Asthma

Asthma is a chronic condition involving the respiratory system in which the airway occasionally constricts, becomes inflamed, and is lined with excessive amounts of mucus, often in response to one or more triggers. These episodes may be triggered by such things as exposure to an environmental stimulant (or allergen) such as cold air, warm air, moist air, exercise or exertion, or emotional stress. In children, the most common triggers are viral illnesses such as those that cause the common cold.^[1] This airway narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing. The airway constriction responds to bronchodilators. Between episodes, most patients feel well but can have mild symptoms and they may remain short of breath after exercise for longer periods of time than the unaffected individual. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and environmental changes.

Public attention in the developed world has recently focused on asthma because of its rapidly increasing prevalence, affecting up to one in four urban children.^[2]

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Etymology

The word 'asthma' is derived from the Greek aazein, meaning "sharp breath." The word first appears in Homer's Iliad;^[3] Hippocrates was the first to use it in reference to the medical condition, in 450 BC. Hippocrates thought that the spasms associated with asthma were more likely to occur in tailors, anglers, and metalworkers. Six centuries later, Galen wrote much about asthma, noting that it was caused by partial or complete bronchial obstruction. In 1190 AD, Moses Maimonides, an influential medieval rabbi, philosopher, and physician, wrote a treatise on asthma, describing its prevention, diagnosis, and treatment.^[4] In the 17th century, Bernardino Ramazzini noted a connection between asthma and organic dust. The use of bronchodilators started in 1901, but it was not until the 1960s that the inflammatory component of asthma was recognized, and anti-inflammatory medications were added to the regimens.

Signs and symptoms

In some individuals asthma is characterized by chronic respiratory impairment. In others it is an intermittent illness marked by episodic symptoms that may result from a number of triggering events, including upper respiratory infection, stress, airborne allergens, air pollutants (such as smoke or traffic fumes), or exercise. Some or all of the following symptoms may be present in those with asthma: dyspnea, wheezing, stridor, coughing, an inability for physical exertion. Some asthmatics that have severe shortness of breath and tightening of the lungs never wheeze or have stridor and their symptoms may be confused with a COPD-type disease.

An acute exacerbation of asthma is referred to as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and either wheezing or stridor.^[5] Although the former is "often regarded as the sine qua non of asthma",^[5] some patients present primarily with coughing, and in the late stages of an attack, air motion may be so impaired that no wheezing may be heard. When present the cough may sometimes produce clear sputum. The onset may be sudden, with a sense of constriction in the chest, breathing becomes difficult, and wheezing occurs (primarily upon expiration, but can be in both respiratory phases).

Signs of an asthmatic episode include wheezing (tachypnea), prolonged expiration, a rapid heart rate (tachycardia), rhonchous lung sounds (audible through a stethoscope), and over-inflation of the chest. During a serious asthma attack, the accessory muscles of respiration (sternocleidomastoid and scalene muscles of the neck) may be used, shown as in-drawing of tissues between the ribs and above the sternum and clavicles, and the presence of a paradoxical pulse (a pulse that is weaker during inhalation and stronger during exhalation).

During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and can experience chest pain or even loss of consciousness. Just before loss of consciousness, there is a chance that the patient will feel numbness in the limbs and palms may start to sweat. Feet may become icy cold. Severe asthma attacks, which may not be responsive to standard treatments (status asthmaticus), are life-threatening and may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few or even no signs of the disease.^[6]

Diagnosis

Asthma is defined simply as reversible airway obstruction. Reversibility occurs either spontaneously or with treatment. The basic measurement is peak flow rates and the following diagnostic criteria are used by the British Thoracic Society:^[7]

• ≥20% difference on at least three days in a week for at least two weeks;
• ≥20% improvement of peak flow following treatment, for example:
  • 10 minutes of inhaled β-agonist (e.g., salbutamol);
  • six week of inhaled corticosteroid (e.g., beclometasone);
  • 14 days of 30mg prednisolone.
• ≥20% decrease in peak flow following exposure to a trigger (e.g., exercise).

In many cases, a physician can diagnose asthma on the basis of typical findings in a patient's clinical history and examination. Asthma is strongly suspected if a patient suffers from eczema or other allergic conditions—suggesting a general atopic constitution—or has a family history of asthma. While measurement of airway function is possible for adults, most new cases are diagnosed in children who are unable to perform such tests. Diagnosis in children is based on a careful compilation and analysis of the patient's medical history and subsequent improvement with an inhaled bronchodilator medication. In adults, diagnosis can be made with a peak flow meter (which tests airway restriction), looking at both the diurnal variation and any reversibility following inhaled bronchodilator medication.

Testing peak flow at rest (or baseline) and after exercise can be helpful, especially in young asthmatics who may experience only exercise-induced asthma. If the diagnosis is in doubt, a more formal lung function test may be conducted. Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Monitoring asthma with a peak flow meter on an ongoing basis assists with self monitoring of asthma. Peak flow readings can be charted on graph paper charts together with a record of symptoms or use peak flow charting software^[8]. This allows patients to track their peak flow readings and pass information back to their doctor or nurse.^[9]

In the Emergency Department doctors may use a capnography which measures the amount of exhaled carbon dioxide,^[10] along with pulse oximetry which shows the amount of oxygen dissolved in the blood, to determine the severity of an asthma attack as well as the response to treatment.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A clinician taking a history should check whether the patient is using any known bronchoconstrictors (substances that cause narrowing of the airways, e.g., certain anti-inflammatory agents or beta-blockers).

Chronic obstructive pulmonary disease, which closely resembles asthma, is correlated with more exposure to cigarette smoke, an older patient, less symptom reversibility after bronchodilator administration (as measured by spirometry), and decreased likelihood of family history of atopy.

Pulmonary aspiration, whether direct due to dysphagia (swallowing disorder) or indirect (due to acid reflux), can show similar symptoms to asthma. However, with aspiration, fevers might also indicate aspiration pneumonia. Direct aspiration (dysphagia) can be diagnosed by performing a Modified Barium Swallow test and treated with feeding therapy by a qualified speech therapist. If the aspiration is indirect (from acid reflux) then treatment directed at this is indicated.

A majority of children who are asthma sufferers have an identifiable allergy trigger. Specifically, in a 2004 study, 71% had positive test results for more than 1 allergen, and 42% had positive test results for more than 3 allergens.^[11]

The majority of these triggers can often be identified from the history; for instance, asthmatics with hay fever or pollen allergy will have seasonal symptoms, those with allergies to pets may experience an abatement of symptoms when away from home, and those with occupational asthma may improve during leave from work. Allergy tests can help identify avoidable symptom triggers.

After a pulmonary function test has been carried out, radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases. In some people, asthma may be triggered by gastroesophageal reflux disease, which can be treated with suitable antacids. Very occasionally, specialized tests after inhalation of methacholine — or, even less commonly, histamine — may be performed.

Asthma is categorized by the United States National Heart, Lung and Blood Institute as falling into one of four categories: intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent night-time symptoms, result in limited physical activity and when lung function as measured by PEV or FEV₁ tests is less than 60% predicted with PEF variability greater than 30%.

There is no cure for asthma. Doctors have only found ways to prevent attacks and relieve the symptoms such as tightness of the chest and trouble breathing.

Pathophysiology

Bronchoconstriction

During an asthma episode, inflamed airways react to environmental triggers such as smoke, dust, or pollen. The airways narrow and produce excess mucus, making it difficult to breathe. In essence, asthma is the result of an immune response in the bronchial airways.^[12]

The airways of asthmatics are "hypersensitive" to certain triggers, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm (an "asthma attack"). Inflammation soon follows, leading to a further narrowing of the airways and excessive mucus production, which leads to coughing and other breathing difficulties.

Stimuli

• Allergens from nature, typically inhaled, which include waste from common household pests, such as the house dust mite and cockroach, grass pollen, mould spores, and pet epithelial cells;^{[citation needed]}
• Indoor air pollution from volatile organic compounds, including perfumes and perfumed products. Examples include soap, dishwashing liquid, laundry detergent, fabric softener, paper tissues, paper towels, toilet paper, shampoo, hairspray, hair gel, cosmetics, facial cream, sun cream, deodorant, cologne, shaving cream, aftershave lotion, air freshener and candles, and products such as oil-based paint.^{[citation needed]}
• Medications, including aspirin,^[13] β-adrenergic antagonists (beta blockers), and penicillin.^{[citation needed]}
• Food allergies such as milk, peanuts, and eggs. However, asthma is rarely the only symptom, and not all people with food or other allergies have asthma.^{[citation needed]}
• Use of fossil fuel related allergenic air pollution, such as ozone, smog, summer smog, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas.^{[citation needed]}
• Various industrial compounds and other chemicals, notably sulfites; chlorinated swimming pools generate chloramines—monochloramine (NH₂Cl), dichloramine (NHCl₂) and trichloramine (NCl₃)—in the air around them, which are known to induce asthma.^[14]
• Early childhood infections, especially viral respiratory infections. However, persons of any age can have asthma triggered by colds and other respiratory infections even though their normal stimuli might be from another category (e.g. pollen) and absent at the time of infection. 80% of asthma attacks in adults and 60% in children are caused by respiratory viruses.^{[citation needed]}
• Exercise, the effects of which differ somewhat from those of the other triggers.^{[citation needed]}
• Allergenic indoor air pollution from newsprint and other literature such as junk mail leaflets and glossy magazines (in some countries).^{[citation needed]}
• Hormonal changes in adolescent girls and adult women associated with their menstrual cycle can lead to a worsening of asthma. Some women also experience a worsening of their asthma during pregnancy whereas others find no significant changes, and in other women their asthma improves during their pregnancy.^{[citation needed]}
• Emotional stress which is poorly understood as a trigger.^{[citation needed]} Emotional stress can affect breathing temporarily, however unlike something such as heart problems, it is unclear if it has any long-term effect.
• Cold weather can make it harder for asthmatics to breathe.^[15]

Bronchial inflammation

The mechanisms behind allergic asthma—i.e., asthma resulting from an immune response to inhaled allergens—are the best understood of the causal factors. In both asthmatics and non-asthmatics, inhaled allergens that find their way to the inner airways are ingested by a type of cell known as antigen presenting cells, or APCs. APCs then "present" pieces of the allergen to other immune system cells. In most people, these other immune cells (T_H0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (T_H2), for reasons that are not well understood. The resultant T_H2 cells activate an important arm of the immune system, known as the humoral immune system. The humoral immune system produces antibodies against the inhaled allergen. Later, when an asthmatic inhales the same allergen, these antibodies "recognize" it and activate a humoral response. Inflammation results: chemicals are produced that cause the airways to constrict and release more mucus, and the cell-mediated arm of the immune system is activated. The inflammatory response is responsible for the clinical manifestations of an asthma attack. The following section describes this complex series of events in more detail.

Pathogenesis

The fundamental problem in asthma appears to be immunological: young children in the early stages of asthma show signs of excessive inflammation in their airways. Epidemiological findings give clues as to the pathogenesis: the incidence of asthma seems to be increasing worldwide, and asthma is now very much more common in affluent countries.

In 1968 Andor Szentivanyi first described The Beta Adrenergic Theory of Asthma; in which blockage of the Beta-2 receptors of pulmonary smooth muscle cells causes asthma.^[16] Szentivanyi's Beta Adrenergic Theory is a citation classic^[17] and has been cited more times than any other article in the history of the Journal of Allergy.

In 1995 Szentivanyi and colleagues demonstrated that IgE blocks beta-2 receptors.^[18] Since overproduction of IgE is central to all atopic diseases, this was a watershed moment in the world of allergy.^[19]

The Beta-Adrenergic Theory has been cited in the scholarship of such noted investigators as Richard F. Lockey (former President of the American Academy of Allergy, Asthma, and Immunology),^[20] Charles Reed (Chief of Allergy at Mayo Medical School),^[21] and Craig Venter (Human Genome Project).^[22]

Causes

Asthma is caused by a complex interaction of genetic and environmental factors that researchers do not fully understand yet.^[23] These factors can also influence how severe a person’s asthma is and how well they respond to medication.^[24] As with other complex diseases, many genetic and environmental factors have been suggested as causes of asthma, but not all of them have been replicated. In addition, as researchers detangle the complex causes of asthma, it is becoming more evident that certain environmental and genetic factors may only affect asthma when combined.

The hygiene hypothesis is a theory about the cause of asthma and other allergic disease, and is supported by epidemiologic data for asthma. For example, asthma prevalence has been increasing in developed countries along with increased use of antibiotics, c-sections, and cleaning products.^[25][26][27] All of these things may negatively affect exposure to beneficial bacteria and other immune system modulators that are important during development, and thus may cause increased risk for asthma and allergy.

Environmental Causes

Many environmental risk factors have been associated with asthma, but a few stand out as well-replicated or that have a meta-analysis of several studies to support their direct association.

• Poor air quality, from traffic pollution or high ozone levels, has been repeatedly associated with increased asthma morbidity and has a suggested association with asthma development that needs further research^[28][29]
• Environmental tobacco smoke, especially maternal cigarette smoking, is associated with high risk of asthma prevalence and asthma morbidity, wheeze, and respiratory infections^[28]
• Viral respiratory infections at an early age, along with siblings and day care exposure, may be protective against asthma, although there have been controversial results, and this protection may depend on genetic context ^[28][30][31]
• Antibiotic use early in life has been linked to development of asthma in several examples; it is thought that antibiotics make one susceptible to development of asthma because they modify gut flora, and thus the immune system (as described by the hygiene hypothesis) ^[25]
• Caesarean sections have been associated with asthma when compared with vaginal birth; a meta-analysis found a 20% increase in asthma prevalence in children delivered by Caesarean section compared to those who were not. It was proposed that this is due to modified bacterial exposure during Caesarean section compared with vaginal birth, which modifies the immune system (as described by the hygiene hypothesis). ^[26]
• Psychological stress on the part of a child's caregiver has been associated with asthma, and is an area of active research. Stress can modify behaviors that affect asthma, like smoking, but research suggests that stress has other effects as well. There is growing evidence that stress may influence asthma and other diseases by influencing the immune system. ^[28]

Genetic Causes

Over 100 genes have been associated with asthma in at least one genetic association study.^[32] However, as with all association studies, replication is important before genetic variation (such as a single nucleotide polymorphism, or SNP) in a certain gene is thought to influence asthma. Through the end of 2005, 25 genes had been associated with asthma in six or more separate populations:^[32]

• GSTM1
• IL10
• CTLA4
• SPINK5
• LTC4S
• LTA
• GRPA
• NOD1
• CC16
• GSTP1
• STAT6
• NOS1
• CCL5
• TBXA2R
• TGFB1
• IL4
• IL13
• CD14
• ADRB2 (the Beta-2 adrenergic receptor)
• HLA-DRB1
• HLA-DQB1
• TNF
• FCER1B
• IL4RA
• ADAM33

However, even among this list of highly replicated genes associated with asthma, the results have not been consistent among all of the populations that have been tested.^[32] This indicates that these genes are not associated with asthma under every condition, and that researchers need to do further investigation to figure out the complex interactions that cause asthma.

Complex Causes: Gene-Environment Interactions

Research is now finding that some genetic variants may only cause asthma when they are combined with specific environmental exposures, and otherwise may not be risk factors for asthma.^[23]

The CD14 SNP C-159T and endotoxin exposure are a well-replicated example of a gene-environment interaction that is associated with asthma. Endotoxin exposure varies from person to person and can come from several environmental sources, including environmental tobacco smoke, dogs, and farms. Researchers have found that risk for asthma changes based on a person’s genotype at CD14 C-159T and level of endotoxin exposure. ^[33]

Asthma and sleep apnea

Main article: sleep apnea

It is recognized with increasing frequency, that patients who have both obstructive sleep apnea (OSA) and bronchial asthma, often improve tremendously when the sleep apnea is diagnosed and treated.^[34] CPAP is not effective in patients with nocturnal asthma only.^[35]

Asthma and gastro-esophageal reflux disease

Main article: gastro-esophageal reflux disease

If gastro-esophageal reflux disease is present, the patient may have repetitive episodes of acid aspiration, which results in airway inflammation and "irritant-induced" asthma.^{[citation needed]} GERD may be common in difficult-to-control asthma, but according to one study, treating it does not seem to affect the asthma.^[36]

Treatment

The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. Desensitization is currently the only known "cure" to the disease.^[37]

As is common with respiratory disease, smoking is believed to adversely affect asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications.^[38] Automobile emissions are considered an even more significant cause and aggravating factor. [1] Asthmatics who smoke or who live near traffic [2] typically require additional medications to help control their disease. Furthermore, exposure of both non-smokers and smokers to wood smoke, gas stove fumes and second-hand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions.^[39] Smoking cessation and avoidance of second-hand smoke is strongly encouraged in asthmatics.^[40]

The specific medical treatment recommended to patients with asthma depends on the severity of their illness and the frequency of their symptoms. Specific treatments for asthma are broadly classified as relievers, preventers and emergency treatment. The Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2)^[40] of the U.S. National Asthma Education and Prevention Program, and the British Guideline on the Management of Asthma^[41] are broadly used and supported by many doctors. On August 29, 2007 the final Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma was officially released. Bronchodilators are recommended for short-term relief in all patients. For those who experience occasional attacks, no other medication is needed. For those with mild persistent disease (more than two attacks a week), low-dose inhaled glucocorticoids or alternatively, an oral leukotriene modifier, a mast-cell stabilizer, or theophylline may be administered. For those who suffer daily attacks, a higher dose of glucocorticoid in conjunction with a long-acting inhaled β-2 agonist may be prescribed; alternatively, a leukotriene modifier or theophylline may substitute for the β-2 agonist. In severe asthmatics, oral glucocorticoids may be added to these treatments during severe attacks.

For those in whom exercise can trigger an asthma attack (exercise-induced asthma), higher levels of ventilation and cold, dry air tend to exacerbate attacks. For this reason, activities in which a patient breathes large amounts of cold air, such as skiing and running, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.^[5]

Researchers at Harvard Medical School (HMS) have come up with convincing evidence that the answer to what causes asthma lies in a special type of natural "killer" cell. This finding means that physicians may not be treating asthma sufferers with the right kinds of drugs. For example, natural killer T cells seem to be resistant to the corticosteroids in widely used inhalers.^[42]

Relief medication

Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. These are typically provided in pocket-sized, metered-dose inhalers (MDIs). In young sufferers, who may have difficulty with the coordination necessary to use inhalers, or those with a poor ability to hold their breath for 10 seconds after inhaler use (generally the elderly), an asthma spacer (see top image) is used. The spacer is a plastic cylinder that mixes the medication with air in a simple tube, making it easier for patients to receive a full dose of the drug and allows for the active agent to be dispersed into smaller, more fully inhaled bits. A nebulizer which provides a larger, continuous dose can also be used. Nebulizers work by vaporizing a dose of medication in a saline solution into a steady stream of foggy vapour, which the patient inhales continuously until the full dosage is administered. There is no clear evidence, however, that they are more effective than inhalers used with a spacer. Nebulizers may be helpful to some patients experiencing a severe attack. Such patients may not be able to inhale deeply, so regular inhalers may not deliver medication deeply into the lungs, even on repeated attempts. Since a nebulizer delivers the medication continuously, it is thought that the first few inhalations may relax the airways enough to allow the following inhalations to draw in more medication.

Relievers include:

• Short-acting, selective beta₂-adrenoceptor agonists, such as salbutamol (albuterol USAN), levalbuterol, terbutaline and bitolterol.
  Tremors, the major side effect, have been greatly reduced by inhaled delivery, which allows the drug to target the lungs specifically; oral and injected medications are delivered throughout the body. There may also be cardiac side effects at higher doses (due to Beta-1 agonist activity), such as elevated heart rate or blood pressure; with the advent of selective agents, these side effects have become less common. Patients must be cautioned against using these medicines too frequently, as with such use their efficacy may decline, producing desensitization resulting in an exacerbation of symptoms which may lead to refractory asthma and death.
• Older, less selective adrenergic agonists, such as inhaled epinephrine and ephedrine tablets, have also been used. Cardiac side effects occur with these agents at either similar or lesser rates to albuterol.^{[43] [44]} When used solely as a relief medication, inhaled epinephrine has been shown to be an effective agent to terminate an acute asthmatic exacerbation.^[43] In emergencies, these drugs were sometimes administered by injection. Their use via injection has declined due to related adverse effects.
• Anticholinergic medications, such as ipratropium bromide may be used instead. They have no cardiac side effects and thus can be used in patients with heart disease; however, they take up to an hour to achieve their full effect and are not as powerful as the β₂-adrenoreceptor agonists.
• Inhaled glucocorticoids are usually considered preventive medications; however, a randomized controlled trial has demonstrated the benefit of 250 microg beclomethasone when taken as an as-needed combination inhaler with 100 microg of albuterol.^[45]

Prevention medication

Current treatment protocols recommend prevention medications such as an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airways, in anyone who has frequent (greater than twice a week) need of relievers or who has severe symptoms. If symptoms persist, additional preventive drugs are added until the asthma is controlled. With the proper use of prevention drugs, asthmatics can avoid the complications that result from overuse of relief medications.

Asthmatics sometimes stop taking their preventive medication when they feel fine and have no problems breathing. This often results in further attacks, and no long-term improvement.

Preventive agents include the following.

• Inhaled glucocorticoids are the most widely used of the prevention medications and normally come as inhaler devices (ciclesonide, beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone).
  Long-term use of corticosteroids can have many side effects including a redistribution of fat, increased appetite, blood glucose problems and weight gain. In particular high doses of steroids may cause osteoporosis. For this reasons inhaled steroids are generally used for prevention, as their smaller doses are targeted to the lungs unlike the higher doses of oral preparations. Nevertheless, patients on high doses of inhaled steroids may still require prophylactic treatment to prevent osteoporosis.
  Deposition of steroids in the mouth may cause a hoarse voice or oral thrush (due to decreased immunity). This may be minimised by rinsing the mouth with water after inhaler use, as well as by using a spacer which increases the amount of drug that reaches the lungs.
• Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
• Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
• Antimuscarinics/anticholinergics (ipratropium, oxitropium, and tiotropium), which have a mixed reliever and preventer effect. (These are rarely used in preventive treatment of asthma, except in patients who do not tolerate beta-2-agonists.)
• Methylxanthines (theophylline and aminophylline), which are sometimes considered if sufficient control cannot be achieved with inhaled glucocorticoids and long-acting β-agonists alone.
• Antihistamines, often used to treat allergic symptoms that may underlie the chronic inflammation. In more severe cases, hyposensitization ("allergy shots") may be recommended.
• Omalizumab, an IgE blocker; this can help patients with severe allergic asthma that does not respond to other drugs. However, it is expensive and must be injected.
• Methotrexate is occasionally used in some difficult-to-treat patients.
• If chronic acid indigestion (GERD) contributes to a patient's asthma, it should also be treated, because it may prolong the respiratory problem.

Additionally, the antidepressant tianeptine has shown significant efficacy in children with asthma.

Long-acting β₂-agonists

  Long-acting bronchodilators (LABD) are similar in structure to short-acting selective beta₂-adrenoceptor agonists, but have much longer side chains resulting in a 12-hour effect, and are used to give a smoothed symptomatic relief (used morning and night). While patients report improved symptom control, these drugs do not replace the need for routine preventers, and their slow onset means the short-acting dilators may still be required. In November of 2005, the American FDA released a health advisory alerting the public to findings that show the use of long-acting β₂-agonists could lead to a worsening of symptoms, and in some cases death.^[46]

Currently available long-acting beta₂-adrenoceptor agonists include salmeterol, formoterol, bambuterol, and sustained-release oral albuterol. Combinations of inhaled steroids and long-acting bronchodilators are becoming more widespread; the most common combination currently in use is fluticasone/salmeterol (Advair in the United States, and Seretide in the United Kingdom). Another combination is budesonide/formoterol which is commercially known as symbicort.

A recent meta-analysis of the roles of long-acting beta-agonists may indicate a danger to asthma patients. "These agents can improve symptoms through bronchodilation at the same time as increasing underlying inflammation and bronchial hyper-responsiveness, thus worsening asthma control without any warning of increased symptoms," said Shelley Salpeter in a Cornell study. The study goes on to say that "Three common asthma inhalers containing the drugs salmeterol or formoterol may be causing four out of five US asthma-related deaths per year and should be taken off the market".^[47] This assertion has drawn criticism from many asthma specialists for being inaccurate. As Dr. Hal Nelson points out in a recent letter to the Annals of Internal Medicine,

"Salpeter and colleagues also assert that salmeterol may be responsible for 4000 of the 5000 asthma-related deaths that occur in the United States annually. However, when salmeterol was introduced in 1994, more than 5000 asthma-related deaths occurred per year. Since the peak of asthma deaths in 1996, salmeterol sales have increased about 5-fold, while overall asthma mortality rates have decreased by about 25%, despite a continued increase in asthma diagnoses. In fact, according to the most recent data from the National Center for Health Statistics, U.S. asthma mortality rates peaked in 1996 (with 5667 deaths) and have decreased steadily since. The last available data, from 2004, indicate that 3780 deaths occurred. Thus, the suggestion that a vast majority of asthma deaths could be attributable to LABA use is inconsistent with the facts."

Dr. Salpeter has since tempered her comments regarding LABAs.^{[citation needed]}

Emergency treatment

When an asthma attack is unresponsive to a patient's usual medication, other treatments are available to the physician or hospital:^[48]

• Oxygen to alleviate the hypoxia (but not the asthma per se) that results from extreme asthma attacks.
• Nebulized salbutamol or terbutaline (short-acting beta-2-agonists), often combined with ipratropium (an anticholinergic).
• Systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone). Some research has looked into an alternative inhaled route.^[49]
• Other bronchodilators that are occasionally effective when the usual drugs fail:
  • Intravenous salbutamol
  • Nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
  • Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine, ipratropium)
  • Methylxanthines (theophylline, aminophylline)
  • Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
  • The dissociative anaesthetic ketamine, often used in endotracheal tube induction
  • Magnesium sulfate, intravenous
• Intubation and mechanical ventilation, for patients in or approaching respiratory arrest.
• Heliox, a mixture of helium and oxygen, may be used in a hospital setting. It has a more laminar flow than ambient air and moves more easily through constricted airways.

Alternative and complementary medicine

Many asthmatics, like those who suffer from other chronic disorders, use alternative treatments; surveys show that roughly 50% of asthma patients use some form of unconventional therapy.^[50][51] There are little data to support the effectiveness of most of these therapies. A Cochrane systematic review of acupuncture for asthma found no evidence of efficacy.^[52] A similar review of air ionisers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators.^[53] A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic manoeuvers, found there is insufficient evidence to support or refute their use in treating asthma;^[54] these manoeuvers include various osteopathic and chiropractic techniques to "increase movement in the rib cage and the spine to try and improve the working of the lungs and circulation"; chest tapping, shaking, vibration, and the use of "postures to help shift and cough up phlegm." On the other hand, one meta-analysis found that homeopathy has a potentially mild benefit in reducing symptom intensity;^[55] however, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding.^[56] Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs^[57] —yogasanas, Pranayama, meditation, and kriyas—to sahaja yoga,^[58] a form of 'new religious' meditation.

The Buteyko method, a Russian therapy based on breathing exercises, has been investigated. A randomized, controlled trial of just 39 patients in 1998 showed a substantial reduction in the need for beta-agonists and a 50% reduction in the need for inhaled steroids. Quality of life scores improved significantly as people were less afraid of their condition and more confident of the future. Lung function remained the same despite the decrease in medication.^[59] A trial in New Zealand in 2000 showed an 85% reduction in the use of beta-agonist medication and a 50% reduction in inhaled steroid use after six months.^[60] The Buteyko method is not rejected out of hand by the mainstream medical community. However, Buteyko has stated that the body has enough oxygen even during an asthmatic attack and to refuse oxygen if offered. This is simply not true. Tests plainly show that the oxygen level is extremely low during asthmatic attacks. The mainstream medical community regards the practice as extremely dangerous and it is frowned upon hugely.^{[citation needed]} In recent years Helminthic therapy has emerged as one of the most promising alternative therapies because research has identified a negative association between helminth infection (hookworm) and asthma and hay fever.^[61] Some have suggested that hookworm infestation, although not medically sanctioned, would cure asthma. There is both anectdotal evidence^[62][63] and peer-reviewed research to support this viewpoint. ^[64]

Guaifenesin, an expectorant available over the counter, may have a small effect in managing thickened bronchial mucus.

Treatment controversies

In November 2007 The New York Times reported a review of more than 500 studies finding that independently backed studies on inhaled corticosteroids are up to four times more likely to find adverse effects than studies paid for by drug companies.^{[65] [66]}

Prognosis

The prognosis for asthmatics is good; especially for children with mild disease. For asthmatics diagnosed during childhood, 54% will no longer carry the diagnosis after a decade. The extent of permanent lung damage in asthmatics is unclear. Airway remodelling is observed, but it is unknown whether these represent harmful or beneficial changes.^[12] Although conclusions from studies are mixed, most studies show that early treatment with glucocorticoids prevents or ameliorates decline in lung function as measured by several parameters.^[67] For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities. The mortality rate for asthma is low, with around 6000 deaths per year in a population of some 10 million patients in the United States.^[5] Better control of the condition may help prevent some of these deaths.

Epidemiology

More than 6% of children in the United States have been diagnosed with asthma, a 75% increase in recent decades. The rate soars to 40% among some populations of urban children.^{[citation needed]}

Asthma is usually diagnosed in childhood. The risk factors for asthma include:^{[citations needed]}

• A personal or family history of asthma or atopy
• Triggers (see Pathophysiology above)
• Premature birth or low birth weight
• Viral respiratory infection in early childhood
• Maternal smoking
• Being male, for asthma in prepubertal children
• Being female, for persistence of asthma into adulthood

There is a reduced occurrence of asthma in people who were breast-fed as babies. Current research suggests that the prevalence of childhood asthma has been increasing. According to the Centers for Disease Control and Prevention's National Health Interview Surveys, some 9% of US children below 18 years of age had asthma in 2001, compared with just 3.6% in 1980 (see figure). The World Health Organization (WHO) reports that some 8% of the Swiss population suffers from asthma today, compared with just 2% some 25–30 years ago.^[68] Although asthma is more common in affluent countries, it is by no means a problem restricted to the affluent; the WHO estimate that there are between 15 and 20 million asthmatics in India. In the U.S., urban residents, Hispanics, and African Americans are affected more than the population as a whole. Globally, asthma is responsible for around 180,000 deaths annually.^[68]

On the remote South Atlantic island Tristan da Cunha, 50% of the population are asthmatics due to heredity transmission of a mutation in the gene CC16.^{[citation needed]}

Population Disparities

Asthma prevalence, morbidity, mortality, and drug response vary greatly across populations. There is an almost 30-fold difference in asthma prevalence between some of the countries included in the International Study of Asthma and Allergy in Childhood[3], with a trend toward more developed and westernized countries having higher asthma prevalence. Westernization can’t explain the entire difference in asthma prevalence between countries, however, and the disparities may also be affected by differences in genetic, social and environmental risk factors.^[28] There are also worldwide disparities in asthma mortality, which is most common in low to middle income countries.^[69]

Asthma prevalence in the US is higher than in most other countries in the world, but varies drastically between diverse US populations.^[28] In the US, asthma prevalence is highest in Puerto Ricans, African Americans, Filipinos and Native Hawaiians, and lowest in Mexicans and Koreans.^[70][71][72] Mortality rates follow similar trends, and response to albuterol is lower in Puerto Ricans than in African Americans or Mexicans. ^[73][74] As with worldwide asthma disparities, differences in asthma prevalence, mortality, and drug response in the US may be explained by differences in genetic, social and environmental risk factors.

Asthma prevalence also differs between populations of the same ethnicity who are born and live in different places. ^[75] US-born Mexican populations, for example, have higher asthma rates than non-US born Mexican populations that are living in the US. ^[76]This probably reflects differences in social and environmental risk factors associated with acculturation to the US.

Asthma prevalence and asthma deaths also differ by gender. Males are more likely to be diagnosed with asthma as children, but asthma is more likely to persist into adulthood in females. Sixty five percent more adult women than men will die from asthma. This difference may be attributable to hormonal differences, among other things. In support of this, girls who reach puberty before age 12 were found to have a later diagnosis of asthma more than twice as much as girls who reach puberty after age 12.

Socioeconomic factors

The incidence of asthma is highest among low-income populations (asthma deaths are most common in low to middle income countries [4]), which in the western world are disproportionately ethnic minorities^[77] and are more likely to live near industrial areas. Additionally, asthma has been strongly associated with the presence of cockroaches in living quarters, which is more likely in such neighborhoods.

Asthma incidence and quality of treatment varies among different racial groups, though this may be due to correlations with income (and thus affordability of health care) and geography. For example, Black Americans are less likely to receive outpatient treatment for asthma despite having a higher prevalence of the disease. They are much more likely to have emergency room visits or hospitalization for asthma, and are three times as likely to die from an asthma attack compared to whites. The prevalence of "severe persistent" asthma is also greater in low-income communities compared with communities with better access to treatment.^[78][79]

Asthma and athletics

Asthma appears to be more prevalent in athletes than in the general population. One survey of participants in the 1996 Summer Olympic Games, in Atlanta, Georgia, U.S., showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication. ^[80] These statistics have been questioned on at least two bases. Athletes with mild asthma may be more likely to be diagnosed with the condition than non-athletes, because even subtle symptoms may interfere with their performance and lead to pursuit of a diagnosis. It has also been suggested that some professional athletes who do not suffer from asthma claim to do so in order to obtain special permits to use certain performance-enhancing drugs.

There appears to be a relatively high incidence of asthma in sports such as cycling, mountain biking, and long-distance running, and a relatively lower incidence in weightlifting and diving. It is unclear how much of these disparities are from the effects of training in the sport, and from self-selection of sports that may appear to minimize the triggering of asthma.^[80][81]

In addition, there exists a variant of asthma called exercise-induced asthma that shares many features with allergic asthma. It may occur either independently, or concurrent with the latter. Exercise studies may be helpful in diagnosing and assessing this condition.

See also

• Reactive airway disease
• Atopy
• Hopkins syndrome
• Hygiene hypothesis
• Immune response
• Asthma and Allergy Foundation of America
• Melatonin
• Occupational asthma

References

• MedLinePlus: Asthma – a U.S. National Library of Medicine page.
• American Academy of Allergy, Asthma, and Immunology – a U.S. organization of medical professionals with a special interest in treating and researching conditions such as allergic rhinitis, asthma, atopic dermatitis/eczema, and anaphylaxis.
• Asthma and Allergy Foundation of America – national nonprofit patient advocacy organization with information about asthma.
• Asthma clinical trials and findings from current research.
• Global Initiative for Asthma (GINA) – evidence-based guidelines for asthma management.
• Video: What is Asthma?
• Asthma UK – a patient-oriented site with information on asthma and ways that UK residents can help improve asthma-related policy.
• Asthma Foundation of Queensland Information and education for Australian asthma sufferers.
• Asthma as Neurogenic Inflammatory Disease Neurogenic aspects of asthma. Pathophysiological links with other inflammatory disorders.
• Asthma and Socio-economic Status
• The Segal Guide to Asthma by Michael Segal MD PhD.
• The Asthma - Causes, Symptoms & Treatment Information on eMedicneHealth.com
• Ourasthma.com – a patient-oriented site with information on asthma inhalers.