Anderson, K.

Cameron, E.J.

Chaudhuri, R.

Donnelly, I.

Evans, T.J.

Gallacher, K.

Greenlaw, N.

Jolly, L.

Mair, F.

McSharry, C.

Morrison, D.

Spears, M.

Thomson, N.C

Weir, C.J.

European Respiratory Journal

English

PubMed

Cameron, Euan J.

Chaudhuri, Rekha

Mair, Frances

McSharry, Charles

Greenlaw, Nicola

Weir, Christopher J.

Jolly, Lisa

Donnelly, Iona

Gallacher, Katie

Morrison, Deborah

Spears, Mark

Evans, Tom J.

Anderson, Kenneth

Thomson, Neil C.

Discovery Research Portal

                                                                    University of DundeeRandomised controlled trial of azithromycin in smokers with asthmaCameron, Euan J.; Chaudhuri, Rekha; Mair, Frances; McSharry, Charles; Greenlaw, Nicola;Weir, Christopher J.Published in:European Respiratory JournalDOI:10.1183/09031936.00093913Publication date:2013Licence:CC BY-NCDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Cameron, E. J., Chaudhuri, R., Mair, F., McSharry, C., Greenlaw, N., Weir, C. J., Jolly, L., Donnelly, I.,Gallacher, K., Morrison, D., Spears, M., Evans, T. J., Anderson, K., & Thomson, N. C. (2013). Randomisedcontrolled trial of azithromycin in smokers with asthma. European Respiratory Journal, 42(5), 1412-1415.https://doi.org/10.1183/09031936.00093913General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 19. Apr. 2023Randomised controlled trial ofazithromycin in smokers with asthmaTo the Editor:Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuatedresponse to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need foralternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolideantibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy inthe treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection afterlung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchialhyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma[7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokerswith asthma.A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for12 weeks. All subjects were aged 18–70 years, were current smokers (o5 pack-years history) with chronicasthma (.1 year duration; defined by international criteria [8]) and had to be free of exacerbation andrespiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit wasperformed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 mgbeclometasone ¡ a long-acting b2-agonist (LABA). Ethical approval was obtained and all subjects providedwritten informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratoryflow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 was calculatedto have an 80% power to detect a mean difference of 25 L?min-1 in change from baseline to 12 weeks inmorning PEF, the primary end-point [9], assuming a standard deviation of changes of 36 L?min-1 using atwo-sample t-test with a 5% two-sided significance level. Recruitment of 80 patients was planned to ensurethat 68 patients completed the study. 77 subjects were randomised with 71 completing the study. Othermeasures of airway responsiveness PC20 (provocation concentration of methacholine causing a 20% fall inforced expiratory volume in 1 s (FEV1)), inflammation (exhaled nitric oxide fraction at 50 mL?s-1 (FeNO50)/induced sputum/blood and sputum supernatant biomarkers), symptom control (Asthma ControlQuestionnaire (ACQ) [10] and Leicester Cough Questionnaire (LCQ) [11]) and quality of life (AsthmaQuality of Life Questionnaire (AQLQ) [10]) were assessed during the study. PEF was recorded using Piko-1electronic peak flow meters (nSpire, Hertford, UK) and symptoms were recorded in a validated diary card[10]. Bacteriological and virological analysis of induced sputum was also undertaken. All statistical testswere two-sided and used a significance level of 5%. All data was analysed using SAS (version 9.2; SASInstitute, Cary, NC, USA). QTc was also measured at baseline and 12 weeks.Baseline demographic data and clinical characteristics of the patients were comparable and the two groupswere well balanced. Placebo versus azithromycin groups: age 42.8¡9.4 years versus 46.4¡8.8 years; malesex 17 (44.7%) versus 20 (51.3%); smoking history 23.6¡15.8 pack-years versus 28.6¡16.4 pack-years;duration of asthma 24.6¡12.6 years versus 18.8¡12.5 years; atopic 23 (60.1%) versus 27 (69.2%); median(interquartile range) total IgE 103 (38–291) IU?mL-1 versus 165 (48–254) IU?mL-1; use of ICS at screening31 (81.6%) versus 35 (89.7%); equivalent beclomethasone dose at screening 709¡564 mg versus603¡457 mg; use of LABA at randomisation 18 (47.4%) versus 15 (38.5%); pre-bronchodilator FEV181.0¡16.8% predicted versus 78.3¡16.4% pred; post-bronchodilator FEV1 89.0¡15.1% pred versus86.8¡15.2% pred; FEV1 11.3¡9.8% reversibility versus 12.3¡10% reversibility; geometric mean PC201.06¡4.10 mg?mL-1 versus 1.07¡3.13 mg?mL-1.At the final study visit (12 weeks) the change in mean morning clinic PEF (primary outcome), as comparedwith baseline, did not differ substantially between the azithromycin and placebo treatment groups (meandifference -10.3 (95% CI 47.1–26.4 L?min-1), p50.58) (table 1). There was no difference in either pre- orpost-albuterol FEV1 at 4, 8 or 12 weeks between the two groups (table 1). No differences were evident forPC20 (baseline to 12 week comparison) between the azithromycin or placebo groups (table 1). None of theself-reported diary card recordings (ACQ, AQLQ or LCQ score) demonstrated any significant differencesbetween the two groups at 4, 8 or 12 weeks. Noninvasive measures of inflammation, i.e. induced sputum,sputum supernatant cytokines, peripheral blood cytokines and FeNO50, did not demonstrate any substantialimprovements after 12-weeks of treatment with azithromycin (table 1). Bacterial colony counts did notLETTERS1412TABLE1ClinicaloutcomesandsputumcellcountsafterazithromycintreatmentorplaceboVariablesBaseline4weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)8weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)12weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)PlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinMorningclinicPEFL?min-1411.1¡124.3390.5¡114.5412.9¡110.6384.2¡143.5-4.2(-30.6–22.2),p50.75406.0¡120.4394.6¡150.71.2(-28.1–30.5),p50.94416.7¡122.7394.2¡156.3-10.3(-47.1–26.4),p50.58FEV1pre-albuterolL2.54¡0.772.43¡0.722.48¡0.742.37¡0.760.08(-0.06–0.23),p50.252.47¡0.772.42¡0.750.03(-0.08–0.14),p50.552.46¡0.752.41¡0.770.03(-0.08–0.14),p50.62FEV1post-albuterolL2.80¡0.802.68¡0.732.73¡0.722.59¡0.740.04(-0.08–0.17),p50.502.72¡0.802.68¡0.740.04(-0.04–0.12),p50.342.70¡0.792.66¡0.770.04(-0.06–0.14),p50.41Relieverinhalerpuffsper24h2.8¡2.92.9¡4.42.5¡2.73.1¡4.4-0.1(-0.8–0.6),p50.782.5¡2.62.4¡2.80.3(-0.5–1.0),p50.502.7¡2.53.0[4.0-0.3(-1.3–0.7),p50.557-pointACQscore1.76¡0.881.73¡0.741.64¡0.901.74¡0.850.12(-0.18–0.42),p50.431.69¡1.031.86¡0.990.21(-0.14–0.55),p50.231.58¡0.961.75¡0.830.21(-0.11–0.53),p50.20logPC20mg?mL-10.07¡1.140.06¡1.41NDNDNDND0.19¡1.290.20¡1.52-0.02(-0.49–0.45),p50.93TotalLCQscore16.90¡3.4916.31¡3.53NDNDNDND17.51¡3.5516.01¡3.02-1.06(-2.16–0.05),p50.06TotalAQLQscore5.09¡0.995.25¡1.18NDNDNDND5.42¡1.315.20¡1.06-0.31(-0.69–0.07),p50.11FeNO50ppb15.6¡21.211.5¡8.9NDNDNDND16.2¡20.111.0¡7.9-1.94(-5.97–2.10),p50.34Totalsputumcellcount6104644¡240626¡245NDNDNDND714¡326668¡2111.0(0.9–1.2),p50.75Neutrophil6104150¡123172¡103NDNDNDND141¡96162¡9719.2(-24.2–62.6),p50.38Neutrophil%33.1¡24.339.0¡22.5NDNDNDND31.0¡19.934.4¡18.63.0(-5.9–11.8),p50.50Eosinophil61044.9¡6.46.9¡9.3NDNDNDND6.8¡13.910.3¡20.11.0(0.5–2.0),p50.89Eosinophil%1.1¡1.51.6¡2.3NDNDNDND1.5¡3.11.6¡3.0-0.4(-1.8–1.0),p50.55Dataarepresentedasmean¡SD,unlessotherwisestated.PEF:peakexpiratoryflowrate;FEV1:forcedexpiratoryvolumein1s;ACQ:AsthmaControlQuestionnaire;PC20:provocationconcentrationofmethacholinecausinga20%fallinFEV1;LCQ:LeicesterCoughQuestionnaire;AQLQ:AsthmaQualityofLifeQuestionnaire;FeNO50:exhalednitricoxidefractionat50mL?s-1;ND:notdone.#:treatmentdifferencefromANCOVAanalysingchangefrombaselineandadjustingforbaselinevalue.1413demonstrate any treatment difference between the placebo and azithromycin groups (p50.66, data notshown). PCR for Mycoplasma pneumonia and Chlamydophila pneumoniae were negative at both baselineand 12 weeks. QTc was unchanged following 12 weeks of treatment with azithromycin.No suspected unexpected serious adverse events occurred during the reporting period of the study.Compliance assessed by capsule count was .90% in each group.In the first randomised controlled study of azithromycin in smokers with asthma we found that there wereno clinically important improvements in both the primary end-point and morning PEF, and in a range ofsecondary clinical outcomes including ACQ score, AQLQ score, spirometry and airway responsiveness, aswell as measures of airway inflammation after 12 weeks of treatment. The median ACQ score of theparticipants recruited to the study was raised at 1.7 indicating that they had poorly controlled disease andscope for clinical improvement. We believe that the choice of a different macrolide from azithromycin or adifferent dose of azithromycin is unlikely to have altered our findings. This study was powered to test thehypothesis on the primary end-point, PEF. We exceeded our minimum recruitment target ensuringadequate numbers completed the study. The lack of response to treatment was such that recruiting greaternumbers would be unlikely to affect either the primary end-point or the majority of secondary analyses.Taken together these findings indicate that short-term therapy with azithromycin does not improve lungfunction or other indices of current asthma control of smokers with mild-to-moderate asthma who are alreadyreceiving treatment with inhaled corticosteroids. This is supported by a recent study where 6 months oftreatment with azithromycin in nonsmokers with severe asthma did not improve lung function [7].Recently published data reported that azithromycin administered over 1 year reduced the rate ofexacerbations in chronic obstructive pulmonary disease (COPD), although this benefit was not found incurrent smokers with COPD, and bronchiectasis was not an exclusion [12, 13]. Moreover, a 6-month studywith azithromycin in nonsmokers with severe asthma powered to measure exacerbation frequency did notfind any statistical difference between treatment and placebo groups [7], although a beneficial effect ofazithromycin on reducing exacerbations was reported in patients with non-eosinophilic asthma [7]. Thesmokers with asthma in our study had non-eosinophilic asthma, but did not respond to azithromycin,although the duration of treatment was not long enough to assess the effects of azithromycin on exacerbations.In conclusion, we have studied the effects of 12 weeks of azithromycin in smokers with asthma, anunderstudied patient group, and provide clear evidence demonstrating lack of efficacy in both clinical andlaboratory outcomes. Further randomised clinical trials exploring new therapies in smokers with asthmawho are unable to stop smoking are required.@ERSpublicationsDaily azithromycin is ineffective in improving indices of asthma control and airway inflammationin smokers with asthma http://ow.ly/nQjynEuan J. Cameron1, Rekha Chaudhuri1, Frances Mair2, Charles McSharry1, Nicola Greenlaw3, Christopher J. Weir3,Lisa Jolly1, Iona Donnelly1, Katie Gallacher2, Deborah Morrison2, Mark Spears1, Tom J. Evans1, Kenneth Anderson4and Neil C. Thomson11Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, 2General Practice and PrimaryCare, Institute of Health and Wellbeing, University of Glasgow, Glasgow, 3Robertson Centre for Biostatistics, Universityof Glasgow, Glasgow, and 4Respiratory Medicine, Crosshouse Hospital, Kilmarnock, UK.Correspondence: N.C. Thomson, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir GraemeDavies Building, 120 University Place, Glasgow, G12 8TA, UK. E-mail: neil.thomson@glasgow.ac.ukReceived: June 03 2013 | Accepted after revision: July 10 2013Support statement: This work was funded by the Medical Research Council UK and supported financially by NHSResearch Scotland (NRS), through the Scottish Primary Care Research Network; study medication (budesonide Easyhalers;Orion Pharma (UK), Newbury, UK) was purchased with an educational grant from AstraZeneca (London, UK).Clinical trial: This study is registered at www.Clinicaltrials.gov with identifier number NCT00852579.Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.comReferences1 Thomson N, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med 2009; 15: 39–45.2 Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013; 41: 716–726.3 Cameron EJ, McSharry C, Chaudhuri R, et al. Long-term macrolide treatment of chronic inflammatory airwaydiseases: risks, benefits and future developments. Clin Exp Allergy 2012; 42: 1302–1312.4 Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treatment for chronic respiratory disease. Eur Respir J 2013;42: 239–251.14145 Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronicrejection after lung transplantation. Eur Respir J 2011; 37: 164–172.6 Sutherland ER, King TS, Icitovic N, et al. A trial of clarithromycin for the treatment of suboptimally controlledasthma. J Allergy Clin Immunol 2010; 126: 747–753.7 Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma(AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329.8 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. GINA, 2010.www.ginasthma.org9 Greening A, Ind P, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients withsymptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219–224.10 Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Societystatement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinicalpractice. Am J Respir Crit Care Med 2009; 180: 59–99.11 Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure for patients withchronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58: 339–343.12 Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365: 689–698.13 Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J2012; 40: 485–494.Eur Respir J 2013; 42: 1412–1415 | DOI: 10.1183/09031936.00093913 | Copyright ERS 2013ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.Use of household cleaning products,exhaled nitric oxide and lung function inchildrenTo the Editor:The application of domestic cleaning agents increases the risk of asthma and respiratory symptoms in adults[1], in particular when products are applied in spray form [2]. Despite the associations observed in adults,the potential effects of passive exposure on children’s respiratory health have not been extensively explored.Analyses of data from birth cohorts have suggested that frequent use of cleaning agents and their use inspray form increased the risk of wheezing and lower respiratory tract infections (LRTIs) during the first yearof life [3, 4] and the risk of persistent wheezing at school age [5, 6]. By contrast, a cross-sectional studyreported protective effects of using bleach at home on the prevalence of asthma and allergic sensitisation atschool age [7]. Our study investigates the effects of the use of 10 common cleaning products on exhalednitric oxide fraction (FeNO) and on lung function (forced vital capacity (FVC) and forced expiratory volumein 1 s (FEV1)) during childhood in a population-based birth cohort in Menorca, Spain [8].Recruitment was performed during pregnancy and 482 children were enrolled at birth. Written informedconsent was obtained from all participants and the study was approved by a committee on ethical practice.Questionnaires on wheezing, asthma, treatment and allergies (rhinitis, eczema or hay fever) wereadministered by the mother repeatedly from birth until the age of 10 years. At the age of 10–13 years, FeNO(NIOX MINO; Aerocrine AB, Solna, Sweden) and forced spirometry (EasyOne; ndd Medical Technologies,Inc., Andover, MA, USA) testing was carried out. In addition, an interviewer-led questionnaire on thefrequency of use of 10 different cleaning products (bleach, ammonia, polishes or waxes, acids, solvents,furniture sprays, glass cleaning sprays, degreasing sprays, air freshening sprays, and air freshening plug-indevices) was carried out. A total of 295 individuals completed the 10-year follow-up visit and the cleaningproducts questionnaire and performed the FeNO and/or the lung function test.For statistical analyses, we computed a combined spray variable incorporating the four sprays (furniture,glass cleaning, degreasing and air freshening sprays) and a semiquantitative total score for cleaning productuse. The means of the reported days of use per week (never50, ,1 day per week50.5, 1–3 days per week52and 4–7 days per week55.5) for each product were summed providing a score ranging from 0 (noexposure) to 55 (exposed to all 10 products used 4–7 days per week). Multivariable linear regression modelswere developed to predict log-transformed FeNO concentration and non-transformed levels of FVC andFEV1. Models were adjusted for sex, age, maternal education, parental smoking indoors, asthmamedication, season of respiratory test measurement, and for height and weight for lung functionmeasurements only. The coefficients obtained from the log-transformed FeNO models were back-transformed1415

Randomised controlled trial of azithromycin in smokers with asthma

Euan J. Cameron

Rekha Chaudhuri

Frances Mair

Charles McSharry

Nicola Greenlaw

Christopher J. Weir

Lisa Jolly

Iona Donnelly

Katie Gallacher

Deborah Morrison

Mark Spears

Tom J. Evans

Kenneth Anderson

Neil C. Thomson

Crossref

Randomised controlled trial of azithromycin in smokers with asthma: Table 1–

                                                                    University of DundeeRandomised controlled trial of azithromycin in smokers with asthmaCameron, Euan J.; Chaudhuri, Rekha; Mair, Frances; McSharry, Charles; Greenlaw, Nicola;Weir, Christopher J.Published in:European Respiratory JournalDOI:10.1183/09031936.00093913Publication date:2013Licence:CC BY-NCDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Cameron, E. J., Chaudhuri, R., Mair, F., McSharry, C., Greenlaw, N., Weir, C. J., Jolly, L., Donnelly, I.,Gallacher, K., Morrison, D., Spears, M., Evans, T. J., Anderson, K., & Thomson, N. C. (2013). Randomisedcontrolled trial of azithromycin in smokers with asthma. European Respiratory Journal, 42(5), 1412-1415.https://doi.org/10.1183/09031936.00093913General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 01. Nov. 2025Randomised controlled trial ofazithromycin in smokers with asthmaTo the Editor:Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuatedresponse to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need foralternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolideantibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy inthe treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection afterlung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchialhyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma[7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokerswith asthma.A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for12 weeks. All subjects were aged 18–70 years, were current smokers (o5 pack-years history) with chronicasthma (.1 year duration; defined by international criteria [8]) and had to be free of exacerbation andrespiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit wasperformed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 mgbeclometasone ¡ a long-acting b2-agonist (LABA). Ethical approval was obtained and all subjects providedwritten informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratoryflow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 was calculatedto have an 80% power to detect a mean difference of 25 L?min-1 in change from baseline to 12 weeks inmorning PEF, the primary end-point [9], assuming a standard deviation of changes of 36 L?min-1 using atwo-sample t-test with a 5% two-sided significance level. Recruitment of 80 patients was planned to ensurethat 68 patients completed the study. 77 subjects were randomised with 71 completing the study. Othermeasures of airway responsiveness PC20 (provocation concentration of methacholine causing a 20% fall inforced expiratory volume in 1 s (FEV1)), inflammation (exhaled nitric oxide fraction at 50 mL?s-1 (FeNO50)/induced sputum/blood and sputum supernatant biomarkers), symptom control (Asthma ControlQuestionnaire (ACQ) [10] and Leicester Cough Questionnaire (LCQ) [11]) and quality of life (AsthmaQuality of Life Questionnaire (AQLQ) [10]) were assessed during the study. PEF was recorded using Piko-1electronic peak flow meters (nSpire, Hertford, UK) and symptoms were recorded in a validated diary card[10]. Bacteriological and virological analysis of induced sputum was also undertaken. All statistical testswere two-sided and used a significance level of 5%. All data was analysed using SAS (version 9.2; SASInstitute, Cary, NC, USA). QTc was also measured at baseline and 12 weeks.Baseline demographic data and clinical characteristics of the patients were comparable and the two groupswere well balanced. Placebo versus azithromycin groups: age 42.8¡9.4 years versus 46.4¡8.8 years; malesex 17 (44.7%) versus 20 (51.3%); smoking history 23.6¡15.8 pack-years versus 28.6¡16.4 pack-years;duration of asthma 24.6¡12.6 years versus 18.8¡12.5 years; atopic 23 (60.1%) versus 27 (69.2%); median(interquartile range) total IgE 103 (38–291) IU?mL-1 versus 165 (48–254) IU?mL-1; use of ICS at screening31 (81.6%) versus 35 (89.7%); equivalent beclomethasone dose at screening 709¡564 mg versus603¡457 mg; use of LABA at randomisation 18 (47.4%) versus 15 (38.5%); pre-bronchodilator FEV181.0¡16.8% predicted versus 78.3¡16.4% pred; post-bronchodilator FEV1 89.0¡15.1% pred versus86.8¡15.2% pred; FEV1 11.3¡9.8% reversibility versus 12.3¡10% reversibility; geometric mean PC201.06¡4.10 mg?mL-1 versus 1.07¡3.13 mg?mL-1.At the final study visit (12 weeks) the change in mean morning clinic PEF (primary outcome), as comparedwith baseline, did not differ substantially between the azithromycin and placebo treatment groups (meandifference -10.3 (95% CI 47.1–26.4 L?min-1), p50.58) (table 1). There was no difference in either pre- orpost-albuterol FEV1 at 4, 8 or 12 weeks between the two groups (table 1). No differences were evident forPC20 (baseline to 12 week comparison) between the azithromycin or placebo groups (table 1). None of theself-reported diary card recordings (ACQ, AQLQ or LCQ score) demonstrated any significant differencesbetween the two groups at 4, 8 or 12 weeks. Noninvasive measures of inflammation, i.e. induced sputum,sputum supernatant cytokines, peripheral blood cytokines and FeNO50, did not demonstrate any substantialimprovements after 12-weeks of treatment with azithromycin (table 1). Bacterial colony counts did notLETTERS1412TABLE1ClinicaloutcomesandsputumcellcountsafterazithromycintreatmentorplaceboVariablesBaseline4weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)8weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)12weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)PlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinMorningclinicPEFL?min-1411.1¡124.3390.5¡114.5412.9¡110.6384.2¡143.5-4.2(-30.6–22.2),p50.75406.0¡120.4394.6¡150.71.2(-28.1–30.5),p50.94416.7¡122.7394.2¡156.3-10.3(-47.1–26.4),p50.58FEV1pre-albuterolL2.54¡0.772.43¡0.722.48¡0.742.37¡0.760.08(-0.06–0.23),p50.252.47¡0.772.42¡0.750.03(-0.08–0.14),p50.552.46¡0.752.41¡0.770.03(-0.08–0.14),p50.62FEV1post-albuterolL2.80¡0.802.68¡0.732.73¡0.722.59¡0.740.04(-0.08–0.17),p50.502.72¡0.802.68¡0.740.04(-0.04–0.12),p50.342.70¡0.792.66¡0.770.04(-0.06–0.14),p50.41Relieverinhalerpuffsper24h2.8¡2.92.9¡4.42.5¡2.73.1¡4.4-0.1(-0.8–0.6),p50.782.5¡2.62.4¡2.80.3(-0.5–1.0),p50.502.7¡2.53.0[4.0-0.3(-1.3–0.7),p50.557-pointACQscore1.76¡0.881.73¡0.741.64¡0.901.74¡0.850.12(-0.18–0.42),p50.431.69¡1.031.86¡0.990.21(-0.14–0.55),p50.231.58¡0.961.75¡0.830.21(-0.11–0.53),p50.20logPC20mg?mL-10.07¡1.140.06¡1.41NDNDNDND0.19¡1.290.20¡1.52-0.02(-0.49–0.45),p50.93TotalLCQscore16.90¡3.4916.31¡3.53NDNDNDND17.51¡3.5516.01¡3.02-1.06(-2.16–0.05),p50.06TotalAQLQscore5.09¡0.995.25¡1.18NDNDNDND5.42¡1.315.20¡1.06-0.31(-0.69–0.07),p50.11FeNO50ppb15.6¡21.211.5¡8.9NDNDNDND16.2¡20.111.0¡7.9-1.94(-5.97–2.10),p50.34Totalsputumcellcount6104644¡240626¡245NDNDNDND714¡326668¡2111.0(0.9–1.2),p50.75Neutrophil6104150¡123172¡103NDNDNDND141¡96162¡9719.2(-24.2–62.6),p50.38Neutrophil%33.1¡24.339.0¡22.5NDNDNDND31.0¡19.934.4¡18.63.0(-5.9–11.8),p50.50Eosinophil61044.9¡6.46.9¡9.3NDNDNDND6.8¡13.910.3¡20.11.0(0.5–2.0),p50.89Eosinophil%1.1¡1.51.6¡2.3NDNDNDND1.5¡3.11.6¡3.0-0.4(-1.8–1.0),p50.55Dataarepresentedasmean¡SD,unlessotherwisestated.PEF:peakexpiratoryflowrate;FEV1:forcedexpiratoryvolumein1s;ACQ:AsthmaControlQuestionnaire;PC20:provocationconcentrationofmethacholinecausinga20%fallinFEV1;LCQ:LeicesterCoughQuestionnaire;AQLQ:AsthmaQualityofLifeQuestionnaire;FeNO50:exhalednitricoxidefractionat50mL?s-1;ND:notdone.#:treatmentdifferencefromANCOVAanalysingchangefrombaselineandadjustingforbaselinevalue.1413demonstrate any treatment difference between the placebo and azithromycin groups (p50.66, data notshown). PCR for Mycoplasma pneumonia and Chlamydophila pneumoniae were negative at both baselineand 12 weeks. QTc was unchanged following 12 weeks of treatment with azithromycin.No suspected unexpected serious adverse events occurred during the reporting period of the study.Compliance assessed by capsule count was .90% in each group.In the first randomised controlled study of azithromycin in smokers with asthma we found that there wereno clinically important improvements in both the primary end-point and morning PEF, and in a range ofsecondary clinical outcomes including ACQ score, AQLQ score, spirometry and airway responsiveness, aswell as measures of airway inflammation after 12 weeks of treatment. The median ACQ score of theparticipants recruited to the study was raised at 1.7 indicating that they had poorly controlled disease andscope for clinical improvement. We believe that the choice of a different macrolide from azithromycin or adifferent dose of azithromycin is unlikely to have altered our findings. This study was powered to test thehypothesis on the primary end-point, PEF. We exceeded our minimum recruitment target ensuringadequate numbers completed the study. The lack of response to treatment was such that recruiting greaternumbers would be unlikely to affect either the primary end-point or the majority of secondary analyses.Taken together these findings indicate that short-term therapy with azithromycin does not improve lungfunction or other indices of current asthma control of smokers with mild-to-moderate asthma who are alreadyreceiving treatment with inhaled corticosteroids. This is supported by a recent study where 6 months oftreatment with azithromycin in nonsmokers with severe asthma did not improve lung function [7].Recently published data reported that azithromycin administered over 1 year reduced the rate ofexacerbations in chronic obstructive pulmonary disease (COPD), although this benefit was not found incurrent smokers with COPD, and bronchiectasis was not an exclusion [12, 13]. Moreover, a 6-month studywith azithromycin in nonsmokers with severe asthma powered to measure exacerbation frequency did notfind any statistical difference between treatment and placebo groups [7], although a beneficial effect ofazithromycin on reducing exacerbations was reported in patients with non-eosinophilic asthma [7]. Thesmokers with asthma in our study had non-eosinophilic asthma, but did not respond to azithromycin,although the duration of treatment was not long enough to assess the effects of azithromycin on exacerbations.In conclusion, we have studied the effects of 12 weeks of azithromycin in smokers with asthma, anunderstudied patient group, and provide clear evidence demonstrating lack of efficacy in both clinical andlaboratory outcomes. Further randomised clinical trials exploring new therapies in smokers with asthmawho are unable to stop smoking are required.@ERSpublicationsDaily azithromycin is ineffective in improving indices of asthma control and airway inflammationin smokers with asthma http://ow.ly/nQjynEuan J. Cameron1, Rekha Chaudhuri1, Frances Mair2, Charles McSharry1, Nicola Greenlaw3, Christopher J. Weir3,Lisa Jolly1, Iona Donnelly1, Katie Gallacher2, Deborah Morrison2, Mark Spears1, Tom J. Evans1, Kenneth Anderson4and Neil C. Thomson11Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, 2General Practice and PrimaryCare, Institute of Health and Wellbeing, University of Glasgow, Glasgow, 3Robertson Centre for Biostatistics, Universityof Glasgow, Glasgow, and 4Respiratory Medicine, Crosshouse Hospital, Kilmarnock, UK.Correspondence: N.C. Thomson, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir GraemeDavies Building, 120 University Place, Glasgow, G12 8TA, UK. E-mail: neil.thomson@glasgow.ac.ukReceived: June 03 2013 | Accepted after revision: July 10 2013Support statement: This work was funded by the Medical Research Council UK and supported financially by NHSResearch Scotland (NRS), through the Scottish Primary Care Research Network; study medication (budesonide Easyhalers;Orion Pharma (UK), Newbury, UK) was purchased with an educational grant from AstraZeneca (London, UK).Clinical trial: This study is registered at www.Clinicaltrials.gov with identifier number NCT00852579.Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.comReferences1 Thomson N, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med 2009; 15: 39–45.2 Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013; 41: 716–726.3 Cameron EJ, McSharry C, Chaudhuri R, et al. Long-term macrolide treatment of chronic inflammatory airwaydiseases: risks, benefits and future developments. Clin Exp Allergy 2012; 42: 1302–1312.4 Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treatment for chronic respiratory disease. Eur Respir J 2013;42: 239–251.14145 Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronicrejection after lung transplantation. Eur Respir J 2011; 37: 164–172.6 Sutherland ER, King TS, Icitovic N, et al. A trial of clarithromycin for the treatment of suboptimally controlledasthma. J Allergy Clin Immunol 2010; 126: 747–753.7 Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma(AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329.8 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. GINA, 2010.www.ginasthma.org9 Greening A, Ind P, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients withsymptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219–224.10 Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Societystatement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinicalpractice. Am J Respir Crit Care Med 2009; 180: 59–99.11 Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure for patients withchronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58: 339–343.12 Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365: 689–698.13 Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J2012; 40: 485–494.Eur Respir J 2013; 42: 1412–1415 | DOI: 10.1183/09031936.00093913 | Copyright ERS 2013ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.Use of household cleaning products,exhaled nitric oxide and lung function inchildrenTo the Editor:The application of domestic cleaning agents increases the risk of asthma and respiratory symptoms in adults[1], in particular when products are applied in spray form [2]. Despite the associations observed in adults,the potential effects of passive exposure on children’s respiratory health have not been extensively explored.Analyses of data from birth cohorts have suggested that frequent use of cleaning agents and their use inspray form increased the risk of wheezing and lower respiratory tract infections (LRTIs) during the first yearof life [3, 4] and the risk of persistent wheezing at school age [5, 6]. By contrast, a cross-sectional studyreported protective effects of using bleach at home on the prevalence of asthma and allergic sensitisation atschool age [7]. Our study investigates the effects of the use of 10 common cleaning products on exhalednitric oxide fraction (FeNO) and on lung function (forced vital capacity (FVC) and forced expiratory volumein 1 s (FEV1)) during childhood in a population-based birth cohort in Menorca, Spain [8].Recruitment was performed during pregnancy and 482 children were enrolled at birth. Written informedconsent was obtained from all participants and the study was approved by a committee on ethical practice.Questionnaires on wheezing, asthma, treatment and allergies (rhinitis, eczema or hay fever) wereadministered by the mother repeatedly from birth until the age of 10 years. At the age of 10–13 years, FeNO(NIOX MINO; Aerocrine AB, Solna, Sweden) and forced spirometry (EasyOne; ndd Medical Technologies,Inc., Andover, MA, USA) testing was carried out. In addition, an interviewer-led questionnaire on thefrequency of use of 10 different cleaning products (bleach, ammonia, polishes or waxes, acids, solvents,furniture sprays, glass cleaning sprays, degreasing sprays, air freshening sprays, and air freshening plug-indevices) was carried out. A total of 295 individuals completed the 10-year follow-up visit and the cleaningproducts questionnaire and performed the FeNO and/or the lung function test.For statistical analyses, we computed a combined spray variable incorporating the four sprays (furniture,glass cleaning, degreasing and air freshening sprays) and a semiquantitative total score for cleaning productuse. The means of the reported days of use per week (never50, ,1 day per week50.5, 1–3 days per week52and 4–7 days per week55.5) for each product were summed providing a score ranging from 0 (noexposure) to 55 (exposed to all 10 products used 4–7 days per week). Multivariable linear regression modelswere developed to predict log-transformed FeNO concentration and non-transformed levels of FVC andFEV1. Models were adjusted for sex, age, maternal education, parental smoking indoors, asthmamedication, season of respiratory test measurement, and for height and weight for lung functionmeasurements only. The coefficients obtained from the log-transformed FeNO models were back-transformed1415

Enlighten: Publications

                                                                    University of DundeeRandomised controlled trial of azithromycin in smokers with asthmaCameron, Euan J.; Chaudhuri, Rekha; Mair, Frances; McSharry, Charles; Greenlaw, Nicola;Weir, Christopher J.Published in:European Respiratory JournalDOI:10.1183/09031936.00093913Publication date:2013Licence:CC BY-NCDocument VersionPublisher's PDF, also known as Version of recordLink to publication in Discovery Research PortalCitation for published version (APA):Cameron, E. J., Chaudhuri, R., Mair, F., McSharry, C., Greenlaw, N., Weir, C. J., Jolly, L., Donnelly, I.,Gallacher, K., Morrison, D., Spears, M., Evans, T. J., Anderson, K., & Thomson, N. C. (2013). Randomisedcontrolled trial of azithromycin in smokers with asthma. European Respiratory Journal, 42(5), 1412-1415.https://doi.org/10.1183/09031936.00093913General rightsCopyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or othercopyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated withthese rights. • Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain. • You may freely distribute the URL identifying the publication in the public portal.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 29. Jun. 2022Randomised controlled trial ofazithromycin in smokers with asthmaTo the Editor:Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuatedresponse to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need foralternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolideantibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy inthe treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection afterlung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchialhyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma[7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokerswith asthma.A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for12 weeks. All subjects were aged 18–70 years, were current smokers (o5 pack-years history) with chronicasthma (.1 year duration; defined by international criteria [8]) and had to be free of exacerbation andrespiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit wasperformed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 mgbeclometasone ¡ a long-acting b2-agonist (LABA). Ethical approval was obtained and all subjects providedwritten informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratoryflow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 was calculatedto have an 80% power to detect a mean difference of 25 L?min-1 in change from baseline to 12 weeks inmorning PEF, the primary end-point [9], assuming a standard deviation of changes of 36 L?min-1 using atwo-sample t-test with a 5% two-sided significance level. Recruitment of 80 patients was planned to ensurethat 68 patients completed the study. 77 subjects were randomised with 71 completing the study. Othermeasures of airway responsiveness PC20 (provocation concentration of methacholine causing a 20% fall inforced expiratory volume in 1 s (FEV1)), inflammation (exhaled nitric oxide fraction at 50 mL?s-1 (FeNO50)/induced sputum/blood and sputum supernatant biomarkers), symptom control (Asthma ControlQuestionnaire (ACQ) [10] and Leicester Cough Questionnaire (LCQ) [11]) and quality of life (AsthmaQuality of Life Questionnaire (AQLQ) [10]) were assessed during the study. PEF was recorded using Piko-1electronic peak flow meters (nSpire, Hertford, UK) and symptoms were recorded in a validated diary card[10]. Bacteriological and virological analysis of induced sputum was also undertaken. All statistical testswere two-sided and used a significance level of 5%. All data was analysed using SAS (version 9.2; SASInstitute, Cary, NC, USA). QTc was also measured at baseline and 12 weeks.Baseline demographic data and clinical characteristics of the patients were comparable and the two groupswere well balanced. Placebo versus azithromycin groups: age 42.8¡9.4 years versus 46.4¡8.8 years; malesex 17 (44.7%) versus 20 (51.3%); smoking history 23.6¡15.8 pack-years versus 28.6¡16.4 pack-years;duration of asthma 24.6¡12.6 years versus 18.8¡12.5 years; atopic 23 (60.1%) versus 27 (69.2%); median(interquartile range) total IgE 103 (38–291) IU?mL-1 versus 165 (48–254) IU?mL-1; use of ICS at screening31 (81.6%) versus 35 (89.7%); equivalent beclomethasone dose at screening 709¡564 mg versus603¡457 mg; use of LABA at randomisation 18 (47.4%) versus 15 (38.5%); pre-bronchodilator FEV181.0¡16.8% predicted versus 78.3¡16.4% pred; post-bronchodilator FEV1 89.0¡15.1% pred versus86.8¡15.2% pred; FEV1 11.3¡9.8% reversibility versus 12.3¡10% reversibility; geometric mean PC201.06¡4.10 mg?mL-1 versus 1.07¡3.13 mg?mL-1.At the final study visit (12 weeks) the change in mean morning clinic PEF (primary outcome), as comparedwith baseline, did not differ substantially between the azithromycin and placebo treatment groups (meandifference -10.3 (95% CI 47.1–26.4 L?min-1), p50.58) (table 1). There was no difference in either pre- orpost-albuterol FEV1 at 4, 8 or 12 weeks between the two groups (table 1). No differences were evident forPC20 (baseline to 12 week comparison) between the azithromycin or placebo groups (table 1). None of theself-reported diary card recordings (ACQ, AQLQ or LCQ score) demonstrated any significant differencesbetween the two groups at 4, 8 or 12 weeks. Noninvasive measures of inflammation, i.e. induced sputum,sputum supernatant cytokines, peripheral blood cytokines and FeNO50, did not demonstrate any substantialimprovements after 12-weeks of treatment with azithromycin (table 1). Bacterial colony counts did notLETTERS1412TABLE1ClinicaloutcomesandsputumcellcountsafterazithromycintreatmentorplaceboVariablesBaseline4weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)8weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)12weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)PlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinMorningclinicPEFL?min-1411.1¡124.3390.5¡114.5412.9¡110.6384.2¡143.5-4.2(-30.6–22.2),p50.75406.0¡120.4394.6¡150.71.2(-28.1–30.5),p50.94416.7¡122.7394.2¡156.3-10.3(-47.1–26.4),p50.58FEV1pre-albuterolL2.54¡0.772.43¡0.722.48¡0.742.37¡0.760.08(-0.06–0.23),p50.252.47¡0.772.42¡0.750.03(-0.08–0.14),p50.552.46¡0.752.41¡0.770.03(-0.08–0.14),p50.62FEV1post-albuterolL2.80¡0.802.68¡0.732.73¡0.722.59¡0.740.04(-0.08–0.17),p50.502.72¡0.802.68¡0.740.04(-0.04–0.12),p50.342.70¡0.792.66¡0.770.04(-0.06–0.14),p50.41Relieverinhalerpuffsper24h2.8¡2.92.9¡4.42.5¡2.73.1¡4.4-0.1(-0.8–0.6),p50.782.5¡2.62.4¡2.80.3(-0.5–1.0),p50.502.7¡2.53.0[4.0-0.3(-1.3–0.7),p50.557-pointACQscore1.76¡0.881.73¡0.741.64¡0.901.74¡0.850.12(-0.18–0.42),p50.431.69¡1.031.86¡0.990.21(-0.14–0.55),p50.231.58¡0.961.75¡0.830.21(-0.11–0.53),p50.20logPC20mg?mL-10.07¡1.140.06¡1.41NDNDNDND0.19¡1.290.20¡1.52-0.02(-0.49–0.45),p50.93TotalLCQscore16.90¡3.4916.31¡3.53NDNDNDND17.51¡3.5516.01¡3.02-1.06(-2.16–0.05),p50.06TotalAQLQscore5.09¡0.995.25¡1.18NDNDNDND5.42¡1.315.20¡1.06-0.31(-0.69–0.07),p50.11FeNO50ppb15.6¡21.211.5¡8.9NDNDNDND16.2¡20.111.0¡7.9-1.94(-5.97–2.10),p50.34Totalsputumcellcount6104644¡240626¡245NDNDNDND714¡326668¡2111.0(0.9–1.2),p50.75Neutrophil6104150¡123172¡103NDNDNDND141¡96162¡9719.2(-24.2–62.6),p50.38Neutrophil%33.1¡24.339.0¡22.5NDNDNDND31.0¡19.934.4¡18.63.0(-5.9–11.8),p50.50Eosinophil61044.9¡6.46.9¡9.3NDNDNDND6.8¡13.910.3¡20.11.0(0.5–2.0),p50.89Eosinophil%1.1¡1.51.6¡2.3NDNDNDND1.5¡3.11.6¡3.0-0.4(-1.8–1.0),p50.55Dataarepresentedasmean¡SD,unlessotherwisestated.PEF:peakexpiratoryflowrate;FEV1:forcedexpiratoryvolumein1s;ACQ:AsthmaControlQuestionnaire;PC20:provocationconcentrationofmethacholinecausinga20%fallinFEV1;LCQ:LeicesterCoughQuestionnaire;AQLQ:AsthmaQualityofLifeQuestionnaire;FeNO50:exhalednitricoxidefractionat50mL?s-1;ND:notdone.#:treatmentdifferencefromANCOVAanalysingchangefrombaselineandadjustingforbaselinevalue.1413demonstrate any treatment difference between the placebo and azithromycin groups (p50.66, data notshown). PCR for Mycoplasma pneumonia and Chlamydophila pneumoniae were negative at both baselineand 12 weeks. QTc was unchanged following 12 weeks of treatment with azithromycin.No suspected unexpected serious adverse events occurred during the reporting period of the study.Compliance assessed by capsule count was .90% in each group.In the first randomised controlled study of azithromycin in smokers with asthma we found that there wereno clinically important improvements in both the primary end-point and morning PEF, and in a range ofsecondary clinical outcomes including ACQ score, AQLQ score, spirometry and airway responsiveness, aswell as measures of airway inflammation after 12 weeks of treatment. The median ACQ score of theparticipants recruited to the study was raised at 1.7 indicating that they had poorly controlled disease andscope for clinical improvement. We believe that the choice of a different macrolide from azithromycin or adifferent dose of azithromycin is unlikely to have altered our findings. This study was powered to test thehypothesis on the primary end-point, PEF. We exceeded our minimum recruitment target ensuringadequate numbers completed the study. The lack of response to treatment was such that recruiting greaternumbers would be unlikely to affect either the primary end-point or the majority of secondary analyses.Taken together these findings indicate that short-term therapy with azithromycin does not improve lungfunction or other indices of current asthma control of smokers with mild-to-moderate asthma who are alreadyreceiving treatment with inhaled corticosteroids. This is supported by a recent study where 6 months oftreatment with azithromycin in nonsmokers with severe asthma did not improve lung function [7].Recently published data reported that azithromycin administered over 1 year reduced the rate ofexacerbations in chronic obstructive pulmonary disease (COPD), although this benefit was not found incurrent smokers with COPD, and bronchiectasis was not an exclusion [12, 13]. Moreover, a 6-month studywith azithromycin in nonsmokers with severe asthma powered to measure exacerbation frequency did notfind any statistical difference between treatment and placebo groups [7], although a beneficial effect ofazithromycin on reducing exacerbations was reported in patients with non-eosinophilic asthma [7]. Thesmokers with asthma in our study had non-eosinophilic asthma, but did not respond to azithromycin,although the duration of treatment was not long enough to assess the effects of azithromycin on exacerbations.In conclusion, we have studied the effects of 12 weeks of azithromycin in smokers with asthma, anunderstudied patient group, and provide clear evidence demonstrating lack of efficacy in both clinical andlaboratory outcomes. Further randomised clinical trials exploring new therapies in smokers with asthmawho are unable to stop smoking are required.@ERSpublicationsDaily azithromycin is ineffective in improving indices of asthma control and airway inflammationin smokers with asthma http://ow.ly/nQjynEuan J. Cameron1, Rekha Chaudhuri1, Frances Mair2, Charles McSharry1, Nicola Greenlaw3, Christopher J. Weir3,Lisa Jolly1, Iona Donnelly1, Katie Gallacher2, Deborah Morrison2, Mark Spears1, Tom J. Evans1, Kenneth Anderson4and Neil C. Thomson11Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, 2General Practice and PrimaryCare, Institute of Health and Wellbeing, University of Glasgow, Glasgow, 3Robertson Centre for Biostatistics, Universityof Glasgow, Glasgow, and 4Respiratory Medicine, Crosshouse Hospital, Kilmarnock, UK.Correspondence: N.C. Thomson, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir GraemeDavies Building, 120 University Place, Glasgow, G12 8TA, UK. E-mail: neil.thomson@glasgow.ac.ukReceived: June 03 2013 | Accepted after revision: July 10 2013Support statement: This work was funded by the Medical Research Council UK and supported financially by NHSResearch Scotland (NRS), through the Scottish Primary Care Research Network; study medication (budesonide Easyhalers;Orion Pharma (UK), Newbury, UK) was purchased with an educational grant from AstraZeneca (London, UK).Clinical trial: This study is registered at www.Clinicaltrials.gov with identifier number NCT00852579.Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.comReferences1 Thomson N, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med 2009; 15: 39–45.2 Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013; 41: 716–726.3 Cameron EJ, McSharry C, Chaudhuri R, et al. Long-term macrolide treatment of chronic inflammatory airwaydiseases: risks, benefits and future developments. Clin Exp Allergy 2012; 42: 1302–1312.4 Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treatment for chronic respiratory disease. Eur Respir J 2013;42: 239–251.14145 Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronicrejection after lung transplantation. Eur Respir J 2011; 37: 164–172.6 Sutherland ER, King TS, Icitovic N, et al. A trial of clarithromycin for the treatment of suboptimally controlledasthma. J Allergy Clin Immunol 2010; 126: 747–753.7 Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma(AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329.8 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. GINA, 2010.www.ginasthma.org9 Greening A, Ind P, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients withsymptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219–224.10 Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Societystatement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinicalpractice. Am J Respir Crit Care Med 2009; 180: 59–99.11 Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure for patients withchronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58: 339–343.12 Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365: 689–698.13 Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J2012; 40: 485–494.Eur Respir J 2013; 42: 1412–1415 | DOI: 10.1183/09031936.00093913 | Copyright ERS 2013ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.Use of household cleaning products,exhaled nitric oxide and lung function inchildrenTo the Editor:The application of domestic cleaning agents increases the risk of asthma and respiratory symptoms in adults[1], in particular when products are applied in spray form [2]. Despite the associations observed in adults,the potential effects of passive exposure on children’s respiratory health have not been extensively explored.Analyses of data from birth cohorts have suggested that frequent use of cleaning agents and their use inspray form increased the risk of wheezing and lower respiratory tract infections (LRTIs) during the first yearof life [3, 4] and the risk of persistent wheezing at school age [5, 6]. By contrast, a cross-sectional studyreported protective effects of using bleach at home on the prevalence of asthma and allergic sensitisation atschool age [7]. Our study investigates the effects of the use of 10 common cleaning products on exhalednitric oxide fraction (FeNO) and on lung function (forced vital capacity (FVC) and forced expiratory volumein 1 s (FEV1)) during childhood in a population-based birth cohort in Menorca, Spain [8].Recruitment was performed during pregnancy and 482 children were enrolled at birth. Written informedconsent was obtained from all participants and the study was approved by a committee on ethical practice.Questionnaires on wheezing, asthma, treatment and allergies (rhinitis, eczema or hay fever) wereadministered by the mother repeatedly from birth until the age of 10 years. At the age of 10–13 years, FeNO(NIOX MINO; Aerocrine AB, Solna, Sweden) and forced spirometry (EasyOne; ndd Medical Technologies,Inc., Andover, MA, USA) testing was carried out. In addition, an interviewer-led questionnaire on thefrequency of use of 10 different cleaning products (bleach, ammonia, polishes or waxes, acids, solvents,furniture sprays, glass cleaning sprays, degreasing sprays, air freshening sprays, and air freshening plug-indevices) was carried out. A total of 295 individuals completed the 10-year follow-up visit and the cleaningproducts questionnaire and performed the FeNO and/or the lung function test.For statistical analyses, we computed a combined spray variable incorporating the four sprays (furniture,glass cleaning, degreasing and air freshening sprays) and a semiquantitative total score for cleaning productuse. The means of the reported days of use per week (never50, ,1 day per week50.5, 1–3 days per week52and 4–7 days per week55.5) for each product were summed providing a score ranging from 0 (noexposure) to 55 (exposed to all 10 products used 4–7 days per week). Multivariable linear regression modelswere developed to predict log-transformed FeNO concentration and non-transformed levels of FVC andFEV1. Models were adjusted for sex, age, maternal education, parental smoking indoors, asthmamedication, season of respiratory test measurement, and for height and weight for lung functionmeasurements only. The coefficients obtained from the log-transformed FeNO models were back-transformed1415

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     Cameron, E.J., Chaudhuri, R., Mair, F., McSharry, C., Greenlaw, N., Weir, C.J., Jolly, L., Donnelly, I., Gallacher, K., Morrison, D., Spears, M., Evans, T.J., Anderson, K., and Thomson, N.C. (2013) Randomised controlled trial of azithromycin in smokers with asthma. European Respiratory Journal, 42 (5). pp. 1412-1415. ISSN 0903-1936    Copyright © 2013 European Respiratory Society    http://eprints.gla.ac.uk/88388    Deposited on:  17 December 2013                          Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk Randomised controlled trial ofazithromycin in smokers with asthmaTo the Editor:Smokers with asthma have poor symptom control, accelerated decline in lung function and an attenuatedresponse to corticosteroids compared to nonsmokers with asthma [1]. There is an unmet need foralternative or additional drugs for smokers with asthma who are unable to stop smoking [2]. Macrolideantibiotics have anti-inflammatory activity [3] and in clinical studies there is good evidence for efficacy inthe treatment of diffuse pan-bronchiolitis and cystic fibrosis, as well as in preventing chronic rejection afterlung transplantation [4, 5]. In asthma, chronic treatment is associated with a reduction in bronchialhyperreactivity in mild-to-moderate asthma [6] and in exacerbation rates in non-eosinophilic severe asthma[7]. To date, no studies have examined the efficacy of macrolide antibiotics exclusively in current smokerswith asthma.A randomised double-blind parallel-group trial compared azithromycin, 250 mg per day, with placebo for12 weeks. All subjects were aged 18–70 years, were current smokers (o5 pack-years history) with chronicasthma (.1 year duration; defined by international criteria [8]) and had to be free of exacerbation andrespiratory tract infection for a minimum 6-week period prior to randomisation. A baseline visit wasperformed following a 4-week run-in period on inhaled corticosteroid (ICS) therapy equivalent to 400 mgbeclometasone ¡ a long-acting b2-agonist (LABA). Ethical approval was obtained and all subjects providedwritten informed consent. Study visits were performed at 4, 8 and 12 weeks. Clinic visit peak expiratoryflow (PEF) after 12 weeks treatment was the primary outcome measure. A sample size of 68 was calculatedto have an 80% power to detect a mean difference of 25 L?min-1 in change from baseline to 12 weeks inmorning PEF, the primary end-point [9], assuming a standard deviation of changes of 36 L?min-1 using atwo-sample t-test with a 5% two-sided significance level. Recruitment of 80 patients was planned to ensurethat 68 patients completed the study. 77 subjects were randomised with 71 completing the study. Othermeasures of airway responsiveness PC20 (provocation concentration of methacholine causing a 20% fall inforced expiratory volume in 1 s (FEV1)), inflammation (exhaled nitric oxide fraction at 50 mL?s-1 (FeNO50)/induced sputum/blood and sputum supernatant biomarkers), symptom control (Asthma ControlQuestionnaire (ACQ) [10] and Leicester Cough Questionnaire (LCQ) [11]) and quality of life (AsthmaQuality of Life Questionnaire (AQLQ) [10]) were assessed during the study. PEF was recorded using Piko-1electronic peak flow meters (nSpire, Hertford, UK) and symptoms were recorded in a validated diary card[10]. Bacteriological and virological analysis of induced sputum was also undertaken. All statistical testswere two-sided and used a significance level of 5%. All data was analysed using SAS (version 9.2; SASInstitute, Cary, NC, USA). QTc was also measured at baseline and 12 weeks.Baseline demographic data and clinical characteristics of the patients were comparable and the two groupswere well balanced. Placebo versus azithromycin groups: age 42.8¡9.4 years versus 46.4¡8.8 years; malesex 17 (44.7%) versus 20 (51.3%); smoking history 23.6¡15.8 pack-years versus 28.6¡16.4 pack-years;duration of asthma 24.6¡12.6 years versus 18.8¡12.5 years; atopic 23 (60.1%) versus 27 (69.2%); median(interquartile range) total IgE 103 (38–291) IU?mL-1 versus 165 (48–254) IU?mL-1; use of ICS at screening31 (81.6%) versus 35 (89.7%); equivalent beclomethasone dose at screening 709¡564 mg versus603¡457 mg; use of LABA at randomisation 18 (47.4%) versus 15 (38.5%); pre-bronchodilator FEV181.0¡16.8% predicted versus 78.3¡16.4% pred; post-bronchodilator FEV1 89.0¡15.1% pred versus86.8¡15.2% pred; FEV1 11.3¡9.8% reversibility versus 12.3¡10% reversibility; geometric mean PC201.06¡4.10 mg?mL-1 versus 1.07¡3.13 mg?mL-1.At the final study visit (12 weeks) the change in mean morning clinic PEF (primary outcome), as comparedwith baseline, did not differ substantially between the azithromycin and placebo treatment groups (meandifference -10.3 (95% CI 47.1–26.4 L?min-1), p50.58) (table 1). There was no difference in either pre- orpost-albuterol FEV1 at 4, 8 or 12 weeks between the two groups (table 1). No differences were evident forPC20 (baseline to 12 week comparison) between the azithromycin or placebo groups (table 1). None of theself-reported diary card recordings (ACQ, AQLQ or LCQ score) demonstrated any significant differencesbetween the two groups at 4, 8 or 12 weeks. Noninvasive measures of inflammation, i.e. induced sputum,sputum supernatant cytokines, peripheral blood cytokines and FeNO50, did not demonstrate any substantialimprovements after 12-weeks of treatment with azithromycin (table 1). Bacterial colony counts did notLETTERS1412TABLE1ClinicaloutcomesandsputumcellcountsafterazithromycintreatmentorplaceboVariablesBaseline4weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)8weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)12weeksTreatmentdifference#,azithromycinminusplacebo(95%CI)PlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinPlaceboAzithromycinMorningclinicPEFL?min-1411.1¡124.3390.5¡114.5412.9¡110.6384.2¡143.5-4.2(-30.6–22.2),p50.75406.0¡120.4394.6¡150.71.2(-28.1–30.5),p50.94416.7¡122.7394.2¡156.3-10.3(-47.1–26.4),p50.58FEV1pre-albuterolL2.54¡0.772.43¡0.722.48¡0.742.37¡0.760.08(-0.06–0.23),p50.252.47¡0.772.42¡0.750.03(-0.08–0.14),p50.552.46¡0.752.41¡0.770.03(-0.08–0.14),p50.62FEV1post-albuterolL2.80¡0.802.68¡0.732.73¡0.722.59¡0.740.04(-0.08–0.17),p50.502.72¡0.802.68¡0.740.04(-0.04–0.12),p50.342.70¡0.792.66¡0.770.04(-0.06–0.14),p50.41Relieverinhalerpuffsper24h2.8¡2.92.9¡4.42.5¡2.73.1¡4.4-0.1(-0.8–0.6),p50.782.5¡2.62.4¡2.80.3(-0.5–1.0),p50.502.7¡2.53.0[4.0-0.3(-1.3–0.7),p50.557-pointACQscore1.76¡0.881.73¡0.741.64¡0.901.74¡0.850.12(-0.18–0.42),p50.431.69¡1.031.86¡0.990.21(-0.14–0.55),p50.231.58¡0.961.75¡0.830.21(-0.11–0.53),p50.20logPC20mg?mL-10.07¡1.140.06¡1.41NDNDNDND0.19¡1.290.20¡1.52-0.02(-0.49–0.45),p50.93TotalLCQscore16.90¡3.4916.31¡3.53NDNDNDND17.51¡3.5516.01¡3.02-1.06(-2.16–0.05),p50.06TotalAQLQscore5.09¡0.995.25¡1.18NDNDNDND5.42¡1.315.20¡1.06-0.31(-0.69–0.07),p50.11FeNO50ppb15.6¡21.211.5¡8.9NDNDNDND16.2¡20.111.0¡7.9-1.94(-5.97–2.10),p50.34Totalsputumcellcount6104644¡240626¡245NDNDNDND714¡326668¡2111.0(0.9–1.2),p50.75Neutrophil6104150¡123172¡103NDNDNDND141¡96162¡9719.2(-24.2–62.6),p50.38Neutrophil%33.1¡24.339.0¡22.5NDNDNDND31.0¡19.934.4¡18.63.0(-5.9–11.8),p50.50Eosinophil61044.9¡6.46.9¡9.3NDNDNDND6.8¡13.910.3¡20.11.0(0.5–2.0),p50.89Eosinophil%1.1¡1.51.6¡2.3NDNDNDND1.5¡3.11.6¡3.0-0.4(-1.8–1.0),p50.55Dataarepresentedasmean¡SD,unlessotherwisestated.PEF:peakexpiratoryflowrate;FEV1:forcedexpiratoryvolumein1s;ACQ:AsthmaControlQuestionnaire;PC20:provocationconcentrationofmethacholinecausinga20%fallinFEV1;LCQ:LeicesterCoughQuestionnaire;AQLQ:AsthmaQualityofLifeQuestionnaire;FeNO50:exhalednitricoxidefractionat50mL?s-1;ND:notdone.#:treatmentdifferencefromANCOVAanalysingchangefrombaselineandadjustingforbaselinevalue.1413demonstrate any treatment difference between the placebo and azithromycin groups (p50.66, data notshown). PCR for Mycoplasma pneumonia and Chlamydophila pneumoniae were negative at both baselineand 12 weeks. QTc was unchanged following 12 weeks of treatment with azithromycin.No suspected unexpected serious adverse events occurred during the reporting period of the study.Compliance assessed by capsule count was .90% in each group.In the first randomised controlled study of azithromycin in smokers with asthma we found that there wereno clinically important improvements in both the primary end-point and morning PEF, and in a range ofsecondary clinical outcomes including ACQ score, AQLQ score, spirometry and airway responsiveness, aswell as measures of airway inflammation after 12 weeks of treatment. The median ACQ score of theparticipants recruited to the study was raised at 1.7 indicating that they had poorly controlled disease andscope for clinical improvement. We believe that the choice of a different macrolide from azithromycin or adifferent dose of azithromycin is unlikely to have altered our findings. This study was powered to test thehypothesis on the primary end-point, PEF. We exceeded our minimum recruitment target ensuringadequate numbers completed the study. The lack of response to treatment was such that recruiting greaternumbers would be unlikely to affect either the primary end-point or the majority of secondary analyses.Taken together these findings indicate that short-term therapy with azithromycin does not improve lungfunction or other indices of current asthma control of smokers with mild-to-moderate asthma who are alreadyreceiving treatment with inhaled corticosteroids. This is supported by a recent study where 6 months oftreatment with azithromycin in nonsmokers with severe asthma did not improve lung function [7].Recently published data reported that azithromycin administered over 1 year reduced the rate ofexacerbations in chronic obstructive pulmonary disease (COPD), although this benefit was not found incurrent smokers with COPD, and bronchiectasis was not an exclusion [12, 13]. Moreover, a 6-month studywith azithromycin in nonsmokers with severe asthma powered to measure exacerbation frequency did notfind any statistical difference between treatment and placebo groups [7], although a beneficial effect ofazithromycin on reducing exacerbations was reported in patients with non-eosinophilic asthma [7]. Thesmokers with asthma in our study had non-eosinophilic asthma, but did not respond to azithromycin,although the duration of treatment was not long enough to assess the effects of azithromycin on exacerbations.In conclusion, we have studied the effects of 12 weeks of azithromycin in smokers with asthma, anunderstudied patient group, and provide clear evidence demonstrating lack of efficacy in both clinical andlaboratory outcomes. Further randomised clinical trials exploring new therapies in smokers with asthmawho are unable to stop smoking are required.@ERSpublicationsDaily azithromycin is ineffective in improving indices of asthma control and airway inflammationin smokers with asthma http://ow.ly/nQjynEuan J. Cameron1, Rekha Chaudhuri1, Frances Mair2, Charles McSharry1, Nicola Greenlaw3, Christopher J. Weir3,Lisa Jolly1, Iona Donnelly1, Katie Gallacher2, Deborah Morrison2, Mark Spears1, Tom J. Evans1, Kenneth Anderson4and Neil C. Thomson11Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, 2General Practice and PrimaryCare, Institute of Health and Wellbeing, University of Glasgow, Glasgow, 3Robertson Centre for Biostatistics, Universityof Glasgow, Glasgow, and 4Respiratory Medicine, Crosshouse Hospital, Kilmarnock, UK.Correspondence: N.C. Thomson, Institute of Infection, Immunity and Inflammation, University of Glasgow, Sir GraemeDavies Building, 120 University Place, Glasgow, G12 8TA, UK. E-mail: neil.thomson@glasgow.ac.ukReceived: June 03 2013 | Accepted after revision: July 10 2013Support statement: This work was funded by the Medical Research Council UK and supported financially by NHSResearch Scotland (NRS), through the Scottish Primary Care Research Network; study medication (budesonide Easyhalers;Orion Pharma (UK), Newbury, UK) was purchased with an educational grant from AstraZeneca (London, UK).Clinical trial: This study is registered at www.Clinicaltrials.gov with identifier number NCT00852579.Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.comReferences1 Thomson N, Chaudhuri R. Asthma in smokers: challenges and opportunities. Curr Opin Pulm Med 2009; 15: 39–45.2 Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J 2013; 41: 716–726.3 Cameron EJ, McSharry C, Chaudhuri R, et al. Long-term macrolide treatment of chronic inflammatory airwaydiseases: risks, benefits and future developments. Clin Exp Allergy 2012; 42: 1302–1312.4 Spagnolo P, Fabbri LM, Bush A. Long-term macrolide treatment for chronic respiratory disease. Eur Respir J 2013;42: 239–251.14145 Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronicrejection after lung transplantation. Eur Respir J 2011; 37: 164–172.6 Sutherland ER, King TS, Icitovic N, et al. A trial of clarithromycin for the treatment of suboptimally controlledasthma. J Allergy Clin Immunol 2010; 126: 747–753.7 Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma(AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322–329.8 Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention. GINA, 2010.www.ginasthma.org9 Greening A, Ind P, Northfield M, et al. Added salmeterol versus higher-dose corticosteroid in asthma patients withsymptoms on existing inhaled corticosteroid. Lancet 1994; 344: 219–224.10 Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Societystatement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinicalpractice. Am J Respir Crit Care Med 2009; 180: 59–99.11 Birring SS, Prudon B, Carr AJ, et al. Development of a symptom specific health status measure for patients withchronic cough: Leicester Cough Questionnaire (LCQ). Thorax 2003; 58: 339–343.12 Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365: 689–698.13 Yamaya M, Azuma A, Takizawa H, et al. Macrolide effects on the prevention of COPD exacerbations. Eur Respir J2012; 40: 485–494.Eur Respir J 2013; 42: 1412–1415 | DOI: 10.1183/09031936.00093913 | Copyright ERS 2013ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 3.0.Use of household cleaning products,exhaled nitric oxide and lung function inchildrenTo the Editor:The application of domestic cleaning agents increases the risk of asthma and respiratory symptoms in adults[1], in particular when products are applied in spray form [2]. Despite the associations observed in adults,the potential effects of passive exposure on children’s respiratory health have not been extensively explored.Analyses of data from birth cohorts have suggested that frequent use of cleaning agents and their use inspray form increased the risk of wheezing and lower respiratory tract infections (LRTIs) during the first yearof life [3, 4] and the risk of persistent wheezing at school age [5, 6]. By contrast, a cross-sectional studyreported protective effects of using bleach at home on the prevalence of asthma and allergic sensitisation atschool age [7]. Our study investigates the effects of the use of 10 common cleaning products on exhalednitric oxide fraction (FeNO) and on lung function (forced vital capacity (FVC) and forced expiratory volumein 1 s (FEV1)) during childhood in a population-based birth cohort in Menorca, Spain [8].Recruitment was performed during pregnancy and 482 children were enrolled at birth. Written informedconsent was obtained from all participants and the study was approved by a committee on ethical practice.Questionnaires on wheezing, asthma, treatment and allergies (rhinitis, eczema or hay fever) wereadministered by the mother repeatedly from birth until the age of 10 years. At the age of 10–13 years, FeNO(NIOX MINO; Aerocrine AB, Solna, Sweden) and forced spirometry (EasyOne; ndd Medical Technologies,Inc., Andover, MA, USA) testing was carried out. In addition, an interviewer-led questionnaire on thefrequency of use of 10 different cleaning products (bleach, ammonia, polishes or waxes, acids, solvents,furniture sprays, glass cleaning sprays, degreasing sprays, air freshening sprays, and air freshening plug-indevices) was carried out. A total of 295 individuals completed the 10-year follow-up visit and the cleaningproducts questionnaire and performed the FeNO and/or the lung function test.For statistical analyses, we computed a combined spray variable incorporating the four sprays (furniture,glass cleaning, degreasing and air freshening sprays) and a semiquantitative total score for cleaning productuse. The means of the reported days of use per week (never50, ,1 day per week50.5, 1–3 days per week52and 4–7 days per week55.5) for each product were summed providing a score ranging from 0 (noexposure) to 55 (exposed to all 10 products used 4–7 days per week). Multivariable linear regression modelswere developed to predict log-transformed FeNO concentration and non-transformed levels of FVC andFEV1. Models were adjusted for sex, age, maternal education, parental smoking indoors, asthmamedication, season of respiratory test measurement, and for height and weight for lung functionmeasurements only. The coefficients obtained from the log-transformed FeNO models were back-transformed1415

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Randomised controlled trial of azithromycin in smokers with asthma

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