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Correspondence to: Yancy Phillips, MD, FCCP, The Southeast Permanente Medical Group, Nine Piedmont Center, 3495 Piedmont Rd, NE, Atlanta, GA 30305
The diagnosis of asthma is usually made after careful consideration of a patient’s individual history and the demonstration of reversible airway obstruction. Those are the easy ones. For many patients with some combination of cough, wheezing, dyspnea, and chest tightness, the diagnosis may remain unclear after initial history, physical examination, and spirometry. In such cases, the methacholine challenge test (MCT) has become the most widely used method of evaluating the likelihood that a given patient’s respiratory symptoms represent asthma. Making a diagnosis of asthma with confidence should lead to appropriate therapy. Refuting the diagnosis can lead to a broadened differential diagnosis that includes less common disorders with similar nonspecific symptoms whose diagnosis is often greatly delayed, such as endobronchial lesions, interstitial lung disease, or pulmonary vascular disease.
Increasing quantities of inhaled methacholine, a synthetic derivative
of acetylcholine, induce increasing degrees of bronchospasm in
susceptible individuals. Normal subjects may also experience some
degree of short-lived airways narrowing if administered large amounts
of methacholine, but their degree of bronchospasm typically plateaus
after a modest decrease in FEV1. The clinical
utility and techniques for the MCT have been recently authoritatively
reviewed.1
Individuals experiencing a significant amount
of airflow limitation (defined as a 
20% fall in
FEV1 compared to baseline) in response to a
threshold concentration of methacholine (typically < 16
mg/mL of inhaled methacholine) are considered to have airways
hyperresponsiveness (AHR), ie, a positive MCT result. The
MCT has excellent sensitivity in identifying patients with asthma, but
AHR can occur in other conditions, including viral tracheobronchitis,
COPD, and congestive heart failure. Even patients with allergic
rhinitis who are without chest symptoms may have a positive MCT result.
Absence of AHR to methacholine challenge provides strong evidence
against the diagnosis of current asthma.
The increasing significance of the MCT as a clinical and research tool is evidenced by Figure 1 , which shows the number of MCT publications listed for each year from 1970 to 2000 in the National Library of Medicine PubMed directory. The search was performed using the phrase, "methacholine challenge" OR "methacholine inhalation" AND asthma. Nine citations were recovered for the entire 1970s, 168 citations for the 1980s, and 471 citations for the 1990s.
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Despite the popularity of the MCT in academic circles evident in the data mentioned, it remains underused in routine clinical practice. Technical challenges include maintaining a predictable delivery of aerosol dose, mixing and storage of the test solution, and the requirement for the patient to produce a large number of interpretable forced expiratory maneuvers over a long and sometimes exhausting test period. The patient must be adequately prepared, which includes withholding antiasthma medicines (including caffeine) for hours or even days before testing. The MCT often requires an hour to complete, and concern over inducing dangerous levels of bronchospasm results in a high level of physician supervision. These factors all contribute to the high cost of the MCT and to the tendency to use it only as a last resort, rather than earlier in the evaluation of nonspecific respiratory symptoms.4 5
In this issue of CHEST (see page 1857), Cockcroft and colleagues report their experience using a test-shortening protocol for the MCT. Using the 2-min tidal breathing method, they report on 1,000 MCTs administered to individuals in whom asthma was in the differential diagnosis. While this is a retrospective, observational study, it does describe a practical guideline for shortening the test protocol while providing reassurance of the safety of the MCT in a carefully selected population. The authors established a protocol in their pulmonary laboratory that allows the technician performing the test to begin the test at a higher concentration of methacholine than the standard 0.03 mg/mL and to omit one or more of the methacholine doses during the test. Test subjects who had normal levels of airflow at baseline, who experienced few daily chest symptoms, and who had no bronchospasm with the saline solution control inhalation were begun at doses of methacholine as high as 2 mg/mL. Test subjects who had a < 5% fall in FEV1 following any concentration of methacholine were allowed to skip the next concentration of methacholine. In so doing, the technicians performing these tests were able to reduce the number of inhaled concentrations from the maximum of seven concentrations to an average of four or fewer concentrations per subject per test for nonresponders. In nearly half of those subjects with a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of > 8 mg/mL (no AHR to methacholine challenge), one or two concentrations of methacholine were omitted. In less than one fourth of those subjects with a PC20 < 8 mg/mL (AHR to methacholine challenge) was a methacholine concentration omitted. According to the authors, reducing the number of administered concentrations shortened the test from the standard 60 min per test to an average of 30 min per test. There were no severe adverse events when the test was shortened using this algorithm.
The fact that the protocol is technician driven is important. Using a clearly written protocol chart, the technician can determine which patients can safely begin the test at a higher-than-standard concentration and which patients can skip a dose during the testing procedure. In practice, the principal guarantee of safety will be the proper selection of patients. Patients with significant baseline obstruction or with frequent symptoms should be approached cautiously lest an attempt to shorten the MCT lead to an uncomfortable and possibly dangerous degree of bronchospasm.
There are a few caveats that should be considered. Only 315 of the 1,000 MCT results were positive. It would be interesting to know what the diagnoses were for the remaining majority of those tested. Similarly, a table cataloguing the presenting symptoms for all tested patients would help the physician know how applicable the report is to his/her patients. The authors state that the 1,000 methacholine tests studied were randomly selected from the approximately 2,000 tests done during the 6-year period they have been using the test-shortening protocol. The method of randomization is not described, and some unintentional bias is conceivable. Although not directly demonstrated, the technique should provide the same, reproducible quantification of airway hyperresponsiveness as is provided by the longer, standard protocol.
Methacholine challenge testing can be very useful in clinical practice when the treating physician must determine the likelihood that asthma represents the cause of a patient’s respiratory symptoms. Cockcroft and colleagues describe their experience with a simple protocol for shortening the test procedure. Adoption of this approach should lower the cost of the MCT without raising undue concern about its safety. We hope that these two factors will result in a wider use of the MCT in clinical practice and an increase in the precision of diagnosing asthma and differentiating it from other disorders with similar respiratory symptoms.
References
This article has been cited by other articles:
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  A. J. Stolz, J. Schutzner, R. Lischke, J. Simonek, and P. Pafko Predictors of prolonged air leak following pulmonary lobectomy Eur. J. Cardiothorac. Surg., February 1, 2005; 27(2): 334 - 336. [Abstract] [Full Text] [PDF]
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 E. Bar-Yishay, D. W. Cockcroft, D. D. Marciniuk, T. S. Hurst, D. J. Cotton, K. F. Laframboise, B. D. McNab, and R. P. Skomro Abbreviated Methacholine Challenge: How Safe Are Short Procedures? Chest, August 1, 2002; 122(2): 752 - 753. [Full Text] [PDF]
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