Reproducibility and validity of a Yan-style portable citric acid cough challenge

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Abstract

Although many different methods of measuring cough reflex sensitivity have been published, few are simple enough to use outside of a hospital or laboratory environment. The aim of this study was to develop a simple, quick, and portable cough challenge, assess its reproducibility, and compare its results with those measured by an existing established hospital protocol.

Twenty-five volunteers performed cough challenges based on an established hospital dosimeter protocol, and, on a separate occasion, by a protocol inhaling citric acid from DeVilbiss 40 hand-held nebulisers (citric acid concentrations of 10–3000 mM). Reproducibility of the hand-held cough challenge was assessed in 11 volunteers.

Cough thresholds were consistently higher by the hand-held method than by the hospital dosimeter method. The geometric mean citric acid concentrations causing two coughs (threshold D2) were 3.14 and 2.77 log mM, respectively (p<0.001). The geometric mean (95% CI) difference between the tests was 0.51 log mM (0.18–0.83) of the average of the two values. Cough D2 thresholds attained by the two techniques did, however, show significant correlation (r=0.95, p<0.0001). The coefficient of repeatability for the hand-held method was 0.40 log mM.

Administering citric acid from DeVilbiss 40 hand-held nebulisers offers a rapid, portable, and reproducible cough challenge in healthy volunteers. The results correlate well with an existing Mefar dosimeter challenge, but give two to three times greater cough thresholds.

Introduction

The first reported human cough challenge utilised inhaled citric acid, and was reported by Bickerman in 1954 [1]. Since that time a wide variety of protocols have been developed to measure cough reflex sensitivity, which have differed in their choice of tussive agent, method of administration, and number of coughs required to attain a threshold [2]. The lack of an accepted standard makes it impossible to compare the results of different studies, and makes large scale multi-centre epidemiological studies impossible.

Yan et al. [3] developed a bronchial challenge specifically for use as an epidemiological research tool, which was a more rapid and portable method of assessing bronchial hyperreactivity than existing techniques. They administered histamine from hand-held glass DeVilbiss No. 40 nebulisers, which are cheap, lightweight, and do not require an electrical supply. The ‘Yan technique’ for measuring non-specific bronchial responsiveness compared favourably with established challenges, and has since been widely used as a research tool in epidemiological and workplace studies [4], [5], [6], [7].

In the past, DeVilbiss No. 40 nebulisers have been used to perform capsaicin cough challenge [8], but there is no published data on the reproducibility or comparability of such challenges. This study aimed to design a simple ‘Yan-style’ cough protocol, and compare it to other existing challenges.

Section snippets

Study subjects

Twenty-five healthy volunteers (16 male and 9 female) were recruited from the Health and Safety Laboratory in Sheffield. Volunteers were screened to exclude those with symptomatic asthma, hay fever, or upper respiratory tract infections in the preceding 6 weeks. The study was cleared to proceed by the Health and Safety Executive's Research Ethics Committee, and all volunteers gave written informed consent.

Study design

In the absence of a gold standard method for measuring cough threshold sensitivity, we

Nebuliser calibration

Nebuliser calibration showed that the mean (95% CI) Mefar dosimeter output was 12.0 μl/s (11.3–12.8) by weight, and 8.4 μl/s (8.0–8.8) by fluoride tracer. The DeVilbiss 40 hand-held nebulisers had a mean (95% CI) output of 2.9 μl/activation (2.6–3.1) by weight, and of 0.8 μl/activation (0.7–1.0) by fluoride tracer.

Method comparison

Two volunteers did not cough with either challenge, and three volunteers did not attain cough thresholds with the hand-held method (being attributed a D2 threshold of 3.48 log mM), but did

Discussion

No gold standard exists for artificially stimulating the cough reflex, and this has lead to research teams separately developing a wide range of different challenge protocols, the results from which are impossible to compare. We designed a simple cough challenge based on the same premise as the Yan histamine challenge [3], measured its reproducibility, and compared cough thresholds with those measured by a well established Mefar dosimeter protocol. We found that all challenges were well

Acknowledgements

This study was funded by the Health and Safety Executive.

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