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In smokers with chronic airflow limitation (CAL), airway hyperresponsiveness (AHR) to stimuli like methacholine, which act directly on airway smooth muscle, are not specific for the pathogenesis which is responsible for AHR to methacholine in subjects with normal spirometry, nor predictive for a beneficial effect of glucocorticosteroid (GCS) treatment. In contrast, AHR to stimuli like hyperventilation, which act indirectly through mediator release, may be specific for the pathogenesis of asthma and predictive for a beneficial effect of GCS. The validation of this possibility requires the demonstration that patients with CAL and AHR to hyper-ventilation demonstrate improvement after treatment with GCS (and have an increase in eosinophils and metachromatic cells in the sputum or bronchoalveolar lavage (BAL), like that seen in asthmatics uncomplicated by CAL).

Current asthma (variable air-flow obstruction) is often excluded by the presence of normal bronchial responsiveness. We report a patient with occupational asthma that was presumed to be caused by sensitization and exposure to toluene diisocyanate (TDI). Variable air-flow obstruction measured by peak flow rates (PFR), and symptoms of asthma reversed by salbutamol, occurred after natural exposure to TDI when methacholine bronchial responsiveness was well into the nonasthmatic range. The asthma occurred at the end of, or just after work, suggesting the occurrence of late asthmatic responses. While the patient continued at work, the late asthmatic responses became progressively more severe as methacholine responsiveness progressively increased into the asthmatic range. This suggests that, in individual subjects, the degree of bronchial responsiveness is a determinant of the severity of the late asthmatic response. When the patient stopped work, spontaneous symptoms of asthma and increased diurnal variation of PFR recurred spontaneously until methacholine responsiveness returned into the normal range. These observations indicate that asthma can occur at a time when methacholine bronchial responsiveness is normal, providing the stimulus is strong enough. They further demonstrate that the magnitude and ease of bronchoconstriction relates to the degree of methacholine responsiveness.

Asthma has been defined as variable airflow obstruction. The symptoms of asthma are not specific for the condition and, therefore, the presence of variable airflow obstruction needs to be objectively confirmed. When airflow obstruction is present and when it can be completely reversed with treatment, confirmation of the diagnosis is easy. When spirometry is normal or when there is chronic airflow limitation, however, other methods of investigation are required. These methods include inhalation tests with histamine or methacholine, diurnal variation of peak flow rates and tests with exercise or hyperventilation. When spirometry is normal, methacholine or histamine tests appear to be the most sensitive method but, if results are normal, they do not exclude past or future asthma. However, when there is chronic airflow limitation neither variable airflow obstruction nor methacholine or histamine hyperresponsiveness are specific for asthma; tests with hyperventilation (and probably others that act through mediator release) may be more specific. The presence of asthma probably requires the release of chemical mediators, from mast cells and other cells, which can produce inflammation. This has been particularly studied after inhalation of allergens or chemical sensitizers which can trigger both early and late asthmatic responses. The late responses are associated with prolonged increases in airway responsiveness and are considered to be a result of the cellular phase of inflammation. It is possible that persistent or recurrent inflammation, due to these and other stimuli, is the cause of the persisting airway hyperresponsiveness and variable airflow obstruction in asthma, as well as the other features of cough and sputum, but this requires further investigation.(ABSTRACT TRUNCATED AT 250 WORDS)

Methacholine inhalation tests are used to help in the diagnosis of asthma when spirometry is normal. However, the significance of increased methacholine responsiveness in patients with rhinitis and no symptoms of asthma is not known. One possibility is that it is a false positive result; another possibility is that it indicates subclinical asthma. We investigated these possibilities in 25 patients with rhinitis, whose attending physician had not made a diagnosis of asthma, by comparing responsiveness to methacholine expressed as the provocation concentration to cause a fall in FEV1 of 20% (PC20) with responsiveness to the natural stimulus of isocapnic hyperventilation of cold air and the diurnal variation of peak flow rate. Asthma was recognized objectively by variable airflow obstruction documented by one of the latter two tests. The PC20 ranged between 4 and greater than 64 mg/ml. In 10 patients the PC20 was less than 16 mg/ml. Five of these patients had bronchoconstriction in response to hyperventilation, and a further two patients demonstrated increased variability of peak flow rates. Thus, in seven of 10 patients, increased bronchial responsiveness was confirmed by the use of two different methods, although they were asymptomatic, and the increased response to methacholine was not a false positive result. In the remaining three patients the PC20 was borderline increased (8 to 16 mg/ml). The results indicate that methacholine responsiveness in the asthmatic range in patients with rhinitis is associated with variable airflow obstruction and subclinical asthma.

There appears to be a close interrelationship among airway responsiveness to mediators and to natural stimuli, the presence and severity of asthma, and endogenous mediator release in the airways. Histamine and methacholine have been most commonly used to measure airway responsiveness. Airway responsiveness to the two drugs is increased in patients with current symptoms of asthma, and the degree of increase relates closely to the degree of variable airflow obstruction and the therapy to control symptoms. The degree of airway responsiveness to histamine also correlates closely with the degree of responsiveness to methacholine and less closely with responsiveness to PGF2 alpha and to natural stimuli such as exercise and allergens. The less close correlations with responsiveness to exercise and allergens is probably because of variations in the ease and type of endogenous mediator release in the airways by these stimuli. Endogenous mediator release from a number of stimuli including allergens and ozone causes inflammation in the airways, asthma, and airway hyperresponsiveness. These various interrelationships indicate that the treatment of asthma should be directed to reduce airway responsiveness, prevent mediator release, and prevent or reverse inflammation.

A number of topical aspects of histamine or methacholine inhalation tests were discussed. First, the reporting of results as the dose delivered to the mouth by the method of aerosol generation and inhalation may allow better interpretation of results between laboratories. However, this requires investigation. Second, the histamine or methacholine dose-response curve differs in asthmatics with a moderate to severe increase in airway responsiveness from asthmatics with a mild increase in responsiveness or nonasthmatics. In the latter groups, the dose-response curve is positioned to the right and has a maximal response plateau. The disappearance of this limited maximal airway narrowing in asthmatics appears to be due to added abnormalities. Third, histamine or methacholine inhalation tests provide a sensitive and specific measure of the presence of variable airflow obstruction (asthma). They are useful to validate the diagnosis when symptoms are suggestive but spirometry is normal. The symptoms of asthma are not specific, and without objective confirmation the diagnosis is frequently misjudged even by the specialist. Finally, airway hyperresponsiveness to histamine or methacholine is not diagnostic of asthma when chronic airflow limitation is present; hyperresponsiveness to isocapnic hyperventilation may be more specific.

The frequency with which disagreement occurs between the clinician's diagnosis of asthma and the objective measurement of methacholine airway responsiveness is not known. We have examined this in 51 consecutive new adult patients presenting with symptoms consistent with asthma but with normal spirometry. Disagreement between the physician's assessment and the result of the methacholine test occurred in 20 patients (39%). Of these, 13 had a clinical diagnosis of asthma but normal responsiveness and 7 had an unexpected increase in methacholine responsiveness. There was no difference in the type of symptoms experienced whether or not there was agreement between the test and the physician's assessment. Thus, an objective measurement like a methacholine inhalation test is clinically useful when spirometry is normal. A normal methacholine test in the presence of symptoms suggestive of asthma should alert the physician to the need for further investigation.