Repeatability of Histamine Bronchial Challenge and Comparability with Methacholine Bronchial Challenge in a Population of Australian Schoolchildren 1- 3
JENNIFER K. PEAT, CHERYL M. SALOME, ADRIAN BAUMAN, BRETT G. TOELLE, SUSIE L. WACHINGER, and ANN J. WOOLCOCK
Introduction Bronchial hyperresponsiveness (BHR) has become widely accepted as an objective measure of airway abnormality in population studies, particularly in those concerned with measuring asthma. The development of a rapid test for measuring BHR (1) and the wide tolerance of this test in the field have led to a number of studies of the prevalen.ce of BHR both in children (2-7) and in adults (8-13). Only two of these studies report the prevalence of BHR measured by methacholine (3, 6); the remainder used histamine as the provoking agent. In population studies, the measurement that is derived from the doseresponse curve, and that is therefore used to define BHR, has not been standardized. The provoking dose that causes a 20070 fall in the FEV1.(PDlOFEV1) is the index most commonly chosen, although it has recently been suggested that the dose-response slope (DRS) may be more useful than provoking dose values because the proportion of subjects with censored data is greatly reduced (14). Although the relation between PDlO FEV 1 range and clinical symptoms is reported (15), the relation of DRS values to clinical symptoms is not known. Before valid comparisons of bronchial responsiveness in populations can be made, the repeatability of a standardized index must be measured and the comparability of different provoking agents must be known. The repeatability of PDlO FEV 1 values measured by histamine inhalation test in adults has been wellreported (10, 16, 17), but there are few reports of the intrasubject variability of PDlO FEV 1 in children (3, 7) and no reports of the repeatability of DRS values. There is only one report of the comparability of PDlOFEV 1 measured using histamine and methacholine as provoking agents in a population sample of adults (18), al338
SUMMARY To measure the repeatability of the bronchial challenge test and the comparability of histamine and methacholine as provoking agents, we studied a population sample of children and conducted histamine bronchial challenge tests on each of 3 consecutive day8 followed by a methacholine bronchial challenge on the fourth day. Bronchial responslvene.. was measured using the rapid Inhalation method. A total of 393 children had satisfactory bronchial challenge data for all 4 days. The measurements derived from the dose-response curve were the PD20 FEY1, which was measured as the provoking dose causing a 20% fall In FEY1, and the dose-response slope (DRS), which . .s measured as the percentage fall In FEY1 at final doseltotal dose administered. Children who had a PD20 FEY1 were categorized as having bronchial hyperresponslveness (BHR). The percentage of children with BHR each day was between 7 and 11. One-third of the children with BHR reacted only to histamine or methacholine. The within-subject range for histamine PD20 FEY1 values compared with methacholine suggested that histamine and methacholine are not directly comparable bronchial challenge agents. The dose-response slope values, which could be obtained for all children, had slightly bettar repeatability than PD20 FEY1 values. Because DRS values obtain data for the entire sample, have good repeatability, and are equally repeatable In children with normal responslvene.. or bronchial hyperresponslvene... they should prove more useful than PD20 FEY1 values AM REV RESPIR DIS 1911; 144:338-343 for measuring bronchial ...sponalvene.. In populations.
though comparisons in the clinic have chial responsiveness measured on each of 4 shown that the two agents are equipo- consecutive days. Each day,children wererandomly allocated to one of three operators. tent in asthmatic subjects (19-21). . Operators did not have access to results of We have studied a population sample of children with histamine bronchial previous tests. Lung function was measured by a Vitalograph'" dry spirometer (Vitalochallenge tests on each of 3 consecutive graph, Buckingham, UK), with the child days, followed by a methacholine bron- standing. Forced expiratory maneuvers were chial challenge test on the fourth day. In repeated until two tracings ofFEV1 reproducthis paper, we report the repeatability of ible to 100 ml were obtained. Measurements PDlO FEV 1 and DRS values using hista- were corrected to BTPS. Bronchial responsiveness was measured mine challenge, and we examine the equivalence of histamine and methacho- using the rapid method (1). Children who had line'as provoking agents in the measurement of bronchial responsiveness. Methods
Population The study was conducted in spring (September/October) 1988.The target population was all children in the third and fourth grades at seven primary schools in Villawood, a western suburb of Sydney, New South Wales. Informed consent was obtained from all parents who agreed for their children to be studied. The methods used for data collection have been described previously in detail (2, 4, 5) and are summarized here.
Lung Function and Bronchial Responsiveness All subjects had their lung function and bron-
(Received in original form July 13, 1990 and in revised form February 25, 199/)
1 From the Departments of Medicine and Public Health, University of Sydney, and the Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. 2 Supported by the National Health and Medical Research Council of Australia, the Asthma Foundation of New South Wales, the Bankstown City Council, the Health Department of New South Wales, and the Community Health and AntiTuberculosis Association. 3 Correspondence and requests for reprints should be addressed to Professor A. J. Woolcock, Institute of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050 Australia.
REPEATABILITY OF HISTAMINE BRONCHIAL CHALLENGE AND COMPARABILITY WITH METHACHOLINE
taken a l3-sympathomimetic aerosol within 6 h or theophylline compounds within 12 h were asked to withhold further medication and to return at least 4 h later. The challenge tests were carried out with increasing doses of histamine from 0.03 to 7.8 umol histamine, or of methacholine from 0.05 to 12.2 umol, delivered from solutions of 3.13,6.25,25, and 50 mg/ml for each agent. The test was halted if there was a fall in FEV 1 of 20070 or greater or if all histamine dose steps to 7.8 umol or methacholine steps to 12.2 umol had been administered. Salbutamol aerosol was administered to aid recovery when necessary. A dose-response curve was obtained from each challenge by plotting the percentage change in FEV 1 from the postsaline value against the logarithm of the dose of agonist. From this curve the dose of histamine or methacholine that caused a 10% fall in FEV 1 (POlO FEV 1) and a 20070 fall in FEV1 (POlO FEV 1) were read. Children with a 20070 fall at less than 7.8 umol histamine or 7.8 umol methacholine were classified as having BHR on that day. The dose-response slope was calculated as a percentage fall in final FEV 1 from baseline divided by the total dose of agonist administered (figure 1). Because many children had an FEV 1 that remained stable or slightly improved during the challenge, a value of 1.0 was added to all ORS values as the minimum value required to eliminate zero and negative slopes and therefore to allow conversion to logarithms.
each challenge, together with their mean FEV land PD1 0 FEV 1 values, is shown in table 2. The prevalenceof children with 30 BHR (a PD1 0 FEV l less than 7.8 umol