ATS GUIDELINES FOR METHACHOLINE AND EXERCISE CHALLENGE TESTING

	To the Editor :

The Guidelines (1) are timely, useful, and well balanced. However, although they are in general evidence-based, the rationale of some recommendations remains unconvincing.

1. The use of PC₂₀/PD₂₀, including the choice of the highest FEV₁ value, is no longer arbitrary. Modeling studies have found that for various physiologic reasons (2), in populations with partial overlap in bronchial responsiveness, PD₂₀ by means of the highest FEV₁ (PD_20h) is more discriminative than lower FEV₁ endpoints, PD₂₀ by means of the lowest FEV₁ (PD_20l) or PD₄₀ by means of SGaw (3).

2. The normative data based on tidal volume challenge with histamine (4) cannot be transferred, as proposed by the Guidelines, to the 5-breath challenge with methacholine. First, the difference between histamine and cholinergic responses may exceed one doubling dose either because of host differences (5, 6) or output differences across De Vilbiss 646 nebulizer (6, 7). Second, PD_20h is predictably higher than PD_20l, 1.5 times higher in normals and 1.15 higher in asthmatic subjects (2, 3). Thus, contrary to the statement on p. 317 of the Guidelines (1), PC_20h and P_C20l are not interchangeable for the very reason given on the same page: diagnostic methacholine challenge is carried out in patients with mild asthma and quasi-normal response to deep inhalation. Third, methacholine challenge with the rapid, 5-breath method may produce cumulative effects whereas histamine inhalation with the slower, tidal breathing method may not ([8]; see also p. 317, first paragraph in Reference 1).

3. It is gratifying that the interest sparked by Reference 3 on Bayesian analysis is also shared by the Guidelines. However, the analysis of normative data is surprising. First, Fig. 3 (1) is based on three sets of (condensed?) normative data but only one is subsequently discussed and recommended. Second, I doubt that the patients that might benefit from methacholine challenge should be compared with a subset of "current asthma" (4). This small subset (17 subjects!) has 100% pre-test probability of asthma, way outside the recommended range of 30-70%, and 100% positive tests to methacholine. Some disease characteristics that may influence methacholine test results are not specified; e.g., length and severity of disease or treatment. Methacholine challenge is usually performed on oligosymptomatic patients, often with atypical triggers; they seem to respond to 2-8 mg/ml methacholine in only 5-14% of the cases (9). Moreover, it is inconsistent with Bayes' theorem to plot on the methacholine curve obtained from normals and the entire asthmatic population, the posttest probability resulting from a pretest probability of a subset of the latter population. The term of comparison for an asthmatic population is not the general population but the asthmatic population with similar asthma characteristics. Consequently, sensitivity, specificity, receiver- operator characteristics (8) and pretest probability should also be different. Finally, the Guidelines should have mentioned that the population used for normative data, age 20-29, (presumably) mostly white (4) is not representative for the entire population.

University of California at Davis, Davis, California

1. American Thoracic Society. Guidelines for methacholine and exercise challenge testing-1999. Am J Respir Crit Care Med 2000;161:309-329.

2. Popa V. Physiologic factors affecting the discriminant ability of provocation doses to histamine. Ann Allergy 1994; 73: 43-55 [Medline].

3. Popa V, Singleton J. Provocation dose and discriminant analysis in histamine bronchoprovocation. Chest 1988; 94: 466-475 [Abstract/Free Full Text].

4. Cockroft DW, Murdock KY, Berscheid BA, Gore BP. Sensitivity and specificity of histamine PC-20 determination in a random selection of young college students. J Allergy Clin Immunol 1992; 89: 23-30 [Medline].

5. Peat J, Salome CM, Bauman A, Toelle BG, Wachinger SL, Woolcock AJ. Repeatability of histamine bronchial challenge and comparability with methacholine bronchial challenge in a population of Australian schoolchildren. Am Rev Respir Dis 1991; 144: 338-343 [Medline].

6. Higgins BG, Britton JR, Chinn S, Jones TD, Vathenen AS, Burney PGJ, Tattersfield AE. Comparison of histamine and methacholine for use in bronchial challenge tests in community studies. Thorax 1988; 43: 605-610 [Abstract/Free Full Text].

7. Bennett JB, Davis RJ. A comparison of histamine and methacholine bronchial challenges using the de Vilbiss 646 nebulizer and the Rosenthal-French dosimeter. Br J Dis Chest 1987; 81: 252-259 [Medline].

8. Godfrey S, Springer C, Bar-Yishay E, Avital A. Cut-off points defining normal and asthmatic bronchial reactivity to exercise and inhalation challenges in children and young adults. Eur Respir J 1999; 14: 659-668 [Abstract].

9. Enarson DA, Vedal S, Schulzer M, DyBuncio A, Chan-Yeung M. Asthma, asthma-like symptoms, chronic bronchitis, and the degree of bronchial hyperresponsiveness in epidemiologic surveys. Am Rev Respir Dis 1987; 136: 613-617 [Medline].

	From the Authors:

We thank Dr. Popa for his comments and apologize for overlooking his study supporting our recommendation to use the highest FEV₁ to calculate PC₂₀ (1). Our rationale in choosing the largest FEV₁ was to avoid falsely low values from suboptimal tests. Although we believe we made the right choice, it may be less important than it appears. A recent retrospective comparison found PC₂₀ values to be almost identical using the highest and lowest FEV₁ in 225 methacholine challenges (2).

We understand the theoretical reasons why PC₂₀ values measured with different methodologies might not be comparable. Here again, a recent study confirms that quite different techniques produce nearly identical outcomes (3). We believe this clinical comparability is because the concentration of the challenge agent is more important than the cumulative dose.

Bennett and Davies did find dosimeter and tidal breathing methods gave different results when using the same DeVilbiss 646 nebulizer (4). However, they studied only 18 patients (who may have increased their use of inhaled corticosteroid during the study period) and reported the dosimeter technique was less reproducible than the tidal breathing technique (c.v. 54% versus 9.7%).

We acknowledge the superiority of using a clinical estimation of the pretest probability of asthma, modified by methacholine challenge results. The document clearly states that our Figure 3 was included only for illustration purposes and should not be used to calculate precise post-test probabilities in patients (5). The pretest probability of asthma in any given patient is only a rough clinical estimate, and our intention was to give a qualitative illustration of how the MCT result could alter the pretest probability estimate. We look forward to research that will allow quantitative estimates of post-test probabilities.

Dr. Popa is right. We should have mentioned the population limitations of the normative data. Healthy elderly persons probably have lower PC₂₀ values compared with younger adults. We are not aware of studies demonstrating an effect of race, ethnicity, or country of origin on PC₂₀ in healthy persons.

The University of Arizona, Tempe, Arizona

Robert Crapo

University of Utah School of MedicineSalt Lake City, Utah

1. Popa V. Physiologic factors affecting the discriminant ability of provocation doses to histamine. Ann Allergy 1994; 73: 43-45 .

2. Davis BE, Cockcroft DW. Calculation of provocative concentration causing a 20% fall in FEV₁: comparison of lowest vs highest post-challenge FEV₁. Chest 2000; 117: 881-883 [Abstract/Free Full Text].

3. Siersted HC, Walker CM, O'Shaughnessy AD, Willan AR, Wiecek EM, Sears MR. Comparison of two standardized methods of methacholine inhalation challenge in young adults. Eur Respir J 2000; 15: 181-184 [Abstract].

4. Bennett JB, Davies RJ. A comparison of histamine and methacholine bronchial challenges using the DeVilbiss 646 nebulizer and the Rosenthal-French dosimeter. Br J Dis Chest 1987; 81: 252-259 .

5. American Thoracic Society. Guidelines for methacholine and exercise challenge testing1999. Am J Respir Crit Care Med 2000;161:309-329.