When should a methacholine
challenge be ordered for a patient
with suspected asthma?

January 2008 | Volume 75 | Number 1| Pages 37-40

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The methacholine challenge test is used in several situations:

If the diagnosis of asthma is in question, eg, if the patient has symptoms that suggest asthma (either typical symptoms such as coughing, wheezing, and dyspnea or atypical symptoms) but normal results on regular spirometric testing and no response to a bronchodilator. Because the test has a high negative predictive value, it is more useful in ruling out asthma (if the result is negative) than in ruling it in (if the result is positive).^1,2 A negative methacholine challenge test nearly rules out asthma; however, a positive test result needs to be interpreted cautiously if the patient is not experiencing symptoms.

In establishing a diagnosis of occupational asthma. For patients with remitting and relapsing symptoms suggestive of asthma associated with a particular work environment, a detailed history, physical examination, and methacholine challenge test can establish the diagnosis. Specific bronchial challenge testing with the suspected offending agent is possible, although this is more frequently used in research and in situations with significant legal or financial implications for the patient, such as workers' compensation cases.³

Possibly, in managing asthma. In several clinical trials,^4,5 outcomes were better when asthma management decisions were based on airway hyperresponsiveness combined with conventional factors (symptoms and lung function) than with management based on conventional factors alone. These findings suggest that asthma management based on serial measurement of airway hyperresponsiveness may be useful in optimizing outcomes of care; however, adjustment in treatment according to response to serial methacholine challenge tests is currently not recommended for routine management of asthma.
In clinical research.

Obstruction Can be Improved or Provoked

Asthma is a chronic inflammatory disorder of the airways associated with characteristic clinical symptoms of wheezing, chest tightness, breathlessness, and cough. These symptoms may be associated with airflow limitation that is at least partially reversible, either spontaneously or with treatment.

Spirometry can confirm the diagnosis of asthma if lung function improves after a bronchodilator is given, as reflected by an increase in forced expiratory volume in 1 second (FEV₁) of more than 12% and more than 0.2 L.^6,7

Conversely, during bronchoprovocation testing, airflow obstruction is provoked by a stimulus known to elicit airway narrowing, such as inhaled methacholine. Bronchial hyperresponsiveness can reliably distinguish patients with asthma from those without asthma.

How the Test is Done

During the test, the patient inhales methacholine aerosols in increasing concentrations; various protocols can be used. Spirometry is performed before and after each dose, and the results are reported as a percent decrease in FEV₁ from baseline for each step of the protocol.

A positive reaction is a 20% fall in FEV₁, and the provocative concentration that causes a positive reaction (the PC₂₀) is used to indicate the level of airway hyperresponsiveness. If the FEV₁ does not fall by at least 20% with the highest concentration of methacholine, the test is interpreted as negative and the PC₂₀ is reported as “more than 16 mg/mL” or “more than 25 mg/mL,” depending on the highest dose given.

The maximum dose of methacholine varies among pulmonary function testing laboratories and asthma specialists; final doses of 16, 25, and 32 mg/mL are commonly used. Studies have defined a range of 8 to 16 mg/mL as an optimal cutoff point to separate patients with asthma from those without asthma.^2,6,7

The response to methacholine can also be expressed in terms of specific airway conductance; however, this is more complicated and requires body plethysmography.

Other stimuli that can be used as bronchoprovocation challenges to diagnose asthma include inhaled histamine, exposure to cold air, or eucapneic hyperventilation. Compared with these alternative stimuli, methacholine is the most feasible as it does not require extensive equipment and is better tolerated than histamine.⁸

Potential Complications

Methacholine elicits airway narrowing in susceptible people and can cause severe bronchoconstriction, hyperinflation, or severe coughing. However, this procedure is generally well tolerated, and respiratory symptoms in patients who react to methacholine typically reverse promptly in response to bronchodilators.

Nevertheless, the test should be performed in a pulmonary function laboratory or doctor’s office with available personnel trained to treat acute bronchospasm and to use resuscitation equipment if needed. Informed consent should be obtained and recorded in the medical record after a detailed explanation of the risks and benefits of this procedure and alternatives to it.

Contraindications

TABLE 1 summarizes the absolute and relative contraindications to this test.⁶

Baseline obstruction. A ratio of FEV₁ to forced vital capacity less than 70% on baseline spirometry defines airway obstruction, and methacholine challenge for diagnostic purposes would not be indicated.

Furthermore, patients with low baseline lung function, who may not be able to compensate for a further decline in lung function due to methacholine-induced bronchospasm, are at increased risk of a serious respiratory reaction. For this reason, an FEV₁ less than 50% of predicted or less than 1.0 L is an absolute contraindication to
methacholine challenge testing, and an FEV₁ less than 60% of predicted or less than 1.5 L must be evaluated on an individual basis.⁹

Myocardial infarction or stroke within the previous 3 months, uncontrolled hypertension, and aortic or cerebral aneurysm are absolute contraindications to this procedure, since induced bronchospasm may cause ventilation-perfusion mismatching resulting in arterial hypoxemia and compensatory changes in blood pressure, cardiac output, and heart rate. There is no increased risk of cardiac arrhythmia during methacholine challenge.¹⁰

Pregnancy is a relative contraindication to methacholine challenge testing; methacholine is classified in pregnancy category C.

Inability to perform spirometry correctly is also a relative contraindication, and therefore this test is not recommended for preschool-age children.

Some Drugs Should be Held

For this test to yield accurate results, the patient should not take any medications that would mask the response. The most common reason for canceling the test is lack of adequate patient preparation. Generally, the recommended periods for withholding medications are based on their duration of action (TABLE 2).^6,11–15

Other factors that can confound the results include smoking,¹⁶ respiratory infection, exercise, and consumption of caffeine (coffee, tea, chocolate, or cola drinks) on the day of the test. Airway responsiveness may worsen due to exposure to allergen or upper airway viral infections. Vigorous exercise could induce bronchoconstriction; therefore, performing other bronchial challenge procedures or exercise testing immediately before methacholine challenge may affect the results.^17,18

Bronchial hyperresponsiveness is seen in a variety of disorders other than asthma, such as smoking-induced chronic airflow limitation, congestive heart failure, sarcoidosis, cystic fibrosis, and bronchiectasis, as well as in siblings of asthmatics and in people with allergic rhinitis.¹⁹ In these situations, the methacholine test can be falsely positive, and one should interpret the results in the context of the clinical history.

*Dr. Lang has disclosed that he has received honoraria or consulting fees for teaching, speaking, consulting, or serving on advisory committees or review panels for the AstraZeneca, Critical Therapeutics, Dey, Genentech GlaxoSmithKline, Merck, Novartis, Schering/Key, Teva, and Verus corporations.

References

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3. Tan RA, Spector SL. Provocation studies in the diagnosis of occupational asthma. Immunol Allergy Clin North Am 2003; 23:251–267.
   
   
4. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP, Sterk PJ. Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 1999; 159:1043–1051.
   
   
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6. Crapo RO, Casaburi R, Coates AL, et al. Guidelines for methacholine and exercise challenge testing—1999. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. Am J Respir Crit Care Med 2000; 161:309–329.
   
   
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8. Fish JE, Kelly JF. Measurements of responsiveness in bronchoprovocation testing. J Allergy Clin Immunol 1979; 64:592–596.
   
   
9. Martin RJ, Wanger JS, Irwin CG, Bucher Bartelson B, Cherniac RM. Methacholine challenge testing: safety of low starting FEV¹. Asthma Clinical Research Network (ACRN). Chest 1997; 112:53–56.
   
   
10. Malerba M, Radaeli A, Politi A, Ceriani L, Zulli R,Grassi V. Cardiac arrhythmia monitoring during bronchial provocation test with methacholine. Chest 2003; 124:813–818.
    
    
11. Cockcroft DW, Swystun VA, Bhagat R. Interaction of inhaled beta 2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med 1995; 152:1485-1489.
    
    
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15. Freezer NJ, Croasdell H, Doull IJ, Holgate ST. Effect of regular inhaled beclomethasone on exercise and methacholine airway responses in school children with recurrent wheeze. Eur Respir J 1995; 8:1488–1493.
    
    
16. Jensen EJ, Dahl R, Steffensen F. Bronchial reactivity to cigarette smoke in smokers: repeatability, relationship to methacholine reactivity, smoking and atopy. Eur Respir J 1998; 11:670–676.
    
    
17. Cheung D, Dick EC, Timmers MC, de Klerk EP, Spaan WJ, Sterk PJ. Rhinovirus inhalation causes longlasting excessive airway narrowing in response to methacholine in asthmatic subjects in vivo. Am J Respir Crit Care Med 1995; 152:1490–1496.
    
    
18. Dinh Xuan AT, Lockart A. Use of non-specific bronchial challenges in the assessment of anti-asthmatic drugs. Eur Respir Rev 1991; 1:19–24.
    
    
19. Ramsdell JW, Nachtwey FJ, Moser KM. Bronchial hyperreactivity in chronic obstructive bronchitis. Am Rev Respir Dis 1982; 126:829–832.
    

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