Need For Diagnostic Laboratory Test of Pharmacologic Bronchoprovocation Challenge Clinical Value

Although a great deal has been written about the value of bronchoprovocation challenge, it has been its research applications that have received most of the attention. The purpose of this report is to review the clinical role of bronchoprovocation challenge in the diagnosis of bronchial asthma. The basic premise which will be developed is that bronchial hyperreactivity is a fundamental feature of symptomatic asthma, and its presence can be demonstrated in the laboratory by the technique of bronchoprovocation challenge.

Consequently, the bronchoprovocation challenge constitutes an objective laboratory test to help diagnose the presence or absence of bronchial asthma. Since bronchoprovocation challenge is most commonly performed using pharmacologic agents, the major focus of this review will be on pharmacologic bronchoprovocation challenge.

To help place the clinical role of pharmacologic bronchoprovocation challenge into perspective, we will consider the following:

  1. Why is a diagnostic laboratory test for bronchial asthma needed?
  2. What is bronchial hyperreactivity?
  3. Why is the demonstration of bronchial hyperreactivity in the laboratory diagnostically useful?
  4. What is a pharmacologic bronchoprovocation challenge, and how is it performed?
  5. Does pharmacologic bronchoprovocation challenge compare favorably to other laboratory techniques for diagnosing asthma?

Need For Diagnostic Laboratory Test

Diagnostic Laboratory Test for Bronchial Asthma

The need for a diagnostic laboratory test for bronchial asthma is based on the poor predictive values of history and physical examination in this disorder. Although the classic triad of symptoms associated with asthma is cough, shortness of breath, and wheeze, it is not unusual for one or more of these findings to be absent. This often results in the diagnosis of asthma being overlooked, particularly when there is no history or physical finding of wheeze. Alternatively, a patient with this classic complex of symptoms may be incorrectly diagnosed as having asthma, since these findings are often present in a variety of other conditions. In either situation, the wrong clinical diagnosis may result, leading to inappropriate and ineffective therapy.

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The following studies have effectively refuted the myth that wheeze by history or physical examination (or both) is a universal finding in symptomatic asthma. Corrao et al described six patients in whom the diagnosis of asthma had originally been missed because cough had been the sole presenting manifestation. Irwin et al not only reconfirmed these results in a prospective study on chronic persistent cough in the adult, but also found that asthma was the sole or contributing cause of cough in 43 percent of the patients and that 57 percent of the asthmatic subjects had never wheezed. Farr et al reported the findings in an asthmatic patient whose only symptom was dyspnea. McFadden described 21 asthmatic subjects who had intermittent attacks solely characterized by dyspnea in 14 and by cough in seven. Moreover, Myers et al have reported the findings in several asthmatic patients who complained only of chest pain, chest tightness, or dyspnea.

Two recently published prospective studies document that wheeze is also not specific for asthma. Shapiro et al studied 166 children and young adults whom they evaluated for a variety of respiratory-tract complaints. Sixty-five percent of their patients were tentatively diagnosed as having asthma on the basis of a positive pharmacologic bronchoprovocation challenge. The diagnosis was subsequently confirmed in all by a favorable response to bronchodilator therapy. In 35 percent of their patients with a negative bronchoprovocation challenge, the lack of any clinical evidence of asthma over a one-year follow-up period ruled out asthma as an explanation for the patients’ symptoms.

Although Shapiro et al found that they could not distinguish between the asthmatic and nonasthmatic patients on the basis of initial history, physical examination, or routine spirometric data, they determined that the results of pharmacologic bronchoprovocation challenge accurately predicted which patients would prove to have asthma on long-term follow-up. A similar study has recently been performed in 34 adults. Twelve patients were diagnosed as asthmatic on the basis of a positive bronchoprovocation challenge and the disappearance of their symptoms with bronchodilator therapy. Twenty-four patients were diagnosed as nonasthmatic on the basis of a negative bronchoprovocation challenge and a favorable response to specific (nonbronchodilator) therapy directed at the underlying condition that was responsible for their symptoms. These authors concluded that a history of wheeze or atopy, a prior diagnosis of asthma, a family history of asthma, and physical examination or routine spirometric data were poor predictors of which patients would prove to have a diagnosis of asthma based upon follow-up evaluation. In contrast, the results of pharmacologic bronchoprovocation challenge again accurately predicted which patients would turn out to have asthma.

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What Is Bronchial Hyperreactivity?

Tracheobronchial Tree

Bronchial hyperreactivity is a nonspecific tendency of the smooth muscle of the tracheobronchial tree to contract to an excessive degree in response to a variety of stimuli (ie, the degree of smooth muscle contraction is increased compared to normal for any given stimulus). This increased contraction of smooth muscle results in a decrease in the caliber of the airways (ie, bronchoconstriction) that can be measured in the pulmonary function laboratory. A comprehensive review of the pathogenesis of hyperreactivity can be found elsewhere.

Diagnostic Utility of Hyperreactivity

The demonstration of bronchial hyperreactivity in the laboratory is diagnostically useful, since it allows one to objectively fulfill the major criteria contained in the most commonly used clinical definition of asthma. This definition, proposed by the American Thoracic Society in 1962, has been used extensively in the selection of patients for numerous clinical research studies on asthma for the past 20 years. It states that “asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and manifested by a widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy.

Bronchial hyperreactivity is a fundamental feature of this statement, and it can be measured as bronchoconstriction in the laboratory (“widespread narrowing of the airways”). Moreover, “various stimuli” have been shown to systematically provoke a far greater degree of bronchoconstriction in known asthmatic subjects compared to normal subjects. These stimuli include:

  • pharmacologic agents such as methacholine, carbachol, and histamine;
  • physical stimuli such as exercise and eucapnic hyperventilation with cold-dry air;
  • immunologic stimuli such as pollens and other allergens, and certain chemicals such as toluene diisocyanate.
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Although the presence of bronchial hyperreactivity can also be demonstrated in the laboratory by observing an exaggerated reversal of bron-choconstriction with bronchodilator drugs or by demonstrating the presence of marked diurnal fluctuations in peak flow rates, the advantage of bron-choprovocation challenge is that it can demonstrate the presence of bronchial hyperreactivity by inducing an exaggerated bronchoconstriction when flow rates are normal.