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From the From the Pulmonary/Critical Care Service (Drs. Roth and Dillard), Department of Medicine and the Physical Examination Section (Dr. Hammers), Soldier Care Service, Madigan Army Medical Center, Tacoma, WA.
Current address: Pulmonary Section, BBR5513, Medical College of
Georgia, Augusta, GA 30912-3135.
Current address: 806 Shetland Pl NW, Concord, NC 28027.
Correspondence to: Lt Col Bernard J Roth, MD, MCHJ-MPU Pulmonary Clinic, Madigan Army Medical Center, Tacoma, WA 98431; e-mail Bernard. Roth@NW.amedd.army.mil
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Design: Prospective, blinded cohort comparison study.
Setting: Pulmonary diseases clinic in a US Army tertiary-care medical center.
Patients: One hundred three college students who were undergoing a physical examination before entering active duty. Group 1 subjects, 58 men and 5 women with an average age of 22.7 years, had no symptoms or personal history of asthma. Group 2 patients, 34 men and 6 women with an average age of 22.2 years, had a history or recent suggestive symptoms of asthma.
Interventions: Methacholine challenge testing using concentrations of 0.025, 0.25, 2.5, 10, and 25 mg/mL for a total dose of 188 inhalation units or until FEV1 had declined by 20%.
Results: Group 2 had significantly more patients with positive results for methacholine challenge tests or reversible airflow obstruction at baseline (23 of 40 patients [57.5%]) than group 1 (8 of 63 patients [12.7%]; p < 0.05). The cadets in group 1 with positive results for methacholine challenge tests reacted with a 20% decline in FEV1 at the following concentrations: 25 mg/mL (188 IU), 2 patients; 10 mg/mL (64 IU), 4 patients; and 2.5 mg/mL (13.8 IU), 2 patients. Using values calculated for the provocative concentration of a substance causing a 20% fall in FEV1 and the new American Thoracic Society criteria, four patients would have borderline bronchial hyperresponsiveness (4 to 16 mg/mL) and three patients (4.8%) would have mild bronchial hyperresponsiveness (1 to 4 mg/mL).
Conclusions: Asymptomatic US Army ROTC cadets with no history of asthma have possible false-positive responses to methacholine at concentrations > 0.25 mg/mL.
Key Words: airway challenge testing • airways hyperresponsiveness • asthma • methacholine
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The diagnosis of asthma can have serious nonmedical implications for young adults. These include potential limitation of occupational or employment options as well as possible denial of life insurance or health insurance coverage. Employers and insurers have the right to question individuals about denial of entry into military service for medical conditions. One example of the potential adverse nonmedical impact of the diagnosis of asthma consists of ineligibility for Reserve Officer Training Corps (ROTC) scholarships to colleges and universities as well as military academies. Current military regulations pertaining to asthma call for methacholine challenge testing in some circumstances where a positive result for a test could exclude entrance into military service.7
Because AHR can occur in asymptomatic individuals, it is unclear how many of these potential military inductees may have false-positive results for methacholine challenge tests. This study attempted to estimate the prevalence of false-positive results of methacholine challenge testing in young college students who were being evaluated for induction into military service through ROTC.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The physical examination director (L.M.H.) recruited consecutive cadets with no abnormalities on the screening questionnaire and physical examination to participate as the study group (group 1). The volunteer agreement signed by the cadets explained that they were being considered as subjects who did not have asthma in order to standardize a test for asthma. No attempt was made to match any characteristics between cadets in groups 1 and 2. We had the capacity to study no more than two group 1 cadets for every cadet in group 2 because of limitations on equipment and technician time to perform the tests. ROTC training did not permit tests on days other than the physical examination days. Recruitment was limited on each physical examination day when the capacity in the pulmonary function laboratory was reached. Group 1 cadets presented to the pulmonary clinic with a consultation request (Standard Form 513) that was indistinguishable from those carried by the group 2 cadets. We identified all the cadets by number only. The clinic physicians and pulmonary technicians were blinded as to the group to which the cadet belonged. Before coming to the pulmonary clinic, group 1 cadets gave written informed consent for the study, which was approved by the Madigan Army Medical Center Institutional Review Board.
A total of 113 cadets (group 1, 71 cadets; group 2, 42 cadets) were referred to the pulmonary clinic for evaluation of possible asthma. All of these cadets completed an additional confidential questionnaire addressing the following: their personal history of asthma; their family history of asthma; the presence of asthma symptoms, including cough, shortness of breath, chest tightness, wheezing, excess sputum production, and difficulty running; the presence of symptoms of allergy, including rhinitis, known allergens, eczema, or hives; smoking history; and the history of a respiratory tract infection within the past 6 months, including colds, flu, bronchitis, sinusitis, sore throat, or pneumonia.
All cadets performed spirometry per American Thoracic Society (ATS) criteria.8 If the initial spirometry revealed airflow obstruction, the cadet received bronchodilator therapy and performed repeat spirometry. Otherwise, the cadet received a methacholine challenge. We defined airflow obstruction as a FEV1/FVC ratio below the lower limit of the 95% confidence interval for the predicted ratio. A response to the bronchodilator was defined as a 12% and 0.2-L improvement in FEV1 or FVC. The bronchodilator consisted of three puffs of albuterol from a metered-dose inhaler that was supervised by a pulmonary technician to ensure appropriate technique. Repeat spirometry was performed 10 min after the administration of the bronchodilator. The predicted normal values were those of Knudson et al9 with race correction as appropriate.
Methacholine challenge testing was performed in a standard manner.10 Inhaled normal saline solution and methacholine (Methapharm Inc; Brantford, Ontario, Canada) were administered using a Rosenthal breath-actuated dosimeter (Pulmonary Data Service Instrumentation; Louisville, CO) and a nebulizer (model 646; DeVilbiss; Jackson, TN) powered with 20 lb per square inch of compressed air, a set delay of 0.60 s, and a dose duration of 1.54 s based on the distributor recommendation (SensorMedics; Yorba Linda, CA). Subjects first received a normal saline solution placebo followed by repeat spirometry 3 min later. Subjects then received five breaths each of methacholine at increasing concentrations of 0.025, 0.25, 2.5, 10, and 25 mg/mL as recommended in the product information (Provocholine; Methapharm).11 Spirometry was repeated 3 min after each dose of methacholine. If the FEV1 had fallen by 20% from the baseline value, no further methacholine was given, the cadet received three puffs of albuterol from a metered-dose inhaler, and spirometry was repeated after 10 min to assure recovery.
All of the challenge tests were interpreted by one of us (T.A.D.)
without knowledge of the status of the cadet (group 1 vs 2). The
challenge tests were reviewed to ensure acceptability, reproducibility
of results, and that a decrement in FEV1 with
methacholine reversed with bronchodilator treatment. A test was
interpreted as being positive if the FEV1 fell by
a total of 
20% from baseline with any of the five doses of
methacholine. The provocative concentration of methacholine for each
positive test was calculated by the following formula:
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Although this protocol was performed before the publication of the ATS guidelines for methacholine and exercise challenge testing,11 the protocol used is considered to be acceptable by that document. The data obtained from these challenge tests were evaluated subsequently using the calculated PC20 FEV1 and the new standards for categorization of bronchial responsiveness recommended by the ATS.11
At the completion of testing, the clinic nurse called the physical
examination section to determine the status of each cadet (group 1 vs
2). The group 1 cadets were excused, and the group 2 cadets then were
evaluated by one of us (B.J.R.) to determine the presence of asthma.
Because of the implication of a positive result for the methacholine
challenge because of asthma (ie, not eligible for active
duty), the human use committee did not allow the interviewing of the
group 1 volunteer cadets with a positive result for the test. For the
purposes of this study, the following diagnostic criteria for asthma
were applied: (1) reversible airways obstruction and recent or
remote symptoms suggestive of asthma lasting > 6 months; (2) a
positive result of a methacholine challenge with a
PC20 FEV1 of 
10 mg/mL
and recent or remote symptoms suggestive of asthma; or (3) a positive
result of a methacholine challenge with a PC20
FEV1 of > 10 and recent symptoms suggestive of
asthma lasting > 6 months.
The following patients were excluded from analysis. One patient in group 2 was unable to perform reproducible spirometry despite repeated coaching. Another patient in group 2 had fixed obstruction on pulmonary function testing and a focal wheeze on physical examination. He was referred for further evaluation by his civilian physician. The result of his methacholine challenge test was negative. Despite having denied having asthma or symptoms of asthma during the official physical examination, two cadets from group 1 related a personal history of asthma. Neither of these two cadets had a positive result for the methacholine challenge. Five more cadets reported recent symptoms suggestive of asthma on the second questionnaire. One of these cadets had reversible obstruction on pulmonary function testing, and one had a positive result for the methacholine challenge test. One other cadet was excluded from group 1 because of a protocol violation, wherein his baseline spirometry showed obstruction but he had been given methacholine incorrectly. His FEV1 dropped by 19%, which reversed with bronchodilator treatment.
We performed data analysis on a total of 40 subjects in group 2, which consisted of 34 men and 6 women with an average age of 22.2 years (range, 20 to 26 years), and 63 subjects in group 1, which consisted of 58 men and 5 women with an average age of 22.7 years (range, 18 to 31 years). In group 2, 23 of 40 cadets (58%) reported a previous diagnosis of asthma. Table 1 shows descriptive data for both groups. Group 2 had lower baseline values for FEV1 than did group 1, which was expected because many patients in group 2 had clinical asthma.
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2 analysis. The average
PC20 for methacholine in the positive tests in
each group was compared with an unpaired t test. The average
age of each group was compared using the unpaired t test,
while the sex and race of each group were compared using
2 analysis. A correlation between risk factors
for asthma and a positive result for the methacholine challenge test
was examined in each group using logistic regression analysis with
appropriate computer software (SPSS; SPSS Inc; Chicago,
IL).12 |
Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.25 mg/mL. Six of the 20 cadets with
positive test results had a PC20
FEV1 of > 10 mg/mL. Altogether, 23 of the 40
patients (57.5%) had evidence of reversible airway obstruction or AHR. All but 2 of these 23 group 2 patients received a diagnosis of asthma after evaluation by a pulmonary physician (B.J.R.). None of the patients with negative results for methacholine challenge tests had a convincing history for asthma. The most common symptom in the 18 patients with negative results for methacholine challenges was dyspnea on exertion, which was reported in 5 patients. The responses to the questionnaires are displayed in Table 2 . None of these responses correlated with the presence of a positive result for a methacholine challenge test.
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By sex, the prevalence of positive results for methacholine challenge
testing was 10% in men and 40% in women in group 1. This difference
had borderline statistical significance (p = 0.056;
2, 3.65). Table 2
summarizes the responses to
the questionnaire concerning risk factors and results of multiple
logistic regression analysis for both groups. None of the risk factors
correlated with a positive result for the methacholine challenge test
in either group.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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After Operation Desert Shield/Desert Storm, the Department of Defense Physical Standards for Enlistment, Appointment, and Induction were modified so that "asthma reliably diagnosed at any age" disqualifies the applicant for accession into the military.7 Previously, asthma before age 12 years with no subsequent symptoms or therapy was permissible for accession and entry into active duty.15 At present, individuals can obtain a waiver to enter into active duty with a history of asthma only if methacholine challenge test results are negative.
The potential problems in applying that regulation involve concerns that inductees often cannot recall their exact symptoms, evaluation, or treatment of a condition they had as a young child. In addition, primary-care practitioners may erroneously make the diagnosis of asthma on clinical grounds.16 Consequently, during military induction, entrance examination staff or recruiters often request spirometry testing to obtain objective evidence. If spirometry results are normal, as is often the case, a methacholine challenge test typically follows. In this setting, a positive result for the test would be interpreted as substantiation that an uncertain remote history indeed reflected asthma. Under current regulations, this would disqualify the applicant in most cases.
Our study shows that 12.7% of asymptomatic ROTC cadets, who were
screened multiple times for any suggestion of asthma, can have a
positive result for the methacholine challenge at doses up to 25 mg/mL.
Using a PC20 10 mg/mL as a cutoff, 9.5% of
these healthy ROTC cadets had positive results for the test. Even using
the much lower cutoff value of 4 mg/mL, which is suggested by the ATS,
three cadets (4.8%) would have a positive test result.
There is some uncertainty about the status of the group 1 cadets because they were not interviewed by a pulmonary physician because of Human Use Committee limitation. Because the cadets understood that a diagnosis of asthma could keep them out of the military, it is possible that they may have withheld symptoms or even a previous diagnosis of asthma. However, the group 1 cadets volunteered for the study with the knowledge that they would undergo a test used for the evaluation of asthma. If they were withholding information about asthma, it would stand to reason that they would not volunteer for the study. In addition, we administered an additional confidential questionnaire asking for any personal history of asthma or symptoms suggestive of asthma. We eliminated seven group 1 cadets because of a reported history of asthma (two cadets) and symptoms of possible asthma (five cadets).
One other possibility in explaining hyperresponsiveness in these cadets is a recent viral respiratory tract infection. Although the answers to the questionnaire regarding recent illness did not correlate with the presence of a positive test result, this does not exclude the possibility that some of the positive test results were because of viral infections. Repeat testing in 3 to 6 months may have answered this question, but it was not possible given our limitations.
One other possibility to explain an increased number of positive responses is the methacholine challenge protocol we used. The Rosenthal dosimeter was set with a dose delay of 0.6 s and a dose duration of 1.54 s. The ATS recommendation is for a dose duration of 0.6 s without a clear recommendation for the delay.11 However, in the same document, the actual need for a dosimeter is questioned, and it notes that the timing of the dose does not appear to affect methacholine response.
The false-positive result rate in group 1 at first glance appears to be lower than the results of Casale et al,4 who found that 28% of 50 healthy volunteers responded. However, that study used five breaths of nine different concentrations of methacholine and a > 20% greater cumulative total dose of methacholine than that used in our study. Also, the study population in the report of Casale et al4 included 60% women, while our group 1 had only 8% women (5 of 63 cadets). Women appear to be more likely than men to have a 20% decline in FEV1, presumably because of smaller airway caliber.5 17 These differences appear to explain the higher prevalence in the study by Casale et al4 compared to our data, although the former study did not report the results by sex.
An important similarity between the results of Casale et
al4
and ours is that none of the healthy subjects had a
positive response to a methacholine dose of < 2.5 mg/mL. It would
seem that a positive response to a low-dose methacholine challenge has
a very high specificity for asthma. However, doses of 2.5 mg/mL can
produce a significant rate of false-positive tests.
Malo et al5 reported that 8 of 100 healthy subjects (50% women) had PC20 FEV1 values for methacholine of < 16 mg/mL (approximately 12 inhalation units) using a protocol that doubled the single-breath concentration of methacholine from 2 to 128 mg/mL. This would compare roughly to our dosing of 2.5 mg (approximately 14 inhalation units) that resulted in 3.1% false-positive test results in group 1. Significantly more women than men responded to methacholine in the study by Malo et al.5 The differences in study populations, dosing protocol, and cumulative dose of methacholine again seem to account for the apparent differences to the present study.
The significance of false-positive results for methacholine challenge tests is not entirely clear. Malo et al5 did not find significant peak flow variability in the group of healthy subjects with a PC20 FEV1 of < 16 mg/mL. In a study by Braman and colleagues18 of patients with both allergic rhinitis and abnormal bronchial hyperresponsiveness but without clinical symptoms of asthma initially, 3 of 16 patients (19%) developed clinical asthma within 5 years of follow-up compared to 0% of rhinitis patients with no bronchial hyperreactivity. For 3 years, Laprise and Boulet19 observed 28 asymptomatic subjects, including 21 with atopy, who had a PC20 FEV1 for methacholine of < 8 mg/mL, as determined by the method of Malo et al,5 and found that asthma symptoms developed in 4 of 28 subjects (14.3%) compared to no asthma symptoms developing in a control group without methacholine reactivity. The best correlate with the onset of symptoms was viral infection followed closely by a PC20 FEV1 that fell below 4 mg/mL and a family history of asthma.
A recent study of active-duty Israeli servicemen estimated a new onset of asthma at 1.2% in combat positions, 0.8% in maintenance positions, and 0.6% in clerical positions over a 30-month interval.20 In addition, 10 to 20% of troops with known histories of asthma had recrudescence of symptoms during that interval. The authors concluded that combat and maintenance duty unmasks asthma in some and induces asthma in others.
In conclusion, a significant number of asymptomatic young ROTC cadets will have hyperresponsiveness to methacholine that is of unclear significance. The risk of potential harm to the cadet of a misdiagnosis of asthma must be weighed against the potential burden that the Army has for a soldier who develops symptomatic asthma while on active duty. The application of methacholine challenge testing to the diagnosis of asthma and the determination for fitness for duty should only follow careful consideration of the dose response to methacholine, history, and concurrent risk factors.
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Acknowledgements |
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Footnotes |
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Supported by Madigan Army Medical Center Department of Clinical Investigation Protocol No. 96110.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Received for publication June 2, 2000. Accepted for publication October 3, 2000.
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References |
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This article has been cited by other articles:
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  D. Miedinger, P. N. Chhajed, M. Tamm, D. Stolz, C. Surber, and J. D. Leuppi Diagnostic Tests for Asthma in Firefighters Chest, June 1, 2007; 131(6): 1760 - 1767. [Abstract] [Full Text] [PDF]
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