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Asthma

Asthma is a disease of the human respiratory system in which the airways narrow, often in response to a "trigger" such as exposure to an allergen, cold air, exercise, or emotional stress. This narrowing causes symptoms such as wheezing, shortness of breath, chest tightness, and coughing, which are the hallmarks of asthma. Between episodes, most patients feel fine. The disorder is a chronic inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyper-responsiveness, inflammation, increased mucus production, and intermittent airway obstruction. The symptoms of asthma, which can range from mild to life threatening, can usually be controlled with a combination of drugs and lifestyle 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. Susceptibility to asthma can be explained in part by genetic factors, but no clear pattern of inheritance has been found. Asthma is a complex disease that is influenced by multiple genetic, developmental, and environmental factors, which interact to produce the overall condition.

History

The word asthma is derived from the Greek aazein, meaning "sharp breath." The word first appears in Homer's Iliad; Hippocrates was the first to use it in reference to the medical condition. 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. Moses Maimonides, an influential medieval rabbi, philosopher, and physician, wrote a treatise on asthma, describing its prevention, diagnosis, and treatment. 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 regimen.

Signs and symptoms

An acute exacerbation of asthma is referred to colloquially as an asthma attack. The clinical hallmarks of an attack are shortness of breath (dyspnea) and wheezing, the latter "often being regarded as the sine qua non." A cough—sometimes producing clear sputum—may also be present. The onset is often sudden; there is 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 are wheezing, rapid breathing (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. Severe asthma attacks may lead to respiratory arrest and death. Despite the severity of symptoms during an asthmatic episode, between attacks an asthmatic may show few signs of the disease.

Diagnosis

In most 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.

Differential diagnosis

Before diagnosing someone as asthmatic, alternative possibilities should be considered. A physician 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. 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. Only a minority of asthma sufferers have an identifiable allergy trigger. 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. Occasionally, allergy tests are warranted and, if positive, may help in identifying avoidable symptom triggers. After pulmonary function has been measured, 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 by 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 NIH Heart Lung and Blood Institute as falling into one of four categories: mild intermittent, mild persistent, moderate persistent and severe persistent. The diagnosis of "severe persistent asthma" occurs when symptoms are continual with frequent exacerbations and frequent nighttime 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%.

Bronchoconstriction

In essence, asthma is the result of an abnormal immune response in the bronchial airways. 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. There are seven categories of stimuli:

  • allergens, typically inhaled, which include waste from common household insects, such as the house dust mite and cockroach, grass pollen, mould spores and pet epithelial cells; medications, including aspirin and β-adrenergic antagonists (beta blockers);
  • air pollution, such as ozone, nitrogen dioxide, and sulfur dioxide, which is thought to be one of the major reasons for the high prevalence of asthma in urban areas;
  • 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:
  • 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.
  • exercise, the effects of which differ somewhat from those of the other triggers; and
  • emotional stress, which is poorly understood as a trigger.

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 (TH0 cells) "check" and usually ignore the allergen molecules. In asthmatics, however, these cells transform into a different type of cell (TH2), for reasons that are not well understood. The resultant TH2 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.

The immune response

When an inhaled antigen becomes trapped in the airways, it is enzymatically degraded into shorter peptides by APCs such as dendritic cells. APCs express the peptides derived from the antigen on the cell surface, in what is known as the binding groove of the class II major histocompatiblity complex (MHC) molecule. Now located on the cell surface, the antigen-MHC complex is presented to T cells, which express a receptor that is specific to the MHC II peptide. Presented with the antigen-MHC II complex, T helper 0 (TH0) cells become activated and start to differentiate into either T helper type 1 (TH1) or type 2 (TH2) cells. The selective differentiation of TH0 cells has profound consequences for the immune system: TH1 cell production leads to cell-mediated immunity, while the production of predominantly TH2 cells provides humoral immunity. The resulting balance of TH1 or TH2 cells is a crucial variable in the development of asthma; the dominance of the TH2 cell type appears to be necessary for the development of asthma. In one study, mice that lacked the ability to create TH1 cells displayed an asthma-like phenotype. The variables that decide the fate of TH1 vs. TH2 cells are not well understood, but depend on many factors, including childhood exposure to infectious agents and the cytokines elicited by those agents. One cytokine secreted by TH2 cells—IL-4—combined with the action of other cytokines induces synthesis by antigen-stimulated B cells of IgE, an allergen-specific antibody. IgE binds allergens and then receptors on mast cells, basophils, and eosinophils in the airway epithelium. Subsequent exposure of the same antigen to these cells in the airway epithelium initiates the acute-phase reaction of asthma. Stimulated mast cells in the airway release preformed granules of mediators such as histamine, eicosanoids, and cytokines. These molecules are responsible for the symptoms of asthma. They affect the mucosa of the airways, increasing mucosal oedema, and mucus production, smooth muscle constriction, and recruit other immune cells, thereby exacerbating the reaction. The late phase of an asthmatic reaction is characterized by an influx of inflammatory and immune cells during the first several hours after antigen exposure. These cells—particularly eosinophils—secrete a series of cytokines, leukotrienes, and polypeptides, which contribute to hyperresponsiveness, mucus secretion, bronchoconstriction, and sustained inflammation.

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. One theory of pathogenesis is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria and other antigens soon after birth, "switching on" the TH1 lymphocyte cells of the immune system that deal with bacterial infection. If this stimulus is insufficient—as it may be in modern, clean environments—then TH2 cells predominate, and asthma and other allergic diseases may develop. This "hygiene hypothesis" may explain the increase in asthma in affluent populations. The TH2 lymphocytes and eosinophil cells that protect us against parasites and other infectious agents are the same cells responsible for the allergic reaction. In the developed world, these parasites are now rarely encountered, but the immune response remains and is wrongly triggered in some individuals by certain allergens. Another theory is based on the correlation of air pollution and the incidence of asthma. Although it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proved that air pollution is responsible for the development of asthma. In Western Europe, most atmospheric pollutants have fallen significantly over the last 40 years, while the prevalence of asthma has risen. Finally, it has been postulated that some forms of asthma may be related to infection, in particular by Chlamydia pneumoniae. This issue remains controversial, as the relationship is not borne out by meta-analysis of the research. The correlation seems to be not with the onset, but rather with accelerated loss of lung function in adults with new onset of non-atopic asthma. One possible explanation is that some asthmatics may have altered immune response that facilitates long-term chlamydia pneumonia infection. The response to targeting with macrolide antibiotics has been investigated, but the temporary benefit reported in some studies may reflect just their anti-inflammatory activities rather than their antimicrobic action.

Treatment

The most effective treatment for asthma is identifying triggers, such as pets or aspirin, and limiting or eliminating exposure to them. Desensitization is commonly attempted, but has not been shown to be effective. As is common with respiratory disease, smoking adversely affects asthmatics in several ways, including an increased severity of symptoms, a more rapid decline of lung function, and decreased response to preventive medications. Asthmatics who smoke typically require additional medications to help control their disease. Furthermore, exposure of both nonsmokers and smokers to secondhand smoke is detrimental, resulting in more severe asthma, more emergency room visits, and more asthma-related hospital admissions. Smoking cessation and avoidance of those who smoke is strongly encouraged in asthmatics. 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) of the U.S. National Asthma Education and Prevention Program, and the British guideline on the management of asthma are broadly used and supported by many doctors. 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 cross-country skiing, tend to be worse for asthmatics, whereas swimming in an indoor, heated pool, with warm, humid air, is less likely to provoke a response.

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—see the image to the right). 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 (salbutamol [albuterol], levalbuterol, terbutaline, bitolterol, pirbuterol, procaterol, fenoterol, reproterol). 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, are available over the counter in the US. Cardiac side effects, although uncommon, occur more often with these less selective drugs. They also provide a shorter period of relief than the selective bronchodilators. Nowadays, they are usually avoided in patients with heart disease. In emergencies, these drugs were sometimes administered by injection. Their use in this situation has declined.

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.

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.

Long-acting β2-agonists

Long-acting bronchodilators (LABD) give a 12-hour effect, and are used to give a smoothed symptomatic effect (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. 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 UK).

Emergency treatment

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

  • oxygen to alleviate the hypoxia (but not the asthma per se) that results from extreme asthma attacks; nebulized salbutamol (a short-acting beta-2-agonist), often combined with ipratropium (an anticholinergic); systemic steroids, oral or intravenous (prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone) other bronchodilators that are occasionally effective when the usual drugs fail: nonspecific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol); anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine); 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; and intubation and mechanical ventilation, for patients in or approaching respiratory arrest. Alternative 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. 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. A similar review of air ionizers found no evidence that they improve asthma symptoms or benefit lung function; this applied equally to positive and negative ion generators. A study of "manual therapies" for asthma, including osteopathic, chiropractic, physiotherapeutic and respiratory therapeutic maneuvers, found no evidence to support their use in treating asthma; these manoeuvres 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; however, the number of patients involved in the analysis was small, and subsequent studies have not supported this finding. Several small trials have suggested some benefit from various yoga practices, ranging from integrated yoga programs—"yogasanas, Pranayama, meditation, and kriyas"—to sahaja yoga, a form of meditation. A randomized, controlled trial of just 39 patients suggested that the Buteyko method may moderately reduce the need for beta-agonists among asthmatics, but found no objective improvement in lung function.

See also Complementary and alternative medicine.

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. 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. 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. Better control of the condition may help prevent some of these deaths.

Epidemiology

The prevalence of childhood asthma has increased since 1980, especially in younger children.

Asthma is usually diagnosed in childhood. The risk factors for asthma include:

  • 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; and
  • 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. 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.

Socioeconomic factors

The incidence of asthma is higher among low-income populations, which in the western world are disproportionately minority, and 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 neighbourhoods. The quality of asthma treatment varies along racial lines, likely because many low-income people cannot afford health insurance and because there is still a correlation between class and race. 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.

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 showed that 15% had been diagnosed with asthma, and that 10% were on asthma medication. These statistics have been questioned on at least two bases. Persons with mild asthma may be more likely to be diagnosed with the condition than others 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. 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.

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