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 Chlamydiapneumoniae and Mycoplasmapneumoniae adenovirus. They are major causes of both mild and serious respiratory infections and are becoming important suspects in many cases of severe adult asthma. (If such respiratory infections occur in young children, they are unlikely to affect adult-onset asthma.) In one study, patients whose asthma occurred after infections had more severe conditions than those whose asthma was due to other causes. The infection-initiated asthma, however, lasted only 5.6 years compared to 13.3 years in the non-infection group.

In any age group, respiratory infections worsen existing asthma in people who have it already. Rhinovirus (the common cold virus) has been reported to be the most common infection associated with asthma attacks. In one study, it was associated with 61% of asthma exacerbations in children and 44% in adults. Some research suggests that colds promote allergic inflammation and increase the intensity of airway responsiveness for weeks.

GERD. At least half of patients with asthma have gastroesophageal reflux disease (GERD), the cause of heartburn. It is not entirely clear which condition causes the other or whether they are both due to common factors.

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.

Sinusitis. Almost half of children and adults with allergic asthma have sinus abnormalities, and in various studies, between 17 - 30% of patients with asthma develop true sinusitis. The presence of sinusitis, however, does not appear to increase the severity of asthma.

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.

Click the icon to see an image of exercise-induced asthma.

Review Date: 12/21/2006
Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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