asthma, a single determination each morning usually suffices. It is important to use the meter at the same times each day and to stand or sit in the same position in order 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 two months, patients and physicians can use the data recorded for administering medications effectively and to recognize problems before they become serious. The overall treatment and management goal should be to achieve a less than 20% and ideally 10% difference between evening and morning rates. New monitoring devices may prove to be useful. In one study, a hand-

held spirometer (Vitalograph), which measures both peak expiratory flow rates and lung function, was more reliable than a peak flow meter. Another hand-held device, called AirWatch, is a 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 person plugs the device into a standard telephone jack and the daily readings are sent to an automated data center which creates tables and charts for the patient and the doctor.

WHAT ARE THE SPECIFIC DRUGS USED TO TREAT ASTHMA?

Bronchodilators: Beta2-agonists
Short-Acting Beta2-agonists. Beta2-agonists do not reduce inflammation or airway responsiveness but serve as bronchodilators , relaxing and opening constricted airways during an acute asthma attack. Albuterol (Proventil, Ventolin), called salbutamol outside the US, is the standard short-acting beta2-agonist in America. Other shortacting beta2-agonists are isoproterenol (Isuprel, Norisodrine, Medihaler-Iso), metaproterenol (Alupent, Metaprel), pirbuterol (Maxair), terbutaline (Brethine, Brethaire, Bricanyl), bitolterol (Tornalate), and isoetharine (Bronkometer, Bronkosol), which is available in nebulizers. Of great interest are new beta2-agonists, including levalbuterol (Xopenex), that have more specific actions than the standard drugs. Studies have indicated that levalbuterol is as effective as albuterol with fewer side effects. Shortacting bronchodilators are generally administered through inhalation and are effective for three to six hours. Short-acting beta2-agonists relieve the symptoms of acute attacks, but they do not control the underlying inflammation, which is always present in asthma, even in its mildest forms and when there are no active symptoms. Patients with mild asthma, then, should use these drugs only to relieve symptoms during asthma attacks or as premedication for exercise-induced asthma. Long-Acting Beta2-agonists. Long-acting beta2-agonists, including salmeterol (Serevent) and formoterol (Foradil), are now available for preventing, but not for treating, an asthma attack. As with short-acting beta2-agonists, the long-acting forms effectively reduce asthma symptoms but have no effect on inflammation. The effects of one dose last for about 12 hours, so these drugs are particularly effective during the night and for prevention of exercise-induced asthma in people who work out or labor for long hours. In one study, salmeterol also protected against aspirin-induced asthma. In comparison studies, salmeterol and formoterol appear to be equally beneficial, although formoterol may have a faster action and a better effect on evening peak expiratory flow (PEF). Most studies to date have been used only with salmeterol, the older drug, but their results can usually be applied to formoterol as well. In two studies, taking the long-acting salmeterol improved the quality of life in patients compared to other regimens. Salmeterol appears to be safe when combined with other drug therapies, including corticosteroids and other bronchodilators, and may allow lower doses of steroids. In fact, a single inhaler (Advair Diskus) that combines both salmeterol and the

corticosteroid fluticasone is safe and more effective than either salmeterol or fluticasone used alone for patients who do not respond well to other treatments. Salmeterol is about four times more potent than a short-acting beta2-agonist and takes up to 20 minutes to become effective. There is a danger then of fatal overdose if a patient does not experience fast relief and takes additional doses. The risk appears to be highest in elderly patients with severe asthma. The medication should not be stored in locations that are easily accessible during acute attacks, such as by the bed or in a pocketbook. Long-acting agents should never be used for treatment of acute episodes; for this purpose, albuterol or other short-acting bronchodilators should be used. Side Effects of Beta2-Agonists. Side effects of all beta2-agonists include anxiety, tremor, restlessness, and headache. Patients may experience fast and irregular heartbeats. A physician should be notified immediately if such side effects occur. People with existing heart conditions who take beta2-agonists, particularly orally or with a nebulizer, face an increased risk for sudden death from cardiac related causes. One 1998 study has found a higher incidence in heart failure in adults taking long-acting beta2-agonists over prolonged periods. The study was very limited, and more research is warranted. Nevertheless individuals with diabetes, existing heart disease, high blood pressure, hyperthyroidism, an enlarged prostate, or a history of seizures should take these drugs with caution. Beta2-agonists have serious interactions with certain other drugs, such as beta-blockers, and patients should tell the physician about any other medications they are taking. Both long- and short-acting beta2-agonists become less effective when taken regularly over time. Studies indicate, for example, that although salmeterol continues to be protective against exercise-induced asthma, the protection time it provides after exercising shortens over time until after about a month the drug has no effect at all. One study has suggested that some people with asthma may be genetically predisposed to develop an insensitivity to beta2-agonists. Another reported that regular use of albuterol actually increased the presence in the airways of eosinophils, the immune cells related to allergic responses. Some experts believe this action may cause a later asthma attack in response to allergens, and others think that it may interfere with the actions of any corticosteroids being taken. Because theoretically this weakening long-term effect could lead to overuse and even overdose of beta2-agonists, some experts suggest that these drugs may be partially responsible for the recent, increased rate in asthma deaths. A number of studies, however, have found no association between the use of shortacting beta2-agonists and any higher mortality rate. Nevertheless, taking short-acting beta2-agonists on a regular schedule provides no additional benefit over taking them only when symptoms occur, and prolonged use with long- or short-acting beta2agonists may worsen asthma control. For those on long-acting beta2-agonists, using slightly higher doses of inhaled steroids and not taking salmeterol daily may be helpful in preventing tolerance. In one study, dry-powder delivery of formoterol allowed patients to take a lower dose, which may help prevent long-term tolerance to these drugs. If symptoms are severe or frequent, the patient should consult a physician before increasing the use of the beta2-agonists.

Other Bronchodilators
Theophylline. Theophylline 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, however, an overdose can easily occur. Toxicity causes nausea, vomiting, headache, insomnia, and, in rare cases, disturbances in heart rhythm and convulsions. A physician should be contacted immediately if any of these side effects occur. The risks for these adverse effects are small if the drug is taken exactly as prescribed. It should be noted that 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. Caution should be exercised if beta2-agonists and theophylline are used together. In any case, theophylline has no impact, either positively or negatively, on the loss of effectiveness observed in long-term use of salmeterol. Theophylline should not be taken by anyone who has a peptic ulcer and should be taken with caution by the elderly and by individuals with heart disease, liver disease, hypertension, seizure disorders, or congestive heart failure. People with heart conditions who take theophylline orally face an increased risk for sudden death from heart-related causes. Anticholinergic Agents. Inhaled ipratropium bromide (Atrovent) acts as a bronchodilator over time. It is not approved specifically for asthma, but it may be useful for certain older patients who also have chronic obstructive lung disease. Ipratropium bromide alone is not useful for acute asthma attacks, nor does it add any benefit to a beta2agonist in the first 90 minutes of an attack. The combination might be helpful, however, for patients who do not initially respond to treatment with beta2-agonists alone. In addition, according to one study, using it for 36 hours after an acute asthma attack may lead to a faster recovery period.

Anti-Inflammatory Drugs: Corticosteroids

Aerosol Corticosteroids. Corticosteroids, also called glucocorticoids or steroids, are powerful anti-inflammatory drugs currently recommended as the primary therapy for any asthmatic condition more serious than occasional episodes of mild asthma or when treatment with bronchodilators is not effective. 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. Inhalation of corticosteroids makes it possible to provide effective local anti-inflammatory activity in the lungs with minimal systemic effects; oral steroids have considerable side effects. Corticosteroids are not bronchodilators (that is, they do not relax the airways) and have little effect if used only for acute asthma attacks. They work over time by reducing inflammation and allowing the lungs to function properly and may even prevent long-term complications. They must be taken regularly; it may take a month to perceive their effects and up to a year to

achieve full benefits. A number of studies have shown that they significantly reduce the rate of rehospitalizations from asthma. The older corticosteroid inhalants are beclomethasone (Beclovent, Vanceril) and dexamethasone (Decadron Phosphate Respihaler and others). Newer, more powerful inhaled steroids include (in order of potency) fluticasone (Flovent), budesonide (Pulmicort), flunisolide (AeroBid), and triamcinolone (Azmacort and others). (The older corticosteroid beclomethasone may be more effective than triamcinolone, although some studies have found them to be about equal.) Of some concern was a study which suggested that fluticasone was significantly more powerful than budesonide in suppressing adrenal function, the cause of major side effects that occur when withdrawing from oral steroids. [ See Side Effects of Corticosteroids, below .] These newer inhaled corticosteroids, such as budesonide, administered with a Turbuhaler or nebulizer, may even be a beneficial and safer alternative to oral steroids, which are used after an acute asthma attack [ see below ]. 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, which may be as effective as taking two or even four doses a day in the standard regimens. Oral Corticosteroid s. Oral (also called systemic) corticosteroids are usually the last drugs to be added to an asthma treatment program and the first to be removed. Common oral corticosteroids include prednisone, prednisolone, methylprednisolone, and hydrocortisone. They very effectively decrease inflammation but are generally used only after hospitalization for an acute attack. In some severe cases, they may be used as maintenance. Side Effects of Corticosteroids. Common side effects of inhaled steroids are throat irritation, hoarseness, and dry mouth. Rashes, wheezing, facial swelling (edema), fungal infections (thrush) in the mouth and throat, and bruising are also possible but are not common with inhalators. 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. Such adverse effects 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. Inhaled corticosteroids are considered safe for pregnant women and their babies, according to a 1999 study, although pregnant women taking both beta2-agonists and corticosteroids are at higher risk for diabetes during pregnancy (gestational diabetes). Steroids appear to cause premature death of bone-forming cells and slow their replacement, and osteoporosis is a common and particularly severe longterm side effect of prolonged steroid use. Medications that can prevent osteoporosis include calcium supplements, parathyroid hormone, alendronate etidronate, or hormone replacement therapy in post-menopausal women. Vitamin C and E may help reduce the risk of cataracts. Long-term use of steroid medications also 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. Uncommonly, switching from oral to inhaled steroids has caused severe adrenal

insufficiency and, in rare cases, has resulted in death. The risk increases during times of stress. Patients should discuss with their physician measures for preventing adrenal insufficiency, particularly during stressful times. No one should stop taking any steroids without consulting a physician first, and if steroids are withdrawn, regular follow-up monitoring is necessary.

Anti-Inflammatory Drugs: Cromolyn and Similar Drugs

Cromolyn sodium (Intal) serves as both an anti-inflammatory drug and a specific blocking agent for triggers such as allergens or exercise. It is often used in children with allergic asthma, but cromolyn is also the treatment of choice for preventing exerciseinduced asthma (EIA) in all age groups, for pregnant women, and possibly for preventing allergic asthma in adults as well. Side effects include nasal congestion, cough, sneezing, wheezing, nausea, nosebleeds, and dry throat. Although cromolyn can help prevent asthma attacks, particularly those precipitated by exercise, cold, and known allergens, it does not effectively treat asthma once an attack is underway. A cromolyn nasal spray called Nasalcrom has been approved for over-the-counter purchase, but only to relieve nasal congestion caused by allergies. Asthmatic patients should not use it for self-medication without the advice of a physician. Nedocromil (Tilade) is similar to cromolyn and also prevents asthmatic reactions to cold and exercise. Both drugs appear to be useful for aspirin-induced asthma. 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. Ketotifen, another similar drug, also has antihistamine qualities and may be useful in preventing allergic asthma, although one study reported that it was not as effective as either cromolyn or the inhaled corticosteroid beclomethasone.

Anti-Inflammatory Drugs: Leukotriene-Antagonists

Leukotriene-antagonists block leukotrienes, 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. They include zafirlukast (Accolate), montelukast (Singulaire), and zileuton (Ziflo). Leukotriene-antagonists are taken orally. Their anti-inflammatory actions are different from those of steroids, and a combination of the two agents are helping some patients whose asthma is not completely controlled with inhaled steroids alone. Leukotriene-antagonists are not used for treating acute asthma attacks, but they are proving to be effective for long-term prevention, for exercise-induced asthma, and for reducing the use of inhaled corticosteroids. Very few side effects, except gastrointestinal distress, have been associated with the use of leukotriene-antagonists. Of some concern, however, 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. Usually the syndrome has occurred, however, in patients who were tapering off steroids and changing over to the leukotrienes-antagonists. Some experts believe that, in such cases, the steroids themselves may have masked the syndrome, which then developed when the steroid drugs were withdrawn. Symptoms include

severe sinusitis, flu-like symptoms, rash, and numbness in the hands and feet.

Experimental Biologic Agents

A number of genetically designed biologic agents are being developed. Monoclonal antibodies (MAb), for example, are genetically-developed agents that are designed to target and attack very specific factors. A Mab known as RhuMAb-E25, prevents the antibody immunoglobulin E (IgE) from triggering the inflammatory events that lead to asthmatic attacks. Early studies are very promising. Keliximab is another monoclonal antibody under investigation that attacks white blood cells called CD4 lymphocytes, which may be important in the asthmatic inflammatory process.

Alternative Treatments
According to some studies, alternative therapies such as acupuncture, hypnosis, breathing relaxation techniques, and homeopathic remedies are being widely used by both children and adults with asthma with some good results. Herbal remedies have been used with apparent success in Eastern nations, but few have been studied rigorously in the United States. It should be noted that even when natural remedies appear to be effective in trials, there are no standards or regulations in the US to guarantee their quality, effectiveness, or safety. Of great concern are their growing use and the possibilities of serious drug interactions. Patients who try alternative treatments must be sure to inform their physician.

Treatment of Disorders that Might Cause Asthma

Treatments for GERD. Treating gastroesophageal reflux disease with drugs that reduce acid back-up appears to reduce symptoms of both conditions in some patients who also have asthma. They may not have much effect, however, on actual lung function. [ See Well-Connected, Report #85 Heartburn and Gastroesophageal Reflux Disease. ] Treatment of Infections. In one small study, asthmatic patients who had blood tests showing current or previous infection by Chlamydia pneumonia were aggressively treated with antibiotics and afterward showed significant or complete improvement in their asthma symptoms. Better controlled studies are needed, and antibiotics, in any case, would not be effective in patients whose asthma was triggered by allergens or unknown causes. Allergy Shots. Allergy shots (immunotherapy) may provide some relief for people whose asthma is worse during ragweed season. One 1999 analysis of several studies reported that patients who completed their course of allergy shots experienced an 80% reduction in their need for daily medications and a 50% reduction in symptoms. Some researchers view this therapy as impractical for adults, however.

WHAT ARE THE TRIGGERS OR RISK FACTORS FOR ASTHMA ATTACKS AND HOW CAN THEY BE MINIMIZED?
About 50% of adults with asthma exhibit allergic responses. Avoidance or control of the triggers that lead to asthma attacks is as much a priority as treatment of the disease.

Common Allergens and Preventing Exposure to Them

An asthma attack can be induced or aggravated by direct irritants to the lungs such as animal dander, pollen, molds, and fungi. The primary allergens that trigger asthma in the home are dust mites, specifically mite feces, which are coated with enzymes that contain a powerful allergen. Cockroaches are also major asthma triggers and may reduce lung function even in people without a history of asthma. The connection between asthma and nonseasonal or seasonal allergic rhinitis (hay fever or rose fever caused by pollen allergies) is unclear. They often coexist together, and although most people with asthma have a history of allergic rhinitis, only 1% to 20% of children with allergic rhinitis actually develop asthma. It is likely that the two conditions have a common cause rather than one causing the other. Controlling Pets. Pets should be kept outside or, if this isn't possible, be confined to carpet-free areas outside the bedroom. Cats harbor significant allergens; dogs usually present fewer problems. Washing cats and dogs 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. Air Filters and Vacuum Cleaners. Air cleaners, filters for air conditioners, and vacuum cleaners with HEPA filters can help remove particles and small allergens found indoors. Air cleaners have little or no effect against cat allergens or dust mite feces that lodge in carpets and bedding. HEPA vacuum cleaners appear to be effective in reducing levels of second-hand smoke and preventing cat allergens from being released into the air. Neither vacuuming nor the use of anti-mite carpet shampoo is effective in removing mites; in fact, vacuuming stirs them up. It is best to avoid carpets if possible. Of some concern are studies reporting no change in asthmatic symptoms after controlling cat or dust mite allergens. More research is needed to identify the reasons for this. Bedding and Curtains. Using semipermeable coverings to fully encase mattresses and pillows is the most proven effective step in reducing dust mite levels. (Vinyl mattress covers limit airflow and may also exacerbate, 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.) Curtains should be replaced with shades or blinds and bedding washed using the highest temperature setting. Exterminating Cockroaches. Cockroaches should be eliminated by professional

exterminators, although a study reported that ridding a home of cockroaches and cleaning the house using standard housecleaning techniques failed to eliminate the cockroach allergens themselves. Outdoor Protection. Camping and hiking trips should not be scheduled during times of high pollen count (in the Northern states, May and June for grass pollen and midAugust 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. 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. Other Recommendations . Damp housing increases the risk for asthma; reducing indoor humidity can lower dust mite populations. On-going humidifiers then can be counterproductive because dust mites thrive in humidity, and because they can develop mold if not cleaned daily with a vinegar solution; humidity levels should not exceed 40%. Patients with asthma should choose electric ovens rather than gas, which release nitrogen dioxide, a substance that can aggravate asthma symptoms.

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 Well-Connected , Report # 41, Smoking.]

Occupational Asthma
A number of studies have estimated that between 2% and 26% of adult-asthma cases are related to work history. Work-related asthma is one of two types: work-aggravated asthma (existing asthma symptoms that are triggered by irritants at the workplace) or occupational asthma (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) or latent (symptoms develop after prolonged exposure to substances in the workplace) . Any worker exposed to occupational triggers may be at risk for asthma, including nonsmokers and people with no previous allergies. (Workers who have allergies, who smoke, or both, however, are at higher risk for many forms of occupational asthma.) Some experts encourage physicians to suspect occupational factors in all cases of adultonset asthma. Occupational Triggers. Over 250 agents have been identified as potential occupational triggers of asthma and the list is growing. A few of the chemicals and substances that are particularly problematic 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 agents ( Bacillus subtilis , pancreatic enzymes); xylanase used in the baking industry; pharmaceutical agents (penicillin, phenylglycine acid chloride); glutaraldehyde used to sterilize medical equipment; and red dye made from the cochineal insect. 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, but often even low levels of chemical agents can trigger a response. In such cases, leaving the job is the only way to prevent the condition from getting worse, especially because increased exposure to asthma triggers in the workplace worsens the condition. Although the effects can be permanent, in one study, 70% of people with asthma experienced significant improvement in symptoms after leaving the job. 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.

Air Pollution
Air pollution has been associated with the development of asthma and asthma-related hospitalization, although a causal relationship is unproven. Specific pollutants targeted for their role in triggering asthma include diesel fumes, sulfur dioxide from power and paper industries, and nitrogen dioxide from exhaust and gas ovens. There are conflicting reports on the effects of ozone levels; studies indicate that high levels do not appear to increase the risk for hospitalization from asthma attacks.

Dietary Recommendations
Food Allergies. Although 67% of asthmatics 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 believe, dairy products do not appear to exacerbate asthma symptoms in people who are not already allergic to them. Obesity and Weight Loss. In both adults and children, the incidence of obesity has been increasing parallel to the rise in asthma over recent years. Studies report a strong association between the two conditions, and there is some evidence that losing weight can relieve asthma symptoms. Some experts suggest that excess weight pressing on the lungs can cause a hyperreactive response. Others believe that asthma itself inhibits physical activity, which in turn produces weight gain. Anyone who is obese and has

asthma should make every attempt to lose weight. [ See the Well-Connected report on Obesity and Weight Loss .] Lung-Healthy Diet. One 1999 study found that antioxidant supplements, such as beta carotene and vitamin C, may protect against exercise-induced asthma. It should be noted that beta carotene supplements may be harmful in some people, with several studies finding an increased risk for lung cancer in smokers. Foods rich in antioxidants are preferred, especially darkly colored fruits and vegetables.

Preventing Respiratory Infections

People with asthma should try to minimize their risk for respiratory tract infections. Washing hands is a very simple but effective preventive measure. Vaccinations against influenza each fall appear to be beneficial and do not appear to worsen asthmatic symptoms. Some people with asthma may also benefit from a single vaccination against pneumococcal pneumonia.

Reducing Stress
People with asthma have no higher rate of anxiety or depression than the general population, but extreme emotions, including stress and depression, are associated with more severe symptoms and even an increased risk of fatal asthma attacks. While negative emotions can discourage proper treatment and the ability to cope, a positive attitude can be of considerable help in the long-term management of asthma.

Avoiding Medications that Trigger Stress

Aspirin and products containing aspirin can cause life-threatening asthma attacks in susceptible individuals. Acetaminophen (eg, Tylenol) is an alternative for relief of minor pain. A pharmacist should be consulted if the ingredients of any over-the-counter preparations are not known. A number of drugs interact with asthma medications, so all drugs being taken should be discussed with the physician. Taking hormone replacement therapy may increase the risk for asthma, although women with asthma who take oral contraceptives may experience fewer symptoms around the time of menstruation.

WHERE ELSE CAN PEOPLE WITH ASTHMA GET HELP?

The American Lung Association, 1740 Broadway, New York, New York 10019-4374. Call (800-LUNG-USA) or on the Internet (www.lungusa.org/) The association is very responsive and offers a wide range of information and services.

American College of Allergy, Asthma & Immunology, 85 West Algonquin Road, Suite 550, Arlington Heights, IL 60005. Call (847-427-1200) or fax: (847-427-1294) or on the Internet (http://allergy.mcg.edu/) This organization publishes information sheets on specific allergies and offers a number for referrals to allergists in local areas. National Heart, Lung, and Blood Institute, P.O. Box 30105, Bethesda, MD 20824-0105. Call (301-251-1222) or on the Internet (www.nhlbi.nih.gov/nhlbi/nhlbi.htm) This government institute publishes booklets and other information.

National Jewish Center for Immunology and Respiratory Medicine, 1400 Jackson Street, Denver, CO 80206. Call (800-222-LUNG or 303-355-LUNG) or for the recorded service Lung Facts call (800-552-LUNG) or on the Internet (www.njc.org/).

Both companies below not only offer products for people with allergies and asthma, but their customer support is friendly, very well-informed, and offers detailed information on their products. National Allergy Supply, 4400 Georgia Highway, 120 PO Box 1658, Duluth, GA 30155. Call (800-522-1448) or (404-623-8077) or fax (404-623-5568) Allergy Control Products, Inc., 96 Danbury Road, Ridgefield, CT 06877. Call (800-422DUST or 3878) or on the Internet (www.allergycontrol.com)

Additional information on the NAEPP and other nhlbi materials on asthma are available online at the NHLBI website (www.nhlbi.nih.gov/nhlbi/nhlbi.htm). The full Expert Panel Report will be available online on February 24. Photocopies can be obtained by sending a check for $20 to the NHLBI Information Center, PO Box 10305, Bethesda, MD20824-0105.

RECENT LITERATURE
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Well-Connected reports are written and updated by experienced medical writers and reviewed and edited by the in-house editors and a board of physicians at Harvard Medical School and Massachusetts General Hospital. The reports are distinguished from other information sources available to patients and health care consumers by their quality, detail of information, and currency. These reports are not intended as a substitute for medical professional help or advice but are to be used only as an aid in understanding current medical knowledge. A physician should always be consulted for

any health problem or medical condition. The reports may not be copied without the express permission of the publisher.

Board of Editors
Harvey Simon, MD, Editor-in-Chief, Massachusetts Institute of Technology; Physician, Massachusetts General Hospital

Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School; Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center

Masha J. Etkin, MD, PhD, Gynecology, Harvard Medical School; Physician, Massachusetts General Hospital

John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts General Hospital

Daniel Heller, MD, Pediatrics, Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital

Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

Carol Peckham, Editorial Director Cynthia Chevins, Publisher

Sherry Knecht Update Editor

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