Asthma

Asthma is a disease in which inflammation of the airways causes airflow into and out of the lungs to be restricted. When an asthma attack occurs, the muscles of the bronchial tree become tight and the lining of the air passages swells, reducing airflow and producing the characteristic wheezing sound. Mucus production is increased.

Most people with asthma have periodic wheezing attacks separated by symptom-free periods. Some asthmatics have chronic shortness of breath with episodes of increased shortness of breath. Other asthmatics may have cough as their predominant symptom. Asthma attacks can last minutes to days, and can become dangerous if the airflow becomes severely restricted.

In sensitive individuals, asthma symptoms can be triggered by inhaled allergens (allergy triggers), such as pet dander, dust mites, cockroach allergens, molds, or pollens. Asthma symptoms can also be triggered by respiratory infections, exercise, cold air, tobacco smoke and other pollutants, stress, food, or drug allergies. Aspirin and other non-steroidal anti-inflammatory medications (NSAIDS) provoke asthma in some patients.

Young asthmatic girl using an inhaler attached to a spacer.

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.

History

The word asthma is derived from the Greek aazein, meaning "sharp breath". The word first appears in Homer's Iliad;

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".

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 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).

Diagnosis

Diagnosing asthma

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, or if chronic obstructive pulmonary disease is suspected, a more formal lung function testing 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).

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.

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 abnormal immune response in the bronchial airways.

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^[6] and the common β-adrenergic antagonist (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;^[7]
• early childhood infections, especially viral respiratory infections;
• 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 (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 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 (T_H0) cells become activated and start to differentiate into either T helper type 1 (T_H1) or type 2 (T_H2) cells. The selective differentiation of T_H0 cells has profound consequences for the immune system: T_H1 cell production leads to cell-mediated immunity, while the production of predominantly T_H2 cells provides humoral immunity. The resulting balance of T_H1 or T_H2 cells is a crucial variable in the development of asthma; the dominance of the T_H2 cell type appears to be necessary for the development of asthma. In one study, mice that lacked the ability to create T_H1 cells displayed an asthma-like phenotype.

One cytokine secreted by T_H2 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 edema, 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 T_H1 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 T_H2 cells predominate, and asthma and other allergic diseases may develop. This "hygiene hypothesis" may explain the increase in asthma in affluent populations. The T_H2 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.

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.

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)

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

A typical inhaler, of Serevent (salmeterol)

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 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 (see top image) 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 vapourizing a dose of medication in a saline solution into a steady stream of foggy vapor, 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, bitolterol, 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, 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, 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-both of which, unlike other medications, are available over the counter in the US under the Primatene brand. Cardiac side effects, although uncommon, occurred more often with the less selective drugs. They also have the disadvantage of providing a shorter period of relief than the selective bronchodiolators. Nowadays, they are usually avoided in patients with heart disease. In emergencies, these drugs were sometimes administered by injection in severe attacks. 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 preventative 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 (fluticasone, budesonide, beclomethasone, mometasone, flunisolide, and triamcinolone).
• Antimuscarinics/anticholinergics (ipratropium, oxitropium), which have a mixed reliever and preventer effect. They are rarely used in asthma.
• Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
• Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
• 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.

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.

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 (2.5-5 mg), usually three in rapid succession ("back-to-back");
• 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 anesthetic 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.

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.^[24] 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

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.

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