Increase in Bronchial Responsiveness to Methacholine and Late Asthmatic Response Deliberations

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The present study demonstrates that in asthmatic subjects, bronchial sensitivity to methacholine can increase after the inhalation of ultrasonically nebulized distilled water. The increase in bronchial responsiveness can persist for more than two hours after the recovery from the bronchospasm induced by the distilled water.

This confirms previous results obtained by Black and co-workers; however, those authors studied the change in responsiveness to methacholine only 40 to 60 minutes after challenge with ultrasonically nebulized distilled water, and their findings have more statistical than physiologic meaning. In fact, the provocative doses of methacholine recorded after challenge with distilled water were within the accepted reproducibility of the test. In our study the changes in PC20M soon after the recovery from bronchoconstriction induced by distilled water were beyond the variability of the test in all of the tested subjects.

Asthmatic Subjects

The increase in responsiveness to methacholine in our patients was associated with a lack of refractoriness to repeated stimulation with ultrasonically nebulized distilled water, and we have previously observed no change or even an increase in PC20M after such inhalation of distilled water in subjects with a refractory period to this stimulus. These findings, taken together, suggest that there is a range of refractoriness to repeated challenge with ultrasonically nebulized distilled water and a change in responsiveness to methacholine in asthmatic subjects who respond to inhalation of distilled water. This point requires further evaluation.

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In the present study the increase in hyperresponsiveness to methacholine waned two hours after the recovery from the bronchoconstriction induced by distilled water in most of our subjects, but at this time, two of them (subjects 3 and 9) had the greatest reduction in PC20M. On the fifth day, these two subjects showed late responses to ultrasonically nebulized distilled water which persisted for four to five hours. After the spontaneous recovery from the late reactions, a slight reduction in PC20M was detected in both subjects, but the change from the baseline value was not greater than twofold.

By contrast, the other patients, who had experienced the maximal increase in hyperresponsiveness to methacholine soon after the recovery from the bron-chospasm induced by distilled water, did not show any significant delayed change in FEVX on the fifth day.

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These findings suggest that:

  • the occurrence of late asthmatic response to inhalation of ultrasonically nebulized distilled water can be preceded by a progressive increase in hyperresponsiveness to methacholine;
  • the subjects who do not show any delayed airflow obstruction after distilled water can also have an increase in sensitivity to methacholine which is shorter lasting.

Although the allergen-induced increase in nonspecific bronchial responsiveness generally follows late responses and may persist for days to weeks after any alteration in the caliber of the airways has disappeared, recent studies have demonstrated that a significant increase in bronchial responsiveness can also precede the onset of late responses. Furthermore, responsiveness to both histamine and methacholine can be enhanced by an allergenic challenge which does not provoke any change in the caliber of the airways; in this case, increased hyperresponsiveness can appear two to three hours after inhalation of allergens.

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These findings suggest that the induced increase in nonspecific bronchial responsiveness may be necessary for, rather than (as previously suggested) conse-qyent upon, the development of a late asthmatic reaction to allergen, and that an early increase in responsiveness can be elicited by inhalation of allergens in the absence of any late response. On the basis of our results, the same seems to be true for hyperresponsiveness induced by ultrasonically nebulized distilled water.

Moreover, from only two subjects, our results can not exclude the possibility that an increase in bronchial responsiveness may also follow the late response induced by distilled water in other subjects, as it follows allergen-induced late reactions; on the other hand, some late response to inhalation of allergens can indeed occur in the absence of any following increase in responsiveness to methacholine.

All of these arguments and the finding that late reactions induced by distilled water have a time course similar to that seen with inhalation of allergens support the hypothesis that the two stimuli at least partly act through a common mechanism. This restricts the usefulness of challenge with distilled water as an alternative method to measure bronchial hyperresponsiveness.

Further studies are in progress in our laboratory to characterize the late asthmatic response provoked by the inhalation of distilled water and to evaluate the mechanism(s) involved.