Asthma

Asthma is a chronic lung condition affecting populations around the world. Public attention has recently focused on asthma because its prevalence and the associated mortality rate have increased over the last several decades. While familial aggregation is observed, no clear pattern of segregation can be discerned. Multiple genetic, developmental, and environmental factors interact to produce the overall condition.

Asthma is a complex disease characterized by bronchial hyperresponsiveness (BHR), inflammation, mucus production and intermittent airway obstruction. A person with asthma may experience wheezing, shortness of breath, chest tightness, and cough, particularly after exposure to an allergen, cold air, exercise, or emotional stress. Asthma is treated with drugs; lifestyle changes can help reduce exacerbations.

Signs and symptoms

The main symptom of asthma is wheezing caused by obstruction of the airways. A cough, sometimes with clear sputum, may also be present. The symptoms are very variable, often with rapid onset, and associated with the triggers listed above. Symptoms can be worse during the night or upon waking. Asthma sometimes occurs with acid indigestion, especially amongst older patients.

Signs of asthma are wheezing, rapid breathing, expiratory phase of breathing longer than inspiratory, in-drawing of tissues between ribs and above sternum & clavicles, over-inflation of the chest, and rhonchi (wheezy noises heard with a stethoscope). During severe attacks the asthma sufferer may be cyanosed (blue), may have chest pain and can lose consciousness. Between attacks a person with asthma may show no signs at all.

Diagnosis

In most cases the physician can make the diagnosis on the basis of typical symptoms and signs. The typical rapid changes in airway obstruction can be demonstrated by decrease in pulmonary function values at baseline, after exercise or inhalation of histamine (less common) or methacholine (more common), and subsequent improvement with an inhaled bronchodilator medication. Pulmonary function test is required to make the diagnosis of asthma because many other lung diseases can masquerade as asthma. Once the diagnosis is made, a peak flow meter can be used to follow the disease.

Many people with asthma have allergies; positive allergy tests support a diagnosis of asthma and may help in identifying avoidable triggers. Some people with asthma have been diagnosed with gastroesophageal reflux disease (GERD) and immune related disorders including atopic dermatitis. Other tests (for example chest X-ray or chest CT scan) may be required to exclude other lung disease after pulmonary function testing has been obtained.

Pathology

Mechanisms

Primary exposure to an antigen or sensitization establishes the potential for asthmatic phenotypes. Following entrapment of the antigen in the airway, the antigen is enzymatically degraded by antigen presenting cells (APCs) such as dendritic cells. The peptide becomes associated with a class II major histocompatiblity complex (MHC) molecule. The complex moves to the surface of the APC where it is presented to a T cell with a receptor specific for the MHC II peptide. Upon antigen presentation and the appropriate costimulatory signal, T helper 0 (Th0) cells become activated and begin to differentiate. Under the influence of interleukin (IL) 12, Th0 cells differentiate into T helper type 1 (Th1) cells. IL4 induces Th0 cells to differentiate into T helper type 2 (Th2) cells. The differentiation of either type of T helper cell restricts the differentiation of the other. Th1 cells primarily secrete IL2, interferon (IFN) γ, and tumor necrosis factor (TNF) β. Th2 cells primarily secrete granulocyte macrophage colony stimulating factor (GM-CSF), IL4, IL5, IL6, IL9, IL10, and IL13. IL4 also enhances synthesis of IgE by antigen-stimulated B lymphocytes that express surface receptors for the antigen. The antigen-specific antibodies produced bind the FcεRI receptor on mast cells and dendritic cells in the airway epithelium.

Subsequent exposure of the same antigen to the cells of the airway epithelium initiates the acute phase reaction. IgE-studded mast cells of the airway degranulate causing release of vasoactive mediators such as histamine, increase the synthesis of prostaglandins and leukotrienes, and increase the transcription of cytokines. The mediators affect the bronchial mucosa by increasing mucosal edema, mucus production, smooth muscle constriction, and chemotactic factors which recruit other immune cells.

The late phase is characterized by the influx of inflammatory and immune cells over the next several hours after challenge. These cells, particularly eosinophils, secrete a series of cytokines, leukotrienes, and polypeptides which contribute to hyperresponsiveness, mucus secretion, bronchoconstriction, and sustained inflammation.

This process can cause the following:

• Infiltration of bronchial mucosa (the lining of the airway) by lymphocytes
• Swelling (oedema) of bronchial mucosa
• Thickening of smooth muscle of bronchioles
• Increased eosinophil granulocytes
• Mucus plugs
• Remodeling (distortion) of the airway

Pathogenesis

• The fundamental problem seems 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 it 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 asthma and other allergic diseases may develop. This "Hygiene Hypothesis" may explain the increase in asthma in affluent populations.
• Related to the above is another theory regarding the part of our immune system which helps protect us against parasites, such as tapeworms. The Th2 lymphocytes and eosinophil cells which protect us against worms are the same cells responsible for the allergic reaction. In the Western world these parasites are now rarely encountered but the immune response remains and is triggered in some individuals by certain allergens.
• A third theory blames the rise of asthma on air pollution. While it is well known that substantial exposures to certain industrial chemicals can cause acute episodes of asthma, it has not been proven that the same 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.
• Typical triggers include:
  • inhaled allergens such as house dust mite and cockroach, grass pollen, mould spores and pet epithelial cells.
  • cold air
  • exercise
  • respiratory infection
  • emotional stress
  • aspirin & similar medications

Treatment

Preventive

Triggers such as pets and aspirin should be identified and managedTemplate:Fn. Current treatment protocols recommend an inhaled corticosteroid (to suppress inflammation and reduce the swelling of the lining of the airway) for anyone who has frequent or severe symptoms. If symptoms persist, additional preventive drugs are added until the patient's asthma is controlled.

• Inhaled corticosteroids (ex. fluticasone, budesonide, beclomethasone, mometasone, flunisolide, triamcinolone)
• Long-acting beta₂-adrenoceptor agonists (ex. salmeterol, formoterol, bambuterol, sustained-release oral albuterol)
• Antimuscarinics/anticholinergics (ex. ipratropium, oxitropium)
• Leukotriene modifiers (ex. montelukast, zafirlukast, pranlukast, zileuton)
• Mast cell stabilizers (ex. cromoglicate (cromolyn), nedocromil)
• Antihistamines are often used to treat allergic symptoms which may underlie the chronic inflammation. In more severe cases, hyposensitization ("allergy shots") may be recommended.
• Omalizumab, an IgE blocker, can help patients with severe allergic asthma that doesn't respond to other drugs. However, it is phenomenally expensive and must be injected.
• If chronic acid indigestion (GERD) contributes to a patient's asthma, it is necessary to treat it as well or it will restart the inflammatory processTemplate:Fn.

Symptomatic

Episodes of wheeze and shortness of breath generally respond to fast-acting bronchodilators. Ordinarily these are provided in pocket-sized metered-dose inhalers, but for patients with severe asthma a nebulizer is sometimes needed.

• Short-acting selective beta₂-adrenoceptor agonists (ex. albuterol (salbutamol), levalbuterol, terbutaline, bitolterol, pirbuterol, procaterol, fenoterol, bitolterol, reproterol)
• Older, less selective adrenergic agonists (ex. inhaled epinephrine and ephedrine tablets - both of which, unlike other medications, are available over the counter in the US under the Primatene brand)

Advanced

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

• Systemic steroids, oral or injected (ex. prednisone, prednisolone, methylprednisolone, dexamethasone, hydrocortisone)
• Oxygen to alleviate the hypoxia (but not the asthma per se) that is the result of extreme asthma attacksTemplate:Fn
• Other bronchodilators that are occasionally effective when the usual drugs fail:
  • Non-specific beta-agonists, injected or inhaled (epinephrine, isoetharine, isoproterenol, metaproterenol)
  • Anticholinergics, IV or nebulized, with systemic effects (glycopyrrolate, atropine)
  • Methylxanthines (ex. theophylline, aminophylline)
  • Inhalation anesthetics that have a bronchodilatory effect (isoflurane, halothane, enflurane)
  • The dissociative anesthetic ketamine, often used in endotracheal tube induction
  • Magnesium sulfate, IV
• Intubation and mechanical ventilation, for patients in or approaching respiratory arrest

References

• Template:Fnb 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.
• Template:Fnb 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.
• Template:Fnb Inwald D, Roland M, Kuitert L, McKenzie SA, Petros A. Oxygen treatment for acute severe asthma. BMJ 2001;323:98-100. PMID 11451788.
• Template:Fnb Asthma Prevention Program of the National Center for Environmental Health Center for Disease Control and Prevention. Asthma At-A-Glance. 1999.

External Links

• Case Studies in Environmental Medicine (CSEM) - Environmental Triggers of Asthma