Asthma
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Asthma is a chronic condition affecting populations around the world. Public attention has recently focused on this condition 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. Most likely, there are multiple genetic, developmental, and environmental factors which interact to produce the overall condition.
Asthma is a complex disease characterized by bronchial hyperresponsiveness (BHR), inflammation, 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 when emotional. Asthma is treated with drugs, whether inhaled or in the form of tablets, but there are lifestyle changes which can be used to reduce exacerbations.
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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. Typically the symptoms are very variable, often with rapid onset, and associated with the triggers listed above. In severe cases, 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). In 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 a fall in pulmonary function tests spontaneously, after exercise or inhalation of histamine or methacholine, and subsequent improvement with an inhaled bronchodilator medication.
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.
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
Symptomatic
Episodes of wheeze and shortness of breath generally respond to inhaled corticosteroids or bronchodilators which work by relaxing the smooth muscle in the walls of the bronchi (airways). More severe episodes may need courses of inhaled, oral, or intravenous steroids which suppress inflammation and reduce the swelling of the lining of the airway.
- Bronchodilators (usually inhaled)
- Short-acting selective beta2-adrenoceptor agonists (ex. albuterol (salbutamol), terbutaline)
- Antimuscarinics (ex. ipratropium, oxitropium)
- Older treatments which have a less selective effect on adrenergic receptors are inhaled epinephrine and ephedrine tablets; unlike other treatments both are available over the counter in the US (as Primatene (http://www.primatene.com))
- Systemic steroids (ex. prednisone, prednisolone, dexamethasone)
- Oxygen to alleviate the hypoxia (but not the asthma per se) that is the result of extreme asthma attacks3.
- If chronic acid indigestion (GERD) is part of the attack, it is necessary to treat it as well or it will restart the inflammatory process1.
- Antihistamines are often used to treat the allergic symptoms which may underlie the chronic inflammation. In more severe cases, allergy shots may be recommended.
Preventive
Triggers such as pets and aspirin should be identified and managed2. People with asthma who are having symptoms most days will usually benefit from regular preventive medication. The most effective preventive medication are the inhaled steroids.
- Inhaled corticosteroids (fluticasone, budesonide, beclomethasone, mometasone)
- Long-acting beta2-adrenoceptor agonists (ex. salmeterol, formoterol)
- Leukotriene modifiers (ex. montelukast, zafirlukast)
- Mast cell stabilizers (ex. cromolyn sodium (sodium cromoglycate), nedocromil)
References
- Note 1: 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.
- Note 2: 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.
- Note 3: Inwald D, Roland M, Kuitert L, McKenzie SA, Petros A. Oxygen treatment for acute severe asthma. BMJ 2001;323:98-100. PMID 11451788.
- Note 4: Asthma Prevention Program of the National Center for Environmental Health Center for Disease Control and Prevention. Asthma At-A-Glance. 1999.cy:Asthma
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