Low level air pollution and exacerbation of existing copd: a case crossover analysis

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1 DeVries et l. Environmentl Helth (2016) 15:98 DOI /s z RESEARCH Open Access Low level ir pollution nd excerbtion of existing copd: cse crossover nlysis Rebecc DeVries *, Dvid Kriebel nd Susn Sm Abstrct Bckground: Excerbtions of chronic obstructive pulmonry disese (COPD) contribute gretly to incresed morbidity, mortlity nd diminished qulity of life. Recent studies report modertely strong positive ssocitions between exposures to severl ir pollutnts nd COPD-relted emergency deprtment (ED) visits nd hospitl dmissions (HA). Studies tht use cliniclly defined excerbtions rther thn counting ED visits nd HA my be more sensitive to environmentl triggers like ir pollution, but very few such studies exist. Prticipnts in COPD disese mngement group living in n re of low ir pollution nd who were followed closely for the erliest signs of n excerbtion provided n opportunity to study ssocitions between ir pollution nd COPD excerbtion. Methods: Associtions between short term exposures to ir pollutnts, including sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), nd prticulte mtter < 2.5 microns (PM 2.5 ), nd COPD excerbtion were ssessed mong 168 ptients residing in centrl Msschusetts, region with ir pollution levels well below USEPA Ntionl Ambient Air Qulity Stndrds (NAAQS). Cse-crossover nlyses nd multivrite conditionl logistic regression were used to estimte ssocitions between 7-dy verge concentrtions of ech ir pollutnt, s mesured t centrl site monitors, nd COPD excerbtion experienced in the ptients homes during the period , while controlling for temperture nd self-reported influenz. Results: We found tht short-term exposures to SO 2 were ssocited with n increse in COPD excerbtion risk (odds rtio (OR) = 2.45, 95 % CI: per 1 ppb increse) fter djustment for PM 2.5. Short-term exposures to NO 2 concentrtions showed weker ssocition, (OR = 1.17, 95 % CI: per 1 ppb increse) fter djustment for PM 2.5. An unexpectedly modest negtive ssocition ws seen for short-term exposures to PM 2.5. Conclusions: Despite living in n re with ir pollution concentrtions below current USEPA NAAQS, these COPD ptients ppered to suffer incresed risk of COPD excerbtion following short-term exposures to incresed concentrtions of SO 2 nd NO 2. An unexpected negtive ssocition with PM 2.5 my result from the complex ir chemistry of low level PM in this region. Keywords: Air pollution, Sulfur dioxide, Nitrogen dioxide, Prticulte mtter, Chronic obstructive pulmonry disese, Cse-crossover Bckground Chronic obstructive pulmonry disese (COPD), chrcterized by irreversible irflow obstruction, is one of the leding cuses of morbidity, mortlity nd helthcre costs in the United Sttes. Excerbtions of existing COPD, defined s short-term episodes during which the norml inflmmtory process is enhnced [1, 2], contribute gretly to incresed morbidity nd diminished qulity * Correspondence: Rebecc_Devries@uml.edu Deprtment of Work Environment, University of Msschusetts Lowell, 1 University Avenue, Lowell, MA 01854, USA of life mong COPD ptients, with higher excerbtion frequencies ssocited with poorer helth sttus, incresed hospitliztions, nd incresed costs [1 3]. In the United Sttes, the estimted direct nd indirect costs of COPD re $29.5 billion nd $20.4 billion, respectively, with excerbtions ccounting for the lrgest proportion of the totl economic burden [1]. The economic burden of COPD is likely to be comprble in other developed countries. Well known risk fctors for these cute excerbtions include bcteril nd virl infections, s well s exposures to tobcco [2] nd some workplce dusts 2016 The Author(s). Open Access This rticle is distributed under the terms of the Cretive Commons Attribution 4.0 Interntionl License ( which permits unrestricted use, distribution, nd reproduction in ny medium, provided you give pproprite credit to the originl uthor(s) nd the source, provide link to the Cretive Commons license, nd indicte if chnges were mde. The Cretive Commons Public Domin Dediction wiver ( pplies to the dt mde vilble in this rticle, unless otherwise stted.

2 DeVries et l. Environmentl Helth (2016) 15:98 Pge 2 of 11 nd fumes [1]. Recent literture lso suggests tht certin wether nd ir qulity conditions my trigger n excerbtion of COPD symptoms [4 6]. COPD excerbtions re studied epidemiologiclly in vriety of wys; the ir pollution literture hs tended to count emergency deprtment (ED) visits, hospitl dmissions (HA), or mortlity, while studies of risk fctors like infection nd lterntive disese mngement strtegies hve used clinicl definitions such s incresed respirtory symptoms or incresed use of steroids nd ntibiotics. USEPA hs set Ntionl Ambient Air Qulity Stndrds (NAAQS) for six criteri ir pollutnts considered hrmful to public helth [7]. Four of these re of prticulr concern to respirtory helth nd include prticulte mtter (PM), sulfur dioxide (SO 2 ), nitrogen dioxide (NO 2 ), nd ozone (O 3 ). PM is complex mixture of solid prticles nd liquid droplets suspended in ir nd is primrily produced during combustion of fossil fuels by trnsporttion nd sttionry sources [8]. NAAQS hve been set for two prticle size frctions; PM 10 which includes inhlble prticles of 10 micrometers or less, nd PM 2.5 which includes fine inhlble prticles of 2.5 micrometers or less. SO 2 is primrily produced from combustion of fossil fuels by electric utilities nd industry, while less so by trnsporttion relted sources [9]. NO 2 typiclly forms from incomplete combustion of nitrogen-contining chemicls, with the lrgest sources in the US being mobile sources, electric generting units, nd industril/ commercil/residentil fuels [10]. O 3 is creted in the tmosphere by chemicl rections between voltile orgnic compounds (VOCs) nd oxides of nitrogen (NO x )[7].Individuls with pre-existing respirtory disese (for exmple, COPD) re potentilly susceptible to low concentrtions of these four outdoor ir pollutnts. This study focuses on short-term exposures to SO 2,NO 2,ndPM 2.5 ;O 3 ws excluded since this pollutnt is not mesured continuously throughout the yer in our study re. Outdoor ir pollutnts (PM 2.5,NO 2,ndSO 2 ) re wellestblished risk fctors for COPD excerbtion [1, 4], lthough most studies evluting these reltionships hve been conducted in regions with high levels of outdoor ir pollution (such s southern Cliforni nd Hong Kong). Less is known regrding the ssocition between low levels of these outdoor ir pollutnts nd cute excerbtions of COPD tht do not result in EDs or HAs. Two epidemiologic studies were identified in published literture tht specificlly evluted outdoor ir pollution nd COPD excerbtions experienced in the ptients homes [11, 12]. Both studies were completed in London; one reporting incresed nd the other reporting decresed risk of excerbtion following exposures t comprble concentrtions. This study quntified the ssocition between short term exposures to low levels of outdoor SO 2,NO 2,nd PM 2.5 nd COPD excerbtion mong group of ptients residing in centrl Msschusetts over 15-month study period, using cse crossover study design. A mjor dvntge of this study design ws tht mny of the importnt potentil subject-level confounders tht remin constnt throughout the study period (i.e., ge, gender, housing chrcteristics, co-morbities, nd smoking history) were controlled by design (in cse-crossover study, ech subject cn be seen s serving s their own control ) [13, 14]. This study lso hd the benefit of controlling for number of potentil subject-level confounders tht vry over time but hve rrely been considered in published literture (i.e., respirtory infections, time spent outdoors, helth sttus prior to the event, nd physicl ctivities). This robust control for confounding coupled with our sensitive cse definition of COPD excerbtion llowed us to detect effects tht my not hve been cptured in some of the lrger time series studies tht evluted COPDrelted ED/HA, prticulrly those in regions with higher levels of ir pollution. Methods Study popultion The study popultion ws drwn from COPD disese mngement group (DMG), mintined by lrge medicl prctice locted in Worcester County, Msschusetts. The city of Worcester, locted in centrl Msschusetts, is the third lrgest city in New Englnd with popultion of pproximtely 180,000 nd n estimted popultion of 6 million within 50 mile rdius [15]. Outdoor ir pollution throughout this region is reltively low, with long term nnul verge concentrtions of ll primry pollutnts consistently flling well below their respective USEPA NAAQS. All recruited prticipnts hd received physicin dignosis of COPD nd hd no other lung disese (such s interstitil lung disese or lung cncer), with the exception of sthm. All study mterils nd protocols were pproved by the Relint Medicl Group Institutionl Review Bord. Dt collected The dt were gthered in prospective cse crossover study designed to evlute the reltionship between indoor nd outdoor environmentl triggers nd excerbtion of existing COPD. Cses were defined s periods of worsening symptoms, which were confirmed by nurse to require dditionl orl steroids or ntibiotics. During 15-month study period (Jnury, 2011 to Mrch, 2012), enrolled prticipnts were instructed to cll clinic nurses when, following their prescribed DMG tretment pln, they hd begun to use their pre-filled medictions to tret worsening respirtory symptoms. On this telephone cll, nurse confirmed whether the ptient ws in fct experiencing n excerbtion nd then sked stndrd series of

3 DeVries et l. Environmentl Helth (2016) 15:98 Pge 3 of 11 questions concerning the ptient s dily living behviors nd ctivities in the previous week, referred to here s the exposures questionnire. These dt, collected t the time of excerbtion (or shortly fter), represented the prticipnts cse periods. The sme exposures questionnire ws lso dministered vi telephone t one to three rndomly identified times when the prticipnts were not experiencing symptoms of n excerbtion. These dt, collected during helthy weeks, represented the prticipnts control periods. A bseline questionnire ws lso dministered upon recruitment to gther informtion on demogrphics, helth sttus, smoking history, occuptionl history nd housing chrcteristics. This pper reports findings of ssocitions between COPD excerbtion nd exposures to outdoor ir pollutnts; second pper covers results of investigtions of household exposures, nd ctivities of dily living. As discussed further below, this division ws fesible becuse we found no evidence of confounding or effect modifiction of the ir pollution risks by ny of these risk fctors. Temperture nd humidity, nd colds nd flu exposures were lso investigted nd re discussed here. Exposure dt: ir pollution, wether nd influenz Rel-time continuous outdoor ir mesurements, reported s hourly verges, were vilble from USEPA s Air Qulity System (AQS) for SO 2,NO 2 nd PM 2.5 t the nerby Worcester (EPA monitor # ), Wre (EPA monitor # ) nd Springfield (EPA monitor # ) centrl site monitors [16]. 24-h dily verge concentrtions were extrcted for ech pollutnt nd monitor combintion. PM 2.5 dt were vilble t ll three monitors s 24-h mss bsed nd 1-h continuous mesurements. For this study, we chose to use continuous monitoring dt for PM 2.5 becuse it resulted in the richest dtset nd is consistent with recent ir pollution studies. However, since there is some debte regrding the ccurcy of these types of continuous mesurements, we verified tht continuous mesurements were pproprite to use for our study period nd loctions with USEPA s PM 2.5 Continuous Monitor Comprbility Assessment online ppliction, prior to this decision [17]. Dt for importnt meteorologicl vribles (i.e., temperture nd humidity) were exported s 24-h dily verges from the Ntionl Ocenic nd Atmospheric Administrtion s (NOAA) Ntionl Climtic Dt Center (NCDC) for the Worcester Regionl Airport meteorologicl site [18]. Dt on regionl trends of influenz were obtined from the US Outptient Influenz-like Illness Surveillnce Network (IliNet), vilble from the Center for Disese Control s (CDC) FluView ppliction [19]. The percent of weekly outptient visits, recorded cross ll of New Englnd, for influenz-like-illness (defined s fever (temperture of 100 F or greter), cough, nd/or sore throt) ws extrcted nd served s proxy for regionl flu trends. Self-reports of respirtory infections in the prior week were lso vilble from the exposures questionnire, nd we compred the two sources of cold/flu dt. Sttisticl nlysis Associtions between short-term exposures to outdoor ir pollution nd COPD excerbtion were quntified with conditionl logistic regression in SAS, Version 9.3. Excerbtions were first modeled for single pollutnts, with ech pollutnt serving s the min explntory vrible nd COPD excerbtion s dichotomous outcome (conditionl on the individul subject IDs), nd then for vrious combintions of multiple pollutnts. Model building ws ccomplished by dding new vribles into the regression model mnully bsed on the 2 log likelihood ( 2LL) nd strength of ssocition. Min effect estimtes were expressed s odds rtios (OR)foronemicropercubicmeter(ug/m 3 )orprt per billion (ppb) increse in pollutnt concentrtion. Pollutnt concentrtions were modeled s the one-toseven-dy verge of dily 24-h verge concentrtions, s reported in Worcester, Wre, nd Springfield, MA. This sptil-temporl exposure metric ws selected fter completing sensitivity nlysis which investigted single dy lgs (up to mximum of seven dys) nd multi-dy verges (0 1 dys, 1 2 dys, 1 3 dys, 1 5 dys nd 1 7 dys) using vrious combintions of the three monitors [4]. In brief, concentrtions were verged cross ll three monitors becuse this ggregtion of dt provided the best fitting models nd the strongest effect estimtes. This pproch is lso consistent with the residentil loction of study prticipnts nd typicl est-to-west wind ptterns observed in this region [18], s well s supported in the USEPA Integrted Science Assessment document for PM [8]. Dily concentrtions were verged cross the seven previous dys becuse this metric resulted in the best fitting models, strongest effect estimtes nd ws consistent with our exposure questionnire, in which prticipnts were sked to recll exposures in the previous week. A multi-dy verging time ws lso pproprite for this study since the exct dte of excerbtion ws defined by the dy tht ptients contcted the nurses to sy their symptoms hd worsened. Ptients my hve been sick few dys before they clled; the nurses took ptients clls during norml working hours (7 m-5 pm, Mondy through Fridy). Confounding ws evluted by dding vribles into the model nd observing chnges in effect size. Potentil confounders were identified priori in published literture nd include meteorologicl vribles (such s temperture nd humidity), self-reported informtion from the

4 DeVries et l. Environmentl Helth (2016) 15:98 Pge 4 of 11 exposures questionnire (such s hours spent outdoors, exercise, respirtory nd non-respirtory infections) nd seson. All confounders were evluted using the sme seven dy verging time s the ir pollutnts, where pplicble. Two chronic COPD fctors were investigted s possible effect modifiers of the ssocition between outdoor ir pollution nd risk of excerbtion: COPD severity nd the presence/bsence of sthm s co-condition. The Globl Inititive for Chronic Obstructive Lung Disese (GOLD) defines widely-used COPD severity clssifiction scheme bsed on the forced expirtory volume in one second (FEV 1 ) [1]. GOLD clssifies severity of irflow limittion mong COPD ptients s mild to very severe s follows; mild=fev 1 80 % predicted, moderte = 50 % FEV 1 < 80 % predicted, severe = 30 % FEV 1 <50%predicted, nd very severe = FEV 1 < 30 % predicted [1]. All prticipnts were dichotomously clssified with either mild-moderte or severe-very severe COPD using this GOLD clssifiction scheme. A co-condition of sthm ws defined using self-reported history of ever receiving doctor dignosis of the disese. Potentil non-liner reltionships between ir pollutnt concentrtions nd COPD excerbtion were evluted by plotting univrite restricted cubic splines (RCS). RCS provide flexible nonprmetric pproch to study the shpe of the ssocition, while replcing the liner function of the exposure with smooth non-liner function [20, 21]. We used the SAS mcro lgtphcurv9, which implements nturl cubic spline methodology to fit potentil non-liner response curves in logistic regression models for cse-control studies [22]. A number of different splies with vrying knots were investigted, with ORs plotted on the y xis nd pollutnt concentrtions on the x xis. All splines were completed while mintining the mtch between study subjects nd with exposure reference levels set to the first qurtile concentrtion of ech pollutnt. RCS were lso developed for temperture nd humidity, with reference vlues represented by ssumed comfortble or low risk conditions (such s temperture of 70 F). Likelihood rtio tests were performed to test for liner reltions nd model fit ws compred between the liner nd spline models. Results A totl of 246 COPD ptients were enrolled in this study; 75 were subsequently excluded since they did not hve t lest one excerbtion over the course of the study period nd three were excluded becuse they were hospitlized or in long-term cre fcility within the seven dys prior to completing one of their exposure questionnires. The finl smple popultion included 168 COPD ptients, contributing informtion to 231 excerbtion nd 389 control periods. In generl, these prticipnts were predominntly white, over the ge of 65, retired nd with severe to very severe COPD (Tble 1). A mjority of prticipnts were ex-smokers while 20 % still smoked t the strt of the study. Nerly hlf hd received doctor dignosis of sthm. 65 % of prticipnts experienced one excerbtion over the study period, while 30 % experienced two excerbtions nd 5 % experienced three excerbtions. Averge dily NO 2 concentrtions mesured in Worcester, Wre nd Springfield rnged from 2.79 ppb to 40 ppb, verge SO 2 concentrtions rnged from 0.28 ppb to 7.51 ppb nd verge PM 2.5 concentrtions rnged from 0.45 ug/m 3 to 37 ug/m 3 (Tble 2). These concentrtions re fr below current Ntionl Ambient Air Qulity Stndrds (NAAQS), set t n nnul concentrtion of 53 ppb for NO 2, n nnul concentrtion of 12 ug/m 3 for PM 2.5, nd one hour concentrtion of 75 ppb for SO 2 [7 10]. The men concentrtion of PM 2.5 ws 71 % of current NAAQS while the men concentrtion of NO 2 ws 21 % of current NAAQS (Tble 2). When SO 2 is compred to the previous 1971 NAAQS, which ws bsed on n nnul men concentrtion, the yerly men in our study loction ws 7 % of the stndrd. We did not compre to current SO 2 NAAQS, s this vlue is now bsed on 1 h mximum. The concentrtions of ll three pollutnts showed typicl ptterns of higher nd more vrible concentrtions in the winter months (dt not shown). Pollutnt concentrtions were highly correlted with one nother in the winter (Tble 3), while in spring nd summer Tble 1 Demogrphics of smple popultion (n = 168 prticipnts) Age (men yers, SD) 70.1 (9.78) Femle, % (n) 60.1 (101) Rce, % (n) White 97 % (163) Blck 1.2 % (2) Other 1.8 % (3) Disese Severity, % (n) Mild 1.8 % (3) Moderte 23 % (38) Severe 50 % (82) Very Servere 18 % (30) Norml FEV1/FVC with COPD symptoms 7.1 % (12) Indequte spirometry (missing) 1.8 % (3) Doctor dignosed sthm, % (n) 43 % (73) Smoking Sttus, % (n) Current smoker 19 % (30) Ex smoker 81 % (131) Never smoked 4.2 % (7) Pck Yers (men, SD) 52 (30.89) Disese severity bsed on GOLD clssifiction

5 DeVries et l. Environmentl Helth (2016) 15:98 Pge 5 of 11 Tble 2 Summry sttistics for ir pollutnt nd meteorologicl vribles Pollutnt or meteorologicl vrible (units) Minimum Mximum Men ± St. dev Men s % of NAAQS b PM 2.5 (ug/m 3 ) ± % NO 2 (ppb) ± % SO 2 (ppb) ± % Reltive Humidity (%) ± 13.9 Temperture ( F) ± 17.1 Temperture ( C) ± 8.3 Air pollutnts: bsed on dily verges mesured in Worcester, Wre nd Springfield Temperture nd humidity: bsed on dily verges from Worcester Regionl Airport b Relevnt USEPA Ntionl Ambient Air Qulity Stndrds (NAAQS) PM 2.5 = 12 ug/m 3 nnul men, verged over 3 yers NO 2 = 53 ppb nnul men SO 2 = 30 ppb nnul men (bsed on USEPA 1971 vlue, which ws revoked in 2010 nd replced with 1-h mximum) they were wekly correlted. Pollutnt concentrtions tended to be poorly correlted with temperture nd humidity, with the exception of PM 2.5 nd temperture in the spring (r =0.52)ndsummer(r =0.62). Self-reported exposure to cold tempertures in the previous week modestly incresed the risk of excerbtion (OR = 1.16, 95 % CI: ), while self-reported exposure to hot tempertures decresed the risk of excerbtion (OR = 0.50, 95 % CI: ). When temperture ws evluted s continuous liner term, using the 1 7 dy verge of mesurements recorded t Worcester Regionl Airport, wek negtive ssocition ws observed (OR = 0.96, 95 % CI: ), further suggesting decresed risk of excerbtion with incresing tempertures. Similr effects were observed when using the 1 2 dy nd 1 3 dy verges of temperture s liner terms. The RCS, however, identified mrkedly non-liner reltionship between temperture nd excerbtion, nd showed considerble improvement in model fit over the liner model ( 2LL = 384 nd 443 for RCS nd liner model, respectively) (Fig. 1). The spline ws therefore used to crete trichotomous vrible with cut points t the pproximte inflection points of 40 F nd 50 F (4.4 C nd 10 C). When this ctegoricl representtion of temperture ws included in the conditionl logistic regression model with cold-cool tempertures set s the reference group, strong positive ssocition ws observed for moderte tempertures nd excerbtion (OR = 2.50, 95 % CI: ), while strong negtive ssocition ws found for the wrmhot tempertures nd excerbtion (OR = 0.55, 95 % CI: ). Humidity ws only modestly correlted with temperture (r = 0.27), but exhibited similr non-liner reltionship with risk of excerbtion. Anlogous to the pproch just described for temperture, dichotomous reltive humidity vrible ws creted from the spline (not shown), which Tble 3 Correltion between ir pollutnt nd meteorologicl vribles SO 2 NO 2 PM 2.5 Temperture b NO 2 Spring: 0.14 Summer: 0.03 Fll: 0.52** Winter: 0.80** PM 2.5 Spring: 0.30** Spring: 0.41** Summer: 0.20* Summer: 0.45** Fll: 0.39** Fll: 0.73** Winter: 0.79** Winter: 0.83** Temperture b Spring: 0.34** Spring: 0.02 Spring: 0.52** Summer: 0.24** Summer: 0.15* Summer: 0.62** Fll: 0.02 Fll: 0.04 Fll: 0.15* Winter: 0.13 Winter: 0.09 Winter: 0.11 Reltive Humidity b Spring: 0.09 Spring: 0.07 Spring: 0.01 Spring: 0.25** Summer: 0.13 Summer: 0.02 Summer: 0.07 Summer: 0.22** Fll: 0.14* Fll: 0.24** Fll: 0.28** Fll: 0.38** Winter: 0.02 Winter: 0.03 Winter: 0.08 Winter: 0.22** Vlues shown re Person Correltion Coefficients; * indictes p < 0.05 nd ** indictes p < h verge concentrtions; Worcester, Wre nd Springfield monitors from 2011 to 2012 b 24-h verge mesurements; Worcester Regionl Airport meteorologicl site from

6 DeVries et l. Environmentl Helth (2016) 15:98 Pge 6 of 11 Fig. 1 Restricted Cubic Spline for Temperture. Notes: Reference exposure vlue set t 70 F, including 5 knots. This figure displys restricted cubic spline from conditionl logistic regression with temperture s the predictor nd COPD excerbtion s the outcome indicted logicl cut point t 65 % reltive humidity. The liner nd dichotomous reltive humidity vribles did not fit the COPD excerbtion risk s well s temperture, nd so humidity ws not further evluted. Strong effects were lso observed for seson, with the strongest risk of COPD excerbtion in the fll (OR = 6.64, 95 % CI: ), followed by spring (OR = 2.59, 95 % CI: ) nd winter (OR = 2.38, 95 % CI: ). Since temperture ws highly correlted, seson ws not further evluted. Severl different vribles were investigted to study effects of respirtory infections on COPD excerbtion including: self-reported respirtory infection, non-respirtory infection, nd sinus infection, s well s regionl influenz trends (Tble 4). The strongest ssocition, by fr, ws found for self-reported respirtory infections (OR = 8.14, 95 % CI: ). This effect ws twice s strong s tht estimted with CDC s indictor of flu (OR = 3.78, 95 % CI: ), suggesting stronger effects when using individul level rther thn popultion level dt. Self-reported exercise nd hours spent outdoors were negtively ssocited with COPD excerbtion (Tble 4). This my be becuse those who exercised nd spent time outdoors were helthy enough to do so nd therefore less likely to excerbte. It my lso be tht those soon to excerbte were wre of the impending excerbtion nd djusted their behvior to intentionlly void more strenuous ctivities. In single-pollutnt models, SO 2 nd NO 2 were found to be positively ssocited with COPD excerbtion, OR = 2.78 (95 % CI: ) nd OR = 1.17 (95 % CI: ), respectively. Effect estimtes were slightly wekened for SO 2 (OR = 2.28 (95 % CI: ) nd NO 2 (OR = 1.06 (95 % CI: ) when temperture nd selfreported respirtory infection were included in the model, suggesting some confounding by these ltter vribles. Unexpectedly, smll negtive effect for PM 2.5 nd COPD excerbtion ws identified (OR = 0.93 (95 % CI: ), which ws unffected by temperture nd self-reported respirtory infection (Tble 5). Self-reported hours outdoors nd exercise did not confound these ssocitions or improve model fit. A positive liner ssocition for both SO 2 nd NO 2 nd risk of COPD excerbtion ws seen in univrite restricted cubic splines (tests for linerity yielded p vlues < ) while negtive liner ssocition ws observed for PM 2.5 nd COPD excerbtion (p = <0.0001). For ll three pollutnts, liner nd RCS models hd comprble fits ( 2LL improvement of less thn 1 %), suggesting tht the use of flexible smoothing splines did not improve upon the more prsimonious liner models. In order to gin insight into which individul pollutnts might influence COPD excerbtion independently of the effects of other pollutnts, multi-pollutnt models were explored (Tble 5). In multi-pollutnt conditionl logistic regression models, effect estimtes were stronger nd model fit improved for SO 2 nd NO 2 fter djustment for PM 2.5, nd vice vers. When both SO 2 nd NO 2 were included in models, the positive effect observed for NO 2 ws removed entirely. When ll three pollutnts were modeled together, stronger positive effects were observed

7 DeVries et l. Environmentl Helth (2016) 15:98 Pge 7 of 11 Tble 4 Non-chemicl triggers nd COPD excerbtion (Wether, flu, nd physicl ctivity) Vrible type Vrible description Odds rtio 95 % confidence intervl 2loglikelihood Wether Spent time in cold ir/cold wether in pst week Seson Spent time in hot ir/hot wether in pst week Locl Temperture (liner 7 dy verge) b Locl Temperture (ctegoricl) c Cool/Cold Moderte Wrm/Hot Locl Reltive Humidity (liner 7 dy verge) b Locl Reltive Humidity (ctegoricl) c High Low Seson, ref = summer Summer Spring Winter Fll Acute Illness Respirtory infection/cold in pst week Non-respirtory Illness in pst week Sinus infection in pst week Regionl Flu Trends; New Englnd d Physicl Activity Totl hours spent outside of the home, e Exercised in pst week Bsed on self-reports from exposure questionnires b Bsed on 7-dy verges using dt from NOAA collected t Worcester Regionl Airport c Ctegoricl representtion of vrible bsed on cut-offs identified in restricted cubic splines d Regionl proxy of flu from CDC dt; represented by percent of weekly outptient visits for influenz-like-illness in New Englnd e Estimted s sum of Hours Reported Outdoors, Hours Reported in Vehicle, nd Hours Reported Indoors but not t home Tble 5 Single nd multi-ir pollutnt models Model Without djustment With djustment b Single Pollutnt Models OR (95 % CI) -2 log likelihood OR (95 % CI) -2 log likelihood 1. NO SO PM Multi-Pollutnt Models 4. NO SO NO PM SO PM NO SO PM Odds Rtios (OR) represent one unit increse in pollutnt concentrtion (ppb or ug/m 3 ) b Adjusted for temperture (ctegoricl representtion bsed on cut-offs from RCS) nd self-reported respirtory infection

8 DeVries et l. Environmentl Helth (2016) 15:98 Pge 8 of 11 for SO 2 nd stronger negtive effects were observed for PM 2.5 ; there ws no impct on NO 2. Bsed on these findings, finl predictive model ws developed, which included SO 2,PM 2.5, nd the two identified confounders (temperture nd self-reported respirtory infection). NO 2 ws not included since inclusion of this pollutnt did not improve model fit or hve ny impct on the pollutnts, when including SO 2 nd PM 2.5.Inthis model, SO 2 showed strong positive effect (OR = 2.45, 95 % CI: ) nd PM 2.5 showed wek negtive effect (OR = 0.91, 95 % CI: ). Both self-reported respirtory infection (OR = 6.70, 95 % CI: ) nd temperture (moderte temperture OR = 2.45, 95 % CI: nd wrm-hot temperture OR = 0.95, 95 % CI: ) lso showed strong effects. As noted in the methods section, we lso investigted the risk of COPD excerbtion ssocited with self-reports of common exposures experienced in everydy life (i.e., ir fresheners, brbequing, rking leves, etc.). We found tht cr nd truck exhust nd scented lundry products were ssocited with incresed risk of excerbtion (Tble 6 in Appendix). These ssocitions, which re explored further in seprte publiction currently in preprtion, did not confound ny of the ssocitions between ir pollutnts nd COPD excerbtion. Nerly hlf (43 %) of the prticipnts reported tht they hd physicin-dignosed sthm s well s COPD. A similr extent of co-occurrence (this hs been termed Asthm nd COPD Overlp Syndrome (ACOS)) ppers to be common; recent met-nlysis found the prevlence of ACOS rnging from 13 to 56 % mong 9 published popultion bsed COPD studies [23]. Our study ws not designed to investigte differences in ir pollution effects in the presence or bsence of n sthm dignosis, but with the vilble dt we ttempted to evlute the hypothesis tht the presence of sthm s co-morbid condition might mke COPD ptients more susceptible to risk of excerbtion from ir pollutnts. In models strtified on sthmtic sttus, the only notble difference observed ws tht NO 2 ppered to hve somewht stronger effect mong non-sthmtics (OR = 1.14, 95 % CI: ) compred to sthmtics (OR = 0.94 ( )), lthough the smller smple size in these subgroups resulted in wide confidence intervls. In n nlogous wy, we evluted the hypothesis tht disese severity might modify response to ir pollution. Compring mild nd moderte to severe nd very severe COPD in the GOLD clssifiction, there did not pper to be importnt differences in the strength of the ssocitions between ny of the ir pollutnts studied nd COPD excerbtion. We repeted ll nlyses fter omitting the 7 % of subjects who hd norml FEV1/FVC with COPD symptoms (Tble 1); there were no importnt differences in the results. Discussion This study provides evidence for effects of short term exposures to reltively low levels of outdoor ir pollution on excerbtion of existing COPD mong ptients residing in centrl Msschusetts. The study found strong positive ssocitions between short-term exposures to outdoor SO 2 nd NO 2 nd COPD excerbtion. The estimte of the effect of NO 2 ws reduced, however, in the presence of SO 2 suggesting confounding or tht the two gseous pollutnts my compete with one nother in regression models. Risk estimtes for both pollutnts were considerbly lrger nd found t lower concentrtions thn reported in other studies of COPD-relted ED visits, HA, nd mortlity [4]. There re severl possible explntions for these findings. First, our study popultion of COPD ptients enrolled in DMG nd the cse-crossover design my hve enbled us to detect erlier nd milder cses of excerbtion tht would not hve resulted in ED visits or HA. Indeed, the gol of the DMG is precisely to intervene erly in the development of excerbtions to prevent these costly outcomes. This is demonstrted by the fct tht only seven of the 231 excerbtions cptured in this study resulted in hospitliztion. Also, the close monitoring of ptients by study nurses mde it possible to economiclly nd firly non-intrusively gther dt from ptients t rndom times when they were not experiencing excerbtions (control periods), which provided essentil comprison dt with which to compre the exposures immeditely prior to n excerbtion. It is lso possible tht these findings were due to chnce or n un-identified bis. For exmple, the mesured pollutnts my ctully represent surrogtes for nother source of ir pollution in this region, nd the findings my be n rtifct of mesurement error t low level concentrtions. Mesurement error is especilly problemtic for SO 2, since concentrtions in this region re often ner USEPA s level of detection (LOD), concentrtions for which there is well documented mesurement uncertinty [9]. On the other hnd, these results were robust upon djustment by mny different potentil confounders, including other criteri pollutnts nd meteorologicl vribles. It is possible tht stronger effects were observed here due to the more sensitive method of identifying excerbtions or since this study ws ble to control for importnt confounders on the individul level, by design. This is one importnt dvntge of the cse-crossover study; covrites which re either fixed or chnge only very slowly with time cnnot confound the observed ssocitions. Among these re ge, gender, smoking, nd occuptionl exposure history. An unexpected negtive ssocition ws found for shortterm exposures to outdoor PM 2.5 nd COPD excerbtion. While this is inconsistent with mjority of the published literture concerning ir pollution nd COPD-relted

9 DeVries et l. Environmentl Helth (2016) 15:98 Pge 9 of 11 ED-HA, there re number of possible explntions. The chemicl composition nd therefore toxicity of PM is highly vrible cross geogrphic res nd through time, mking it difficult to compre results from studies conducted in different regions nd in different sesons/ yers. For exmple, PM constituents in the estern US re known to hve higher sulfte concentrtions thn much of the rest of the country [8]. Furthermore, in the estern US, the sulfte component of PM is higher in the summer, when oxidtion of SO 2 occurs t fster rte thn in the winter [8]. PM components re lso known to vry by temperture, reltive humidity, nd wind speed [24]. A review of PM specition dt for USEPA fixed site monitors locted in Chicopee, MA (djcent to Springfield) nd Wre, MA demonstrted the complex temporl nd sptil nture of PM chemistry. In brief, the rtios of sulftes nd sulfur to totl PM 2.5 mss concentrtion were reltively stble cross the four sesons but consistently higher in the urbn re of Chicopee thn in rurl re of Wre. The rtios of nitrtes to totl PM, on the other hnd, were similr t both loctions but nerly two-folder higher in winter nd fll thn in the spring nd summer. It is lso possible our understnding of the effects of PM2.5 my need to be djusted to reflect long term chnges in ir pollution levels. USEPA estimtes tht PM 2.5 concentrtions dropped 10 % between 1999 nd 2007 [8], nd s pollutnt concentrtions continue to decline nd source contributions chnge, results estimted from studies published cross decdes my not be comprble in the sme wy tht results cross geogrphic res nd sesons my not be comprble. The unexpected results for PM 2.5 my lso be due to the selected exposure window. A mjority of published literture hs evluted shorter time periods of exposure (such s one or two dys) even though EPA recommends including longer time spns when evluting ssocitions between PM nd respirtory outcomes, in their ISA documents [8]. Longer lg/verging times re considered biologiclly plusible due to PM effects on llergic sensitiztion nd lung immune defenses, which hve been observed in controlled humn exposure nd niml toxicologicl studies [8]. Still, it is not cler whether the seven-dy window tht we chose to use ws pproprite nd whether n even longer exposure period my hve been more suitble. When exploring temporl vrition in our sensitivity nlyses, evidence for ir pollutnt effects on COPD excerbtion ws observed s fr s thirty dys prior to the helth event (dt not shown). Finlly, these unexpected results rise the interesting question of publiction bis, which will occur if the published literture is systemticlly unrepresenttive of the popultion of studies tht were ctully completed [25]. If other studies hve been completed in res of similr concentrtions but not published due to wek, null, negtive or inconsistent findings, it could led to the flse conclusion tht our results re inconsistent with the generl stte of the science. Consistent with existing literture, this study found tht temperture nd seson were ssocited with COPD excerbtion, independent of ir pollution, with higher risks in colder sesons [26, 27]. This study lso found tht low humidity incresed the risk COPD excerbtion while higher humidity ppered protective, lthough confidence intervls were wide. Similr findings were reported by Qui nd collegues in recent time series study tht evluted theimpctofsesonndhumidityoncopdhospitliztions in Hong Kong [28]. They reported stronger effects on cold nd dry dys, hypothesizing tht humid conditions protect mucous membrnes ginst toxic insults [28]. Since temperture nd humidity re independent risk fctors for COPD excerbtion but lso mjor drivers of dy-to-dy fluctutions of ir pollution concentrtions, tesing prt the independent effects of ir pollution nd climte cn be difficult. Correltions mong pollutnts nd meteorologicl vribles vried considerbly cross sesons nd therefore models fit to dt for n entire yer my retin importnt residul confounding or result in over-fitting for some sesons [29]. This study quntified ir pollution exposures using secondry dt collected t USEPA fixed centrl monitors, covering the ctchment re of the study popultion. This introduced the potentil for exposure misclssifiction, which my hve bised results. This includes exposure misclssifiction due to; 1) nlyticl mesurement error (which likely vries cross pollutnts nd by seson); 2) dy-to-dy vribility t the monitor versus dy-to-dy vribility in the lrger geogrphic region; nd 3) discrepncies between personl exposures nd outdoor ir pollution concentrtions. We expect tht the misclssifiction from these sources ws likely nondifferentil with respect to COPD excerbtions nd thus on verge would be expected to result in n underestimtion of the true ssocition. Although the cse crossover study design hs mny dvntges when studying cute outcomes, the mtched nture of this design could hve introduced some bis. The cse crossover design is limited in its bility to explore effect modifiction by vribles tht chnge through time (such s seson,temperture,ndhumidity).itispossiblethtwe might hve found different results, prticulrly for PM 2.5,if we were ble to look t risk seprtely within the different sesons. This is especilly true since the ir pollution effect estimtes were smll reltive to the estimted effects of seson. It is lso possible tht we might hve observed different effects if we hd bidirectionl control smpling, where control periods were ssigned shortly before nd fter excerbtion within the sme seson [30, 31]. However, this design is difficult in prctice for debilitting outcome like COPD excerbtion, which cn lst up to month.

10 DeVries et l. Environmentl Helth (2016) 15:98 Pge 10 of 11 Conclusions This study found consistent positive effects of SO 2 nd modest negtive effects of PM 2.5 on COPD excerbtion, t concentrtions below current USEPA NAAQS. The mgnitude of risk of COPD excerbtion from exposure to outdoor SO 2 ws generlly higher thn reported in other studies. This study lso found positive effect of NO 2 ; however, this effect ws only significnt when included in models with PM 2.5. If supported by dditionl studies with better exposure ssessments, these findings my suggest risk of COPD excerbtion t lower ir pollution concentrtions thn reported for COPD-relted ED, HA, nd mortlity. Chrcteriztion of ir pollution in the context of COPD excerbtion studied here (experienced in the persons home nd therefore not necessrily requiring visit to the emergency room or hospitl) should be conducted in other loctions with different sources of pollutnts nd climte. This would improve our understnding of the complex reltionships between ir pollutnt nd meteorologicl vribles nd their influence on risk of COPD excerbtion. Appendix Tble 6 Finl model including cr/truck exhust nd scented lundry Vrible Odds rtio 95 % confidence intervl SO PM Temperture b Cool/Cold Moderte Wrm/Hot Respirtory Infection/Cold c Cr/Truck Exhust c Scented Lundry c Bsed on 7-dy verges using dt from USEPA collected in Springfield, Wre nd Worcester b Bsed on 7-dy verges using dt from NOAA collected t Worcester Regionl Airport c Bsed on self-reports of exposures in previous week; collected from questionnires Abbrevitions AQS: Air qulity system; CDC: Center for Disese Control; COPD: Chronic obstructive pulmonry disese; DMG: Disese mngement group; ED: Emergency deprtment visit; FEV 1 : Forced expirtory volume in one second; GOLD: Globl Inititive for Chronic Obstructive Lung Disese; HA: Hospitliztion; IliNet: Influenz like illness surveillnce network; LOD: Level of detection; NAAQS: Ntionl Ambient Air Qulity Stndrds; NCDC: Ntionl Climtic Dt Center; NOAA: Ntionl Ocenic nd Atmospheric Administrtion; NO2: Nitrogen dioxide; OR: Odds rtio; O: Ozone; PM 10 : Prticulte mtter; PM 2.5 : Prticulte mtter; ppb: Prts per billion; SO2: Sulfur dioxide; RCS: Restricted cubic splines; ug/m 3 : Microgrm per cubic meter; 2LL: 2 log likelihood Acknowledgments The uthors thnk Dr. Rebecc Gore, sttisticl nlyst in the Deprtment of Work Environment t the University of Msschusetts Lowell, for ssistnce with dt mngement nd nlysis. We lso thnk K. Allin, B. Vlenti, M. Li, C. Anderson, D. Sundresn nd R. Rosiello, MD (Relint Medicl Group) for superb project mngement nd the COPD ptients who generously greed to prticipte in our study. Funding Ntionl Institute of Helth R21-ES Ntionl Institute for Occuptionl Sfety nd Helth T01-OH Avilbility of dt nd mterils Supporting dt nd mterils cn be mde vilble upon request. Authors contributions DK nd SS designed the study nd obtined federl funding for this reserch. All three uthors prticipted in dt collection nd nlysis. RD took the led on the nlysis of ir pollution effects nd drfted the pper. All three uthors prticipted in writing the pper nd pproved the finl mnuscript. Competing interests The uthors declre tht they hve no competing interests. Consent for publiction Not pplicble. Ethics pprovl nd consent to prticipte All study mterils nd protocols were pproved by the Relint Medicl Group Institutionl Review Bord. Received: 22 October 2015 Accepted: 10 September 2016 References 1. 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