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.[1] 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.

Contents
1 History
2 Signs and symptoms
3 Diagnosis
3.1 Differential diagnosis
4 Pathophysiology
4.1 Bronchoconstriction
4.2 Bronchial inflammation
4.3 The immune response
4.4 Pathogenesis
5 Treatment
5.1 Relief medication
5.2 Prevention medication 
 
History
The word asthma is derived from the Greek aazein, meaning “sharp breath.” The word first appears in Homer's Iliad;[2] 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.[3] 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.

Recommended reading: Asthma & Allergy Cure -Drug Free.

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.”[4] 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).[4] 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 perfoming 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%.

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.[5] 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[6] 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;[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 (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.[5]

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.[8] 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 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 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.

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.[9] 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.[10] Smoking cessation and avoidance of those who smoke is strongly encouraged in asthmatics.[11]

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)[11] of the U.S. National Asthma Education and Prevention Program, and the British guideline on the management of asthma [12] 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.[4]

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 (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 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, 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—both of which, unlike other medications, are available over the counter in the US under the Primatene brand. Cardiac side effects, although uncommon, occur more often with the 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.

Preventive agents include the following.

Inhaled glucocorticoids (fluticasone, budesonide, beclomethasone, mometasone, flunisolide, and triamcinolone).
Leukotriene modifiers (montelukast, zafirlukast, pranlukast, and zileuton).
Mast cell stabilizers (cromoglicate (cromolyn), and nedocromil).
Antimuscarinics/anticholinergics (ipratropium, oxitropium), 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.