Asthma diagnosis and treatment
The bronchoprotective effect of inhaling methacholine by using total lung capacity inspirations has a marked influence on the interpretation of the test result

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Methacholine tests are widely used as a diagnostic aid for asthma. Their strength has been reputed to be the high sensitivity and very infrequent occurrence of false-negative test results (ie, high negative predictive value). There are 2 commonly used methods that have been outlined by the American Thoracic Society. These methods were thought to give equivalent results. However, in 3 investigations in which we have compared the 2 methods, we have demonstrated a marked lack of comparability. In subjects with borderline to mild airway responsiveness (tidal breathing, methacholine PC20 >2 mg/mL), the 5 deep inhalations required of the dosimeter method produce marked bronchoprotection in some subjects with asthma. The result of this bronchoprotection is that in 55 subjects with asthma, 50% of those whose tidal breathing PC20 value was greater than 2 mg/mL and 25% of the total had negative methacholine challenge results. This indicates that the standardized dosimeter method has an unacceptable loss of diagnostic sensitivity. We recommend that the dosimeter method not be performed as outlined by the American Thoracic Society and that methacholine should be administered by means of submaximal inhalations or tidal breathing.

Section snippets

Deep inhalations and bronchoprotection

Maximal lung inflation, as achieved by taking deep inhalations, to total lung capacity (TLC) has long been known to be both a bronchodilator4 and a bronchoprotector.5, 6 The bronchoprotective effect in healthy subjects is quite potent, and it has been hypothesized that its loss might be one of the fundamental mechanisms underlying the development of asthma.6 Some have stated that bronchoprotection does not occur in asthma.5 However, significant bronchoprotection does occur in some subjects with

Methacholine methods

There are many published methods for the performance of methacholine challenges. Recently, the American Thoracic Society (ATS) published methods for 2 of the commonly used techniques: the 2-minute tidal breathing method and the 5-breath dosimeter method.3 The methodology outlined is identical for both methods, with the exception of the methods of aerosol generation and inhalation. The 2-minute tidal breathing method12 was modified from an earlier Dutch 30-second tidal breathing method.13

Methods comparisons

Before the publication of the methacholine comparison study noted above,19 we undertook a larger study to compare the 2 ATS methods in subjects with asthma. The major rationale behind this undertaking was to confirm whether the 2 methods did indeed produce identical results when there was at least some theoretical reason to suspect the possibility of nonidentity. We expected that if the 2 methods were not identical, the differences should be uniform across the range of airway responsiveness.

Our

The problem

This issue raises a major concern in the interpretation of methacholine challenge test results. The 2 methods as outlined by the ATS do not produce equivalent results. The lack of equivalency, however, is not uniform throughout the range of AHR but is limited to subjects with borderline-to-mild AHR, precisely the range in which most positive diagnostic methacholine challenge results will fall. In our opinion the dosimeter method as performed by using standard (ATS) criteria produces an

Recommendation

We would make a strong recommendation that diagnostic methacholine challenges should be done with an inhalation method that does not involve TLC inhalations. The tidal breathing method is easy, inexpensive, and reproducible and excellent for untrained subjects. A modified dosimeter method with sub-TLC inhalations21 would also suffice.

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    Citation Excerpt :

    Responders to histamine demonstrated reduction in surrogate spirometric indices of airway size and airway size relative to lung size.80 Similar to the bronchodilator studies, one explanation for these findings would be preexisting airway narrowing, in that findings of a further small reduction in airway caliber induced by a bronchoconstrictive agent would produce a large increase in resistance, because airway resistance is inversely proportional to the fourth power of the radius.81 Support came from further studies demonstrating the ability of: (1) pretreatment with ipratropium bromide to attenuate hyperresponsiveness to ultrasonically nebulized distilled water; (2) pretreatment with baclofen and oxybutynin chloride, both with anticholinergic properties, to inhibit methacholine hyperresponsiveness; and (3) pretreatment with metaproterenol to attenuate methacholine and histamine-induced hyperresonsiveness.76,79,82,83

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Disclosure of potential conflict of interest: D. Cockcroft is on the advisory board of Methapharm, Merck, AstraZeneca, and Novartis; has received grants from Methapharm, IVAX, BI, Topigen, Merck, and AstraZeneca; and is on the speakers' bureau for Merck, GlaxoSmithKline, and AstraZeneca. B. E. Davis has declared that she has no conflict of interest.

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