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Asthma

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File:Inhaler girl.png
A young girl with asthma using an inhaler.

Asthma is a disease affecting the respiratory system, in which the airways unexpectedly and suddenly 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 cough, which are the hallmarks of asthma. In between episodes, patients normally feel fine.

Medically speaking, asthma is a chronic inflammatory condition in which the airways develop increased responsiveness to various stimuli, characterized by bronchial hyperresponsiveness (BHR), inflammation, 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 has become focused on asthma recently due to its rapidly increasing prevalence in the developed world, affecting up to 1 in 4 urban children. Susceptibility to asthma can be explained in part by genetic factors, but no clear pattern of inheritance has been found so far. Asthma is a complex disease influenced by multiple genetic, developmental, and environmental factors, all interacting to produce the overall condition.


Signs and symptoms

The main symptom and hallmark of asthma is wheezing, caused by obstruction of the airways. Shortness of breath is common, and a cough, sometimes with clear sputum, may also be present. The symptoms can come rapidly and with varying intensity, often in response to the triggers mentioned above, and can be worse during the night or upon waking.

Signs of asthma are wheezing, tachypnea (rapid breathing), prolonged expiration, and tachycardia (rapid heart rate), rhonchi (wheezy noises heard with a stethoscope), and overinflation of the chest. During a serious asthma attack, there may be use of accessory muscles of respiration, shown as in-drawing of tissues between ribs and above the sternum and clavicles, and the presence of a paradoxical pulse. During very severe attacks, an asthma sufferer can turn blue from lack of oxygen, and experience chest pain, loss of consciousness, or even death. Despite the severity of symptoms during an asthmatic episode, between attacks a person with asthma may show no symptoms of the disease at all.

Diagnosis

In most cases, the physician can make the diagnosis on the basis of the history of typical symptoms and examination signs. 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 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 peak flow meter testing of diurnal variation of lung capacity, in addition to observing the reversibility of any variation in lung capacity in response to inhaled bronchodilator medication. In making a diagnosis, asthma will be suspected particularly if the patient suffers from eczema or other allergic conditions (suggesting a general atopy condition) or has a family history of asthma.

If the diagnosis is in doubt or chronic obstructive pulmonary disease is suspected, then more formal pulmonary lung function testing may be carried out. Testing lung function at rest (or baseline) and after exercise can be helpful. Very occasionally, specialized tests after inhalation of methacholine, or even less commonly histamine, may be performed. Radiological tests, such as a chest X-ray or CT scan, may be required to exclude the possibility of other lung diseases after pulmonary function has been measured.

As suggested above, many people with asthma have allergies. Positive allergy tests support a diagnosis of asthma and may help in identifying avoidable symptom triggers. In addition, some people with asthma have been diagnosed with gastroesophageal reflux disease (GERD in U.S., GORD in UK) and immune-related disorders including atopic dermatitis.

Once a diagnosis of asthma is made, a patient can use peak flow meter testing to monitor the severity of the disease.

Pathophysiology

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 abnormal immune response in the bronchial airways. The airways of asthmatics are "hypersensitive" to certain trigger factors, also known as stimuli (see below). In response to exposure to these triggers, the bronchi (large airways) contract into spasm ("asthma attack"). Inflammation soon follows, leading to further narrowing of the airway as well as excess mucus production, which leads to a cough and creates difficulty breathing.

There are seven major categories of stimuli:

Mechanisms

Most is known about allergic asthma; that is, asthma with an immune response triggered by inhaled allergens. In short, when these are inhaled by any person (asthmatic or not), if the molecules reach the inner airways, they are ingested by cells there and the pieces presented to cells of the immune system. In most people the immune cells (TH0 cells) check and then ignore the molecules; however, for reasons unknown, in some people, they then transform into a different type of cell (TH2). This cell activates mainly the antibody-related part of the immune system, and antibodies are produced. When the asthmatic later inhales the same allergen, the antibodies react and the immune system is activated. Chemicals are which cause the airways to constrict and more mucus to be produced; other immune cells are also summoned and are responsible for the later effects of the asthma attack.

More precisely, primary exposure to a foreign antigen, such as pollen or cigarette smoke, can trigger the development of asthmatic symptoms. Once an inhaled antigen becomes trapped in the airway, it is enzymatically degraded into shorter peptides by antigen presenting cells (APCs) such as dendritic cells. APCs take the peptides derived from the antigen and express them on the cell surface in 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 specific for the MHC II peptide.

Presented with the antigen-MHC II complex, T helper 0 (TH0) cells become activated and begin to differentiate into either T helper type 1 (TH1) or T helper 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. Studies indicate that the dominance of the TH2 cell type appears to be necessary for the development of asthma. In one study, mice that lack the ability to create TH1 cells displayed an asthma-like phenotype (Finotto and Glimcher, 2004). The variables that decide TH1 vs. TH2 cell fate 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 of IgE, an allergen-specific antibody, by antigen-stimulated B cells. IgE binds allergens and then binds 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. It is these molecules which are responsible for the symptoms of asthma. They affect the mucosa of the airways, increasing mucosal edema, mucus production, smooth muscle constriction, and recruit other immune cells, exacerbating the reaction.

The late phase of an asthmatic reaction is characterized by an influx of inflammatory and immune cells over the next 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. Epidemiology gives clues to the pathogenesis: the incidence of asthma seems to be increasing worldwide; asthma is more common in more affluent countries, and more common in higher socioeconomic groups within countries.

One theory is that asthma is a disease of hygiene. In nature, babies are exposed to bacteria soon after birth, "switching on" the TH1 lymphocyte cells of the immune system which deal with bacterial infection. If this stimulus is insufficient (as perhaps 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 which 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 correlates the rise of asthma with increasing air pollution. Though it is well known that substantial exposures to certain industrial chemicals can cause acute asthmatic episodes, it has not been proven that air pollution is responsible for the development of asthma. In Western Europe, most atmospheric pollutants have fallen significantly in the last forty years, while the prevalence of asthma has risen.

Treatment

The most effective treatment for asthma is identifying triggers such as pets and aspirin and limiting or eliminating exposure. Desensitization is commonly attempted, but this has not been shown to be effective. While occasional symptom relievers may be used, a stepwise use of additional preventitive medications is often used to control the disease.[1] Most patients use a metered-dose inhaler with a short-acting β2-agonist such as albuterol; those with more severe asthma may also regularly take a long-term control medication such as a glucocorticoid. Leukotriene modifiers may be used instead for long-term control, although they are effective in a limited number of patients. There are a wide variety of drug choices; the precise medications and dosages depend on the clinical situation.

Rapid relief

A typical inhaler.

Symptomatic control of episodes of wheezing and shortness of breath is generally achieved with fast-acting bronchodilators. Ordinarily, these are provided in pocket-sized, metered-dose inhalers (MDI). In younger 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 using an inhaler (generally the elderly), a device called an asthma spacer is used. An asthma spacer is an enclosed 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 (see top image). For a minority of patients with severe asthma, a nebulizer, which provides a larger, continuous dose of drug to the patient, is sometimes needed.

Relievers include:

Preventive

Current treatment protocols recommend an inhaled corticosteroid, which helps to suppress inflammation and reduces the swelling of the lining of the airway, for 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 patient's asthma is controlled.

Preventive agents include:

Long-acting β2-agonists

Long-acting bronchodilators (LABD) give a 12-hour effect and are used to give a smoothed symptomatic effect during the day (used morning and night). While patients report improved symptom control, they do not replace the need for routine preventers, and their slow onset of action means the short-acting dilators may still be required.

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 and salmeterol, marketed under the trade name Advair.

Emergency treatment

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

Prognosis

Asthma prevalence in children has increased since 1980, especially in younger children.

Approximately half of the children that suffer of asthma during their childhood will "grow out" of their symptoms by the time they pass puberty. For those who continue to suffer from mild symptoms, corticosteroids can help most to live their lives with few disabilities.

Epidemiology

Asthma patients mostly present during childhood. The incidence of asthma seems to be increasing worldwide; asthma is more common in affluent countries, and more common in higher socioeconomic groups within countries.

References

  • ^ Diagnosing Childhood Asthma in Primary Care, Patient UK PatientPlus article written for doctors
  • ^ British guideline on the management of asthma - Scottish Intercollegiate Guidelines Network (SIGN) Online Full PDF Summary PDF
  • Asthma Prevention Program of the National Center for Environmental Health Center for Disease Control and Prevention. Asthma At-A-Glance. 1999.
  • Finotto S, Glimcher L. “T cell directives for transcriptional regulation in asthma.” Springer Semin. Immunopathology 2004, 25(3-4):281-94. PMID 15007632.
  • Inwald D, Roland M, Kuitert L, McKenzie SA, Petros A. Oxygen treatment for acute severe asthma. BMJ 2001;323:98-100. PMID 11451788.
  • Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004;328:434. PMID 14976098.
  • Lilly CM, “Diversity of asthma: Evolving concepts of pathophysiology and lessons from genetics.” J Allergy Clin Immunol 2005, S526-31. PMID 15806035.
  • Maddox L, Schwartz DA. “The Pathophysiology of Asthma.” Annu. Rev. Med. 2002, 53:477-98. PMID 11818486.
  • Mujica VR, Rao SS. Recognizing atypical manifestations of GERD; asthma, chest pain, and otolaryngologic disorders may be due to reflux. Postgrad Med J 1999;105:53-55. PMID 9924493.
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