Asthma

Definitions

Traditionally, asthma has been classified as intrinsic or extrinsic. Extrinsic asthma was that associated with a clear allergic component. Frequently, asthma associated with a non-allergic stimulus, i.e. cold or exercise, has been classified as extrinsic. Intrinsic asthma has no allergic or other exogenous stimulus and is most often a disease of adults. Patients frequently have manifestations of both.

It is important to remember that asthma comprises a spectrum of clinical entities ranging from non-productive cough, through intermittent exacerbations with normal intercurrent periods, to severe chronic, unremitting airflow obstruction.

Magnitude of the problem

Pathophysiology

The histologic findings in the asthmatic airway include bronchial occlusion with mucous and cellular debris, denudation of the epithelial layer, edema and inflammatory infiltrate in the submucosa, mucous gland hypertrophy, and bronchial smooth muscle hypertrophy. The obstruction caused by this exudate is uneven.

The pathogenesis of the histologic findings involves activation of mast cells with subsequent release of mediators which in turn induce the inflammatory response. The mediators include histamine, chemotactic factors, and arachadonic acid metabolites (notably prostaglandins, thromboxane, leukotrienes, and HETE). Leukotrienes C4, D4, and E4 were previously known as slow reacting substance of anaphylaxis (SRS-A). Thus, mast cell activation is believed to be an early event in the pathogenesis of asthma. Since most of the research pertaining to mast cell activation involved the use of allergenic stimuli, the mechanism by which non-antigenic stimuli activate mast cells remains to be elucidated.

The eosinophil is a prominent constituent in the bronchial wall of the asthmatic. In fact, asthma has been described as chronic eosinophilic desquamative bronchitis. Although the exact mechanism of recruitment is not clear, once present in the bronchial wall the eosinophil releases cytotoxic mediators such as major basic protein, eosinophil cationic protein, eosinophil peroxidase, and eosinophil derived neurotoxin. In addition, the eosinophil amplifies the asthmatic response by releasing leukotrienes which are felt to play such an important role in the inflammatory response.

The role of the neutrophil in the asthmatic response is more controversial. Clearly, this cell has the potential to cause significant tissue injury through the release of oxygen metabolites, proteases, and cationic materials. These cells are found in increased numbers in the airways of asthmatics and have been shown to affect airway function in experimental models.

Platelets, by nature of their elaboration and secretion of platelet activating factor (a potent bronchoconstrictor) and histamine-releasing factors (HRF) may well contribute to the early events in the asthmatic response. However, several other cells manufacture these mediators which presents some difficulty in establishing the relative contribution of platelets to the pathogenesis of asthma.

The role of the macrophage as an antigen presenting cell is clearly established. These cells take up antigen by endocytosis, process it, and re-express it on the cell surface in conjunction with MHC class I (viral antigens) and class II (soluble antigens) for recognition by T cells. This capacity for activation of the efferent arm of the immune system creates a potential for pathological activation although the precise role of the macrophage in airway immunity and pathophysiology remains to be determined.

Helper T cells play a central role in orchestrating immune responses. Th cytokines such as the interleukins and GM-CSF are critical to the growth and differentiation of eosinophils, mast cells and basophils and as such may be important in the pathogenesis of the asthmatic response.

Epithelial injury
A consequence of airway inflammation is epithelial cell injury. Individual cells and indeed whole areas of epithelial desquamate. These events explain the recovery of large numbers of epithelial cells in bronchial secretions. Epithelial damage contributes to the pathogenesis of airway hyper-responsiveness in several fashions: 1) exposure of nerve endings; 2) exposure of effector cells to antigen; 3) decreased production of intrinsic bronchodilator substances (i.e. prostaglandins and HETE²s).Thus the epithelium not only functions as a barrier but as an active regulator of bronchomotor tone.

Neural mechanisms
Asthmatic airways are hyper-responsive to cholinergic substances such as methacholine. This enhances responsiveness could be due changes in parasympathetic regulation of the airways due to increased cholinergic activity or qualitative changes in muscarinic receptor sensitivity. Unfortunately, antagonists which block the cholinergic are not the best bronchodilators.

Airway sensory nerves are present throughout the airway and, when stimulated, result in cough, bronchoconstriction, and mucous secretion. Pro-inflammatory neuropeptides (i.e. substance P) mediate this response in part. The duration of action of these mediators is limited by enkephalinase which cleaves the neuropeptide and inactivates it. Conceivably, down regulation of enkephalinase may allow for exaggerated effects of the neuropeptides.

Mucous secretion is controlled both by the autonomic (parasympathetic) nervous system and neuropeptides. Since mucous plugging is universal in patients who die from asthma, the importance of this neural control of airway function cannot be underestimated.

Smooth muscle
Smooth muscle function in asthmatics may be abnormal. For example, "normal" first degree relatives of asthmatics are hyper-responsive to methacholine. Furthermore, asthmatics have abnormal stimulus-response coupling in other autonomic events such as glycogenolysis, sweat gland function, and pupillary reaction.

In summary, the concept of asthma as an episodic bronchospasm superimposed on otherwise normal airways is no longer tenable. Asthma is a disease of chronic airway inflammation with intermittent acute exacerbations. This concept of chronic inflammation has revolutionized contemporary thought pertaining to pathophysiology of asthma, and more importantly, has had profound therapeutic implications for this condition.

Clinical Manifestations

The physical examination may be normal in minimally symptomatic patients. However, it is important to look for specific findings that might be overlooked in a non-directed examination. For example, evaluate for the presence of rhinitis and sinusitis. Nasal polyps may be found in atopic individuals. Listen carefully over each lobe for wheezing or ronchi.(The absence of wheezing is an ominous finding implying severely compromised airflow.)

In the acutely decompensated asthmatic, the physical examination helps to assess the severity of airflow obstruction, and hence the potential for respiratory failure. The two findings of documented import in this regard are a pulsus paradox and use of accessory muscles. A pulsus paradox of greater than 12 mm Hg or the use of sternocleidomastoid muscles implies severe airflow obstruction.

The laboratory evaluation of the asthmatic usually includes pulmonary function testing which may show obstructive physiology and an increased FRC suggesting air trapping. If PFT's are normal, methacholine inhalational challenge can be used to detect those patients with chronic airway inflammation but normal PFT's.

Chest x-ray is usually normal except in the acutely ill patient where hyperinflation may be present. The presence of specific IgE to allergens in the patient's environment may be helpful in guiding avoidance and immunotherapy.

Peak expiratory flow rate (PEFR) is an extremely useful method both to manage the stable asthmatic at home as well as to gauge the severity of an acute exacerbation in the ER. PEFR of 25% predicted implies severe airflow obstruction and impending respiratory failure. Similar parameters hold for FEV-1.

Arterial blood gases are also useful in assessing acutely ill asthmatics. Generally, these are not necessary unless the PEFR is less than 25% predicted. Hypoxemia is generally not severe but does decline linearly with worsening airflow obstruction. CO2 is low in mild exacerbations and rises with severity of obstruction. A normal CO2 in an acutely ill asthmatic is thus an ominous finding. If the exacerbation progresses unabated, respiratory failure ensues with the concomitant respiratory acidosis.

Differential Diagnosis

Treatment of Asthma

Bronchodilators

Beta-adrenergic agonists
The binding of beta adrenergic agonists to the beta-2 adrenergic receptor on bronchial smooth muscle cells results in bronchodilation by the activation of adenylate cyclase and resultant increase in intracellular cAMP. Cyclic AMP activates protein kinase A, which inhibits phosphorylation pf myosin and lowers intracellular calcium, resulting in smooth muscle relaxation. These agents are available in oral and inhaled form. In general, the inhaled forms are preferred because their efficacy is at least as good, if not better, than that of the oral forms and their systemic toxicity is much less. Beta adrenergic agonists can be administered as a drug aerosol or, more conveniently, via a hand held metered-dose inhaler. As mentioned above, these agents are currently under scrutiny as potential culprits in the rising mortality of asthma in this country and others.

Anticholinergics
Binding of acetylcholine to the cholinergic receptor results in activation of guanylate cyclase which catalyses the synthesis of cGMP, the second messenger mediating bronchoconstriction. Anticholinergic agents such as atropine inhibit this parasympathetic input and thus favor bronchodilation. Atropine is systemically absorbed, and consequently has significant toxicity. Conversely, ipratropium bromide has very low systemic bioavailability and is the preferred agent of this class. Ipratropium is available in metered dose inhaler form. Unfortunately, these agents are only modestly effective in asthmatics and find their role more in the patients with emphysema and/or bronchitis.

Anti-inflammatory Drugs

Cromolyn Sodium
The exact mechanism of action of cromolyn is not known but it is believed to stabilize mast cells and thus prevent degranulation, which explains its efficacy in blocking situational (i.e. exercise-induced) asthma. Cromolyn also blocks late phase responses which suggests actions on eosinophils and macrophages as well. In addition, cromolyn blocks bronchoconstriction to sulfur dioxide which may in part be neurally mediated suggesting effects of sensory nerves in the airway as well. Cromolyn is not effective in all patients. However, one cannot predict which patients will respond. Therefore, a therapeutic trial is usually needed to determine effectiveness in any given patient.

Others
As the concept of asthma as an inflammatory disease has gained acceptance, much of the current research regarding therapeutic management has focused on methods of modulating inflammation. Methotrexate has been found to be an effective agent in asthma. However, due to its significant toxicities, this agent is reserved for those patients with intolerable side effects of systemic corticosteroids. Recently, specific antagonists of platelet activating factor, prostaglandins, and leukotrienes have been developed which look very promising as future therapeutic options in asthma.

Environmental and allergy management

Co-Directors
Peter Kaplan, M.D.

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