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By Richard L. Sheldon, MD, FACP, FCCP
Peer Reviewers: Felipe A. Rubio, MD
Theodore Shankel, MD
(Editor’s note: This is the first of a multi-part series on a practical, structured approach to managing asthma in the adult patient. In this issue of Asthma Management, we will cover the epidemiology, etiology, definition, and pathophysiology of asthma.
In next month’s issue, we will cover clinical features and differential diagnosis, as well as special tests. In future issues, we will cover disease management procedures, pharmacology, hospital treatment, and alternative medicine therapies.)
Although it is so commonly seen in the ambulatory setting, primary care physicians (PCPs) have in recent years received poor marks from specialists for properly diagnosing and treating asthma. National attention has identified increasing mortality rates in asthma, and PCPs have been criticized for using improper and often inadequate prescribing protocols. Theophylline, once a mainstay of asthma therapy, has recently fallen from favor because of its toxicity and the availability of more effective and safer agents.
In recent years, several newer drugs have come to the market, and these drugs provide the clinician with more choices. These newer and more potent agents (such as leukotriene-blocking agents) have targeted other avenues to reverse or modify the primary causative factor in asthma inflammation.
Managed care has taken greater interest in asthma because of the high cost and complications associated with hospitalization for status asthmaticus. Many of these admissions could and should have been averted through wider education of patients and family, use and monitoring of peak flow meters, and prompt recognition and physician intervention to anticipate exacerbations and inciting events.
The National Asthma Education and Prevention Program (NAEPP) of the National Institutes of Health (NIH) has identified classification of asthma severity and has recommended a step-wise therapeutic approach for long-term control and quick relief. Advances in home therapy for interventions in asthma exacerbations have also been developed.
The lay press has recently highlighted several deaths due to the inappropriate use of over-the-counter asthma remedies, which has led to the re-emphasis on the importance of early identification of the asthma patient and the necessity of prompt and rational medical therapy. This issue addresses these concerns and underscores the etiology, pathogenesis, and effective treatment options for asthmatic patients in our practices.
Among disease entities, concern about asthma has managed to dominate the last decade due to its remarkable increase in incidence, mortality, and, thus, economic importance.1 Epidemiologists, in frustration, report on this increase despite a better understanding of asthma’s pathogenesis and better means of treatment.
Most asthma begins in childhood and early teens. However, the 64 years and older population is the fastest growing population in the United States and represents the second most important group at risk for asthma-related morbidity and mortality. The presence of coexisting diseases requires the elderly to take, on the average, six to eight different medications, making the addition of asthma medications a serious complicating factor to their health care.2 More than 14 million U.S. citizens are afflicted, with 450,000 hospital admissions and 5000 deaths reported annually.3 Primary care physicians provide 65% of the ambulatory care to asthmatics. Allergists and pulmonologists deliver 30% of the outpatient care.4
It is useful to compare methods of treatment, outcomes, and cost within different national systems (see Table 1). It will be interesting to see how costs have changed when the year 2000 data are published.
|Comparison of Direct & Indirect Costs of Asthma from Five Countries, Adjusted to 1990 U.S. Dollars|
|Country, Year of Data||Asthma Prevalence in 1990||Direct Medical Costs||Indirect Costs||Total Costs||Cost per Patient per Year|
||$250 million||$207 million||$457 million||
||$355 million||$181.1 million||$536.1 million||
||$90.8 million||$257.5 million||$348.3 million||
|United Kingdom, 1988||
||$722.5 million||$1.07 billion||$1.79 billion||
|United States, 1990||
||$3.6 billion||$2.6 billion||$6.4 billion||
|Source: Adapted from Am J Respir Crit Care Med. Supplement on National Asthma Education and Prevention Program Task Force Report on the Cost Effectiveness, Quality of Care and Financing of Asthma Care 1996; 154:S87.|
There are many culprits implicated in the etiology of asthma (see Table 2). Among them are the following interesting concepts: There may be synergy between air pollution and allergies to dust mites, pollens, cats, and mold,5 lower socioeconomic status,6 occupational dust exposure,7 attitudes of adolescents about smoking,8 race and gender (blacks and males having a higher incidence of asthma),9 and harsh climatic conditions.10
|Common Asthma Triggers|
o House dust mites
o Tobacco smoke
|Source: Adapted from Managing Asthma Today: Integrating New Concepts. American Medical Association Publication. Chicago; 1997.|
Special mention should be made of the relationship between viruses and wheezing. In infants, the respiratory syncytial virus (RSV) is responsible for recurrent but transient wheezing. Early viral infections may affect the developing immune system, thereby modifying the subsequent risk of asthma. In children and adults with asthma, the common cold viruses can trigger an acute attack of asthma.11
The genetics of asthma are being studied more intensely. Currently, researches suggest that there are strongly inherited components of the asthma phenotype. Specific genes responsible for the phenotype have not been identified. It is anticipated that discovery of primary asthma genes, asthma severity-modifying genes, and asthma treatment-modifying genes will provide tools that can improve diagnosis and management.12
Exposure of asthma patients to irritants to which they are sensitive will increase asthma symptoms and cause exacerbations. All patients with asthma, regardless of its severity, should avoid: exposure to allergens to which they have a known sensitivity, tobacco smoke, exercise when air pollution is significant, use of beta-blockers, and eating foods containing sulfites.3
Patients with asthma, nasal polyps, and sensitivity to aspirin/non-steroidal anti-inflammatory drugs (NSAIDs) should refrain from using these drugs. Furthermore, patients with rhinitis, sinusitis, and gastroesophageal reflux should be vigorously treated for these disorders since they can cause exacerbations of wheezing.3
The definition of asthma has expanded as the understanding of the inciting factors, pathophysiology, and new treatment modalities have expanded. The current working definition from the Expert Panel Report of the NAEPP is as follows:
"Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular: mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and ephithelial cells. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning.
These episodes are usually associated with widespread but variable airflow obstruction that is often reversible either spontaneously or with treatment.
The inflammation also causes an associated increase in the existing bronchial hyperresponsiveness to a variety of stimuli. Moreover, recent evidence indicates that subbasement membrane fibrosis may occur in some patients with asthma and that these changes contribute to persistent abnormalities in lung function."3
The description of the pathophysiology of asthma now includes new ways to characterize this disorder-upper airway and lower airway, mild, moderate, and severe, childhood onset and adult onset, and early and late phase-all making the old concept of "extrinsic" vs. "intrinsic" mostly inadequate.
The factors that lead to the chronic inflammation of the airways are multiple but involve a variety of different inflammatory cells and "mediators." The implicated cells are mast cells, eosinophils, epithelial cells, macrophages, and activated T-lymphocytes.
Resident cells of the airways, such as fibroblasts and endothelial and epithelial cells, can also release mediators.
No single cell or "mediator" is involved, but, rather, a complex interaction between cells and their preformed mediators. Additionally, "on the spot," newly produced mediators react to inflame the airways and sensitize smooth muscle lining the airway.
Cell derived mediators alter airway smooth muscle tone, increase vascular permeability, activate neurons, and increase mucus secretion. The mediators involved include histamine, leukotrienes, chemokines, cytokines, chemotactic factors, and platelet activating factor.13
Virus-induced wheezing is due to the ability of viruses to coordinately activate epithelial cells and endothelial cells and leukocytes to cause airway edema, obstruction and increased airway responsiveness by producing pro-inflammatory cytokines and mediators.14
Once the asthma "cascade" is initiated by one or more triggers, the pathophysiologic process can be seen as three phases:
• the early (acute);
• late (chronic) phases.
The early phase almost always leads to the later phases if it is left to proceed untreated.
Chronic asthma, with inadequate control of inflammation, will lead to lung remodeling, chronic airway edema, and increased mucus viscosity and secretion. The net effect of these actions is permanent changes in lung function, mucosal thickening, and persistent airway plugging.
Newly described "adhesion proteins" found in the bronchial epithelium, vascular tissue, and lung parenchyma play an important role in maintaining the inflammation found in the airways.15
S-nitrosothiol concentrations in the trachea of asthmatic children is lower than in the trachea of normal children. Low concentrations of airway S-nitrosothiols may represent a distinct metabolic consequence of asthmatic inflammation and provide an easy way to measure nitric oxide in asthmatics. This could help to identify subgroups of asthmatics needing specific interventions.16
Richard L. Sheldon, MD, FACP, FCCP, is a Clinical Professor of Medicine at Loma Linda University, and a Staff Pulmonologist/Intensivist at Beaver Medical Group in Redlands, CA.
The article was peer reviewed by Felipe A. Rubio, MD, Clinical Chief of the Department of Medicine at Kettering Medical Center; and Theodore Shankel, MD, Pulmonary and Critical Care Medicine, Beaver Medical Clinic in Redlands, CA.
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