Complex Thoughts on Asthma

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.

Hyperreactive Response

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.

Inflammatory Response

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.

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).

The Allergic Response

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.

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.

Remodeling and Causes of Persistent Asthma

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.

Genetic Factors

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.

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.

Female Hormones

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.

NSAIDs and Acetaminophen

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).

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. Some asthmatic episodes have been linked to high consumption of acetaminophen among adults.

Exercise-Induced Asthma

Exercise-induced asthma (EIA) is a limited form of asthma in which exercise triggers coughing, wheezing, or shortness of breath.

Nocturnal Asthma

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).

Contributing Medical Conditions

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 Chlamydia Pneumoniae and Mycoplasma pneumoniae 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.]

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.

Exercise-Induced Asthma (EIA)

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. (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.

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.

Risk Factors for Very Severe or Fatal Asthma

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

Symptoms of a Life-Threatening Attack

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.

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.

Degree of Severity

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.

Long-Term Outlook

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.

Miscellaneous Complications or Associations

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.

Gender

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.

Obesity

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 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.]

Smoking

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.

Population Differences

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.

Ruling out Other Diseases

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).

Pulmonary Function Tests

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.

Allergy Tests

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.

Other Tests

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

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 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.

Guidelines for Treating Asthma at Home

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.

Understanding the Difference Between Treating Symptoms and Controlling the Disease

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. According to a few studies, most patients do not discriminate between medications that provide rapid short-term relief and long-term symptom control.

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

Administering Inhaled Drugs

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.

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.

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.

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.

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 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).

• 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.

Medications for Treatment and Prevention of Asthma
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.

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. 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.

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. 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.

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.

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.

Anticholinergic Drugs

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.

Systemic Corticosteroids

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.

Inhaled Corticosteroids

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, 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

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 and Similar Drugs

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.

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

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 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).

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. 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.

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

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.

Omalizumab

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 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 Chlamydia Pneumoniae. Dapsone, a drug known as a sulfone, is also under investigation.

Alternative Treatments

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.

Indoor Protection

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.

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.

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.]

Outdoor Protection

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.

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.

Occupational Asthma and Reducing Risk

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.

Medications for Treating Seasonal Allergies

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 medicine 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, however, especially for children with poorly controlled asthma.

[For detailed information, see In-Depth Report #77: Allergic rhinitis and chronic nasal congestion and In-Depth Report #05: Asthma in children and adolescents.]

Treating and Preventing Medical Conditions that Trigger Asthma

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.

Dietary Factors

Weight Loss. People who have asthma and who are overweight may help reduce asthma symptoms 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).

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.

Exercise

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.

Reducing Stress and Mood Disorders

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.