Influence of outdoor temperature and humidity on the methacholine challenge test

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<ul><li><p>ORIGINAL PAPER</p><p>Influence of outdoor temperature and humidityon the methacholine challenge test</p><p>Bruno Sposato Marco Scalese </p><p>Andrea Pammolli Carlo Pareo Raffaele Scala</p><p>Received: 21 February 2012 / Accepted: 18 July 2012 / Published online: 1 August 2012</p><p> Springer Science+Business Media B.V. 2012</p><p>Abstract Objective of this study was to evaluate</p><p>whether outdoor temperature and humidity can influ-</p><p>ence methacholine test results in outpatients living in</p><p>temperate areas. 4,723 subjects (2,391 males; age:</p><p>35.1 16.15; FEV1 = 100.36 % [relative interquar-</p><p>tile range (IQR):92.34108.8]) that performed metha-</p><p>choline tests for suspected asthma between 2000 and</p><p>2010 were considered. Outdoor minimum, mean, and</p><p>maximum temperature values (C), relative humidity(%), and dew point (Tdp), registered when performing</p><p>the tests, were examined. Airways hyperresponsive</p><p>patients, with PD20 (provocative dose to obtain a 20 %</p><p>fall in FEV1) \3,200 lg were 2,889 (61.2 %) andmedian PD20 was 359 lg [IQR:160-967]. On receivingoperating curve (ROC) analysis, temperature, humidity,</p><p>and Tdp did not significantly predict airways hyperre-</p><p>sponsiveness (AHR), even using a 200, 800, and</p><p>3,200 lg cutoffs to identify AHR. When subjects weresubdivided into subgroups, according to different levels</p><p>of temperature, humidity, and dew point, no differences</p><p>in PD20 and prevalence were found. Only a higher</p><p>number of hyperresponsive subjects was detected in</p><p>smokers when they were tested in hot and humid</p><p>conditions. A weak but significantly positive relation-</p><p>ship between PD20 and mean, maximum, and minimum</p><p>temperatures was detected in severe hyperresponsive</p><p>subjects (PD20 \ 200 lg) (r = 0.100, 0.112, 0.110,respectively; p = 0.001). The regression logistic model</p><p>showed that maximum temperature was a significantly</p><p>protective factor for AHR (OR:0.995, 95 % CI:</p><p>0.9820.998; p = 0.012) especially in severe hyperre-</p><p>sponsive subjects (OR:0.988, 95 % CI: 0.9770.999;</p><p>p = 0.035). In conclusion, weather conditions do not</p><p>seem to influence PD20 values obtained with metha-</p><p>choline tests in real life. Hot and humid environments</p><p>may increase the prevalence of AHR in smokers while a</p><p>temperature increase may reduce the AHR risk espe-</p><p>cially in severe hyperresponsive subjects.</p><p>This article was presented at Amsterdam 2011 Congress of</p><p>European Respiratory Society as Poster presentation (number</p><p>P4049) in Thematic Poster Session on 09/27/2011 and</p><p>published only as an Abstract in Abstract book: Eur Respir J</p><p>2011; 38: Suppl. 55, 739 s. However, this manuscript has never</p><p>been submitted in this form for publication elsewhere. The</p><p>authors alone are responsible for the contents and writing of the</p><p>paper.</p><p>B. Sposato (&amp;)Unit of Pneumology, Misericordia Hospital,</p><p>Via Senese 161, 58100 Grosseto, Italy</p><p>e-mail: bsposat@tin.it</p><p>M. Scalese</p><p>Institute of Clinical Physiology, National Research</p><p>Council (CNR), Pisa, Italy</p><p>A. Pammolli</p><p>Department of Physiopathology, Experimental Medicine</p><p>and Public Health University of Siena, Siena, Italy</p><p>C. Pareo</p><p>Unit of Pneumology, Carlo Urbani Hospital, Jesi, Italy</p><p>R. Scala</p><p>Unit of Pneumology and UTIP, S.Donato Hospital,</p><p>Arezzo, Italy</p><p>123</p><p>Aerobiologia (2013) 29:187200</p><p>DOI 10.1007/s10453-012-9272-0</p></li><li><p>Keywords Airway hyperresponsiveness Temperature Humidity Methacholine test Asthma Environment</p><p>1 Introduction</p><p>Asthma is a chronic inflammatory disease of the</p><p>airways characterized by bronchial obstruction, often</p><p>reversible either spontaneously or with treatment. It is</p><p>also characterized by airways hyperresponsiveness</p><p>(AHR) that can be defined as an exaggerated airways</p><p>obstructive response to a variety of pharmacological,</p><p>chemical, and physical stimuli (histamine, methacho-</p><p>line, cold air, etc.) (ATS 2000). In subjects with</p><p>suspected symptoms of asthma and a normal baseline</p><p>spirometry without a significant increase in lung</p><p>function after inhaling bronchodilators, it is often</p><p>necessary to perform a methacholine challenge test to</p><p>detect AHR and therefore to confirm a diagnosis of</p><p>asthma. In case the provocative dose or concentration</p><p>(PD20 or PC20) of methacholine required to obtain a</p><p>20 % fall in forced expiratory volume in one second</p><p>(FEV1) is lower after the test, the possibility that the</p><p>suggestive symptoms may be due to asthma is high,</p><p>whereas this probability is low if PD20 or PC20 values</p><p>are higher (ATS 2000). AHR seems to be character-</p><p>ized by seasonal variations according to the changes in</p><p>seasonal exposition to various allergens (pollens and</p><p>house dust mites) (Tilles and Bardana 1997). In fact, a</p><p>higher exposure to house dust mites in autumn, when</p><p>they increase in number, or to a greater quantity of</p><p>pollens in spring, seems to increase AHR in subjects</p><p>with rhinitis or asthma (Riccioni et al. 2001; van der</p><p>Heide et al. 1997; Beier et al. 2003). Also, respiratory</p><p>infections, especially in cold seasons, might increase</p><p>hyperresponsiveness in asthmatics (Busse 1990), thus</p><p>influencing AHR variability.</p><p>On the contrary, it is not clear whether temperature</p><p>and humidity may have a direct influence on AHR.</p><p>Extreme values of temperature and humidity and a</p><p>prolonged exposure to them may determine AHR</p><p>variations (Helenius et al. 1996; Langdeau et al. 2000;</p><p>Bougalt et al. 2010). In fact, some studies highlighted</p><p>how AHR prevalence, induced by methacholine, was</p><p>higher in athletes that inhaled cold and humid air during</p><p>training in comparison with those that performed</p><p>training in environments with either dry air or a mixture</p><p>of dry and humid air (Hemingson et al. 2004; Langdeau</p><p>et al. 2000; Bougalt et al. 2010). Furthermore, very high</p><p>and very low values of humidity (95 %) and temper-</p><p>ature (-18 C), respectively, can increase exercise-induced bronchoconstriction (Stensrud et al. 2006,</p><p>2007). However, these conclusions were drawn after</p><p>studying athletes and not common people; furthermore,</p><p>these subjects were often studied only in extreme</p><p>environmental conditions, and sometimes, results were</p><p>obtained in artificial indoor environments and only with</p><p>exercise challenge testing. On the other hand, a non-</p><p>extreme temperature and humidity seem to influence</p><p>weakly exercise-induced AHR (Koh and Choi 2002)</p><p>but not methacholine- or histamine-induced AHR (Koh</p><p>and Choi 2002; Schmidt and Bundgaard 1986; Tessier</p><p>et al. 1988) in subjects with asthma who are not athletes.</p><p>However, these studies were carried out on few patients</p><p>and therefore there are still doubts whether exposure to</p><p>normal range of outdoor temperature and humidity,</p><p>which alternate during the seasons, may influence</p><p>AHR. Especially, we do not know if a methacholine</p><p>challenge test results may be differently influenced by a</p><p>higher or lower value of environmental outdoor tem-</p><p>perature and/or humidity to which a subject is exposed</p><p>before the test. Therefore, the aim of this study was to</p><p>evaluate whether the results of a methacholine chal-</p><p>lenge test can be influenced by different daily outdoor</p><p>temperature and humidity values when the test is</p><p>performed on a large number of outpatients living in</p><p>temperate climates where temperature and humidity</p><p>never reach extreme values.</p><p>2 Materials and methods</p><p>2.1 Study design and subjects</p><p>For this retrospective study, we took out from the</p><p>spirometer data files of our pneumology departments</p><p>of Grosseto and Arezzo (Tuscany, Italy) and analyzed</p><p>the results of 5,023 consecutive methacholine chal-</p><p>lenge tests performed between 2000 and 2010. All</p><p>tests were carried out to confirm or exclude an asthma</p><p>diagnosis. In fact, all patients had suspected asthma</p><p>symptoms (unexplained episodes of cough and/or</p><p>wheezing and/or dyspnea) with a normal spirometry</p><p>and therefore, for this reason, they were subjected to a</p><p>methacholine challenge test. For every test, FEV1,</p><p>FEV1/FVC, forced vital capacity (FVC), PD20FEV1,</p><p>smoking habits, and body mass index (BMI) were</p><p>188 Aerobiologia (2013) 29:187200</p><p>123</p></li><li><p>considered. Also, minimum, medium, and maximum</p><p>values of temperature (T), relative humidity (H), and</p><p>temperature dew point (Tdp), measured on the days</p><p>when the tests were performed, were also taken into</p><p>account. The purpose was to relate T, H, and Tdp with</p><p>the results of the methacholine tests measured on the</p><p>same date.</p><p>Only 4,723 consecutive subjects (2,391 M; mean</p><p>age 35.1 16.17; median FEV1 % 100.36 [IQR:92.24</p><p>108.75] and FEV1/FVC 86.33 [IQR:81.590.88])</p><p>were suitable for the study. Three hundred subjects</p><p>were excluded. Most of them had not completed the</p><p>challenge: some were intolerant to testing and others</p><p>had interrupted the test because they had shown a fall</p><p>in FEV1 [ 10 % with buffer solution. One hundredand three subjects were not considered because the</p><p>temperature and humidity on the day when the test was</p><p>carried out were not known. Only the first challenge of</p><p>those few who had repeated the test several times was</p><p>taken into consideration.</p><p>These subjects were subdivided into subgroups on</p><p>the basis of the PD20 value, sex, age, smoking habits,</p><p>and BMI, in order to evaluate possible effects of</p><p>temperature and humidity on the above said catego-</p><p>ries. Unfortunately, allergic sensitizations in the</p><p>subjects recruited for this study were not recorded</p><p>and therefore these were not available. BMI value of</p><p>25 was used as a cutoff to subdivide subjects with</p><p>normal weight or underweight (BMI \ 25) fromoverweight or obese subjects (BMI [ 25). Interna-tional cutoff points for BMI, to assess overweight and</p><p>obese children, were used to subdivide subjects with</p><p>age\18 years into underweight normal or overweightobese (Cole et al. 2000).</p><p>The methacholine test was put off for at least 4 weeks</p><p>when subjects had shown an exacerbation of symptoms</p><p>or an airway infection. B2-agonist bronchodilators werenot taken 24 h before the test, whereas inhaled or</p><p>systemic corticosteroids were suspended 3 weeks</p><p>before performing it. Antihistamines were also sus-</p><p>pended at least 10 days before the challenge test. The</p><p>use of the data recorded in each spirometer, which were</p><p>necessary for this study and its protocol, was approved</p><p>by the local ethical committees.</p><p>2.2 Methacholine challenge testing</p><p>The challenge test was performed by using a dosimeter</p><p>method (Chai et al. 1975). The same kind of</p><p>instrument and method was used in Grosseto and</p><p>Arezzo from 2000 to 2010. Methacholine sulfate was</p><p>provided by Lofarma (Milan, Italy) and administered</p><p>in aerosol form using an MEFAR MB3 dosimeter</p><p>(output: 9 ll/puff; MEFAR Elettromedicali Brescia,Italy) with an MB2 ampoule model. Buffer and</p><p>methacholine were diluted with distilled water and</p><p>then two different progressive methacholine solutions</p><p>were prepared for the test: an ampoule with a</p><p>methacholine concentration of 4 mg/ml (40 lg inha-lation dose) and another with a concentration of</p><p>40 mg/ml (400 lg inhalation dose). The buffer solu-tion was administered first, followed by 40 lg ofmethacholine, increasing the doses step by step until</p><p>PD20FEV1 was obtained or until the maximum dose of</p><p>muscarinic agonist was reached. FEV1 was measured</p><p>after administering 40, 80, 120, 240, 400, 800, 1,600,</p><p>2,400, and 3,200 lg of cumulative methacholinedoses. At the end of exhalation during tidal breathing,</p><p>patients inhaled methacholine slowly and deeply from</p><p>the nebulizer in 5 s and then held their breaths for 5</p><p>more seconds. The test was interrupted if a fall in</p><p>FEV1 [ 10 % was obtained with the buffer solution.The time interval between the two steps was 2 min,</p><p>calculated from the start of one step to the next. FEV1was measured at 30 and 90 s after nebulization. An</p><p>acceptable quality FEV1 was obtained at each step. No</p><p>more than two maneuvers after each dose were</p><p>performed and the highest FEV1 value was taken into</p><p>account. AHR was defined by a 20 % fall in FEV1following a challenge test with a cumulative metha-</p><p>choline dose\3,200 lg. Subjects who did not achievea 20 % fall in FEV1 with a methacholine dose of</p><p>3,200 lg were considered normal.All AHR subjects with PD20 B 200, 200 \ PD20 B</p><p>800, and PD20 [ 800 were arbitrarily consideredaffected by severe, moderate, and mild AHR with</p><p>the purpose of evaluating the effects of temperature</p><p>and humidity on the different levels of AHR.</p><p>FEV1 was measured before and during the chal-</p><p>lenge test using a spirometer HP 47120E Pulmonary</p><p>System Desk (Hewlett Packard, Waltham, Massachu-</p><p>setts, USA). PD20 FEV1 was calculated by linear</p><p>interpolation of the doseresponse curves. The FEV1measured before inhaling the buffer solution was</p><p>considered as the baseline value, whereas the FEV1measured after the buffer solution was used as the</p><p>referral to calculate FEV1 decrease and thus the PD20value. FEV1 and FVC were expressed as percentages of</p><p>Aerobiologia (2013) 29:187200 189</p><p>123</p></li><li><p>the predicted value, whereas FEV1/FVC was reported</p><p>only as a ratio (reference equation: CECA, 1971).</p><p>2.3 Assessing temperature and humidity values</p><p>Data concerning daily temperature, relative humidity,</p><p>and Tdp observed between 2000 and 2010 were</p><p>measured in the Italian Air Force meteorological</p><p>stations of Grosseto (coordinate: WMO 16206; ICAO</p><p>LIRS; LAT 42.75; LON 11.07; H 7m) and Arezzo</p><p>(coordinate: WMO 16172; ICAO LIQB; LAT 43.47;</p><p>LON 11.85; H 249m) airports. All data were kindly</p><p>provided by the Meteorology National Centre of the</p><p>Italian Air Force where they were recorded (Airport</p><p>M. DE BERNARDI, Pratica di Mare, Pomezia,</p><p>ROME; http//www.meteoam.it). Temperature and Tdpwere considered in C, whereas relative humidity wasin percentage. Data concerning temperature, humidity,</p><p>and Tdp, recorded on that particular day, were associ-</p><p>ated to the methacholine test results performed on the</p><p>same date. We considered the daily average, minimum</p><p>and maximum temperatures, relative humidity, and Tdpvalues on each day the test was performed. With the</p><p>purpose of evaluating the combined effects of tem-</p><p>perature and relative humidity on hyperresponsiveness</p><p>prevalence and PD20, different arbitrary mean levels of</p><p>temperature and humidity (T B 10 C, T [ 10 C andB20 C, T [ 20 C; H B 60 %, H [ 60 % andB80 %, H [ 80 %) were used to subdivide subjectsinto subgroups. Also, for Tdp, different arbitrary cutoff</p><p>values were used to assess a probable influence on the</p><p>prevalence of AHR and PD20 (Tdp B 5 C, Tdp [ 5and B12 C and Tdp [ 12 C).</p><p>2.4 Statistical analysis</p><p>Categorical variables are expressed as percentages.</p><p>Continuous variables that had a normal distribution</p><p>are expressed as mean values, accompanied by their</p><p>standard deviations. All continuous variables that had</p><p>a non-normal distribution are expressed as median</p><p>values, accompanied by their relative interquartile</p><p>range (IQR25 and 75 quartiles). Comparisonsbetween groups were made with the chi-square and</p><p>KruskalWallis tests, where appropriate. Associations</p><p>between continuous variables are expressed as Pear-</p><p>son correlations.</p><p>The influence of temperature, humidity, and Tdpwas assessed by the receiving operating curve (ROC),</p><p>being the area under the curve equal to the probability</p><p>to discriminate from the risk of being or not being</p><p>hyperresponsive, identified by three different cutoffs</p><p>(\ or [3200, \ or [800, \ or [200 lg).Logisti...</p></li></ul>

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