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Association of Occupational Exposure to Disinfectants With Incidence of Chronic Obstructive Pulmonary Disease Among US Female Nurses

Association of Occupational Exposure to Disinfectants With Incidence of Chronic Obstructive... Key Points Question Is exposure to disinfectants IMPORTANCE Exposure to disinfectants in health care workers has been associated with respiratory and cleaning products associated with health outcomes, including asthma. Despite the biological plausibility of an association between incidence of chronic obstructive disinfectants (irritant chemicals) and risk of chronic obstructive pulmonary disease (COPD), available pulmonary disease among health data are sparse. care workers? Findings In a cohort study of 73 262 US OBJECTIVE To investigate the association between exposure to disinfectants and COPD incidence female nurses participating in the in a large cohort of US female nurses. Nurses’ Health Study II who were followed up from 2009 to 2015, DESIGN, SETTING, AND PARTICIPANTS The Nurses’ Health Study II is a US prospective cohort occupational exposure to cleaning study of 116 429 female registered nurses from 14 US states who were enrolled in 1989 and followed products and disinfectants was up through questionnaires every 2 years since. The present study included women who were still in significantly associated with a 25% to a nursing job and had no history of COPD in 2009, and used data from the 2009 through 2015 38% increased risk of developing questionnaires. Clean and complete data used for this analysis were available in July 2018, and chronic obstructive pulmonary disease analyses were conducted from September 2018 through August 2019. independent of asthma and smoking. EXPOSURES Occupational exposure to disinfectants, evaluated by questionnaire and a job-task- Meaning This study’s findings suggest exposure matrix (JTEM). that regular use of chemical disinfectants among nurses may be a MAIN OUTCOMES AND MEASURES Incident physician-diagnosed COPD evaluated by risk factor for developing chronic questionnaire. obstructive pulmonary disease. RESULTS Among the 73 262 women included in the analyses, mean (SD) age at baseline was 54.7 Supplemental content and Audio (4.6) years and 70 311 (96.0%) were white, 1235 (1.7%) black, and 1716 (2.3%) other; and 1345 (1.8%) Hispanic, and 71 917 (98.2%) non-Hispanic. Based on 368 145 person-years of follow-up, 582 nurses Author affiliations and article information are listed at the end of this article. reported incident physician-diagnosed COPD. Weekly use of disinfectants to clean surfaces only (16 786 [22.9%] of participants exposed) and to clean medical instruments (13 899 [19.0%] exposed) was associated with COPD incidence, with adjusted hazard ratios of 1.38 (95% CI, 1.13-1.68) for cleaning surfaces only and 1.31 (95% CI, 1.07-1.61) for cleaning medical instruments after adjustment for age, smoking (pack-years), race, ethnicity, and body mass index. High-level exposure, evaluated by the JTEM, to several specific disinfectants (ie, glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds) was significantly associated with COPD incidence, with adjusted hazard ratios ranging from 1.25 (95% CI, 1.04-1.51) to 1.36 (95% CI, 1.13-1.64). Associations were not modified by smoking or asthma status (P for interaction > .15). CONCLUSIONS AND RELEVANCE These longitudinal results suggest that regular use of chemical disinfectants among nurses may be a risk factor for developing COPD. If future studies confirm these (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 1/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Abstract (continued) results, exposure-reduction strategies that are compatible with infection control in health care settings should be developed. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide and among the diseases contributing the most to disability-adjusted life-years. Although tobacco smoke remains the major risk factor for COPD development in the United States and other industrialized countries, occupational exposures contribute substantially to the burden of disease. A growing body of data suggests that 15% to 20% of cases of COPD are attributable to occupational 3,4 exposures. However, despite the general recognition of an association between occupational 2,5 5,6 exposures and COPD, few individual causal agents have been identified. Most studies on occupation and COPD have investigated broad exposure categories (eg, “vapor, gases, dust, or fumes”), which include many agents. Industry-specific studies, which generally provide more insight regarding specific causal agents than population-based studies, have focused on a limited number of occupational settings, which are often occupations with predominantly male workers. Although chemical exposures are an important component of vapor, gases, dust, or fumes and may account 4,8 3 for a large part of COPD risk, their association with COPD remains unclear. Exposure to cleaning products and disinfectants is common at work and at home and remains 9,10 11 more frequent among women. Exposure levels are particularly high in the health care industry, one of the largest employment sectors in the United States and Europe. The respiratory health risks associated with exposure to cleaning products and disinfectants are increasingly recognized. 13-15 Although investigators have primarily focused on asthma, the irritant properties of many chemicals contained in disinfectants support the study of a broader range of respiratory effects. A 16,17 few European studies have reported an increased risk of COPD, accelerated lung function 9 18 decline, and higher rates of death due to COPD among cleaning workers. However, to our knowledge, no study to date has investigated the association of occupational exposure to disinfectants and cleaning products with COPD risk among health care workers, nor has any study suggested specific chemicals that may underlie the association between cleaning jobs and COPD. Determining specific agents associated with adverse health outcomes is crucial in health care settings. Indeed, prevention strategies are often based on avoidance of the causal agent(s); however, adequate levels of disinfection must be maintained in health care settings to protect patients and workers from nosocomial infections. Using data from the Nurses’ Health Study II (NHSII), a large, ongoing, prospective study of US female nurses, we investigated the association between exposure to disinfectants and cleaning products and risk of incident COPD. Methods Population The NHSII began in 1989 when 116 429 female registered nurses from 14 US states, aged 25 to 44 years, completed a questionnaire about their medical history and lifestyle characteristics. Follow-up questionnaires have been sent every 2 years since. The NHSII was initially designed to study women’s health (eg, long-term health effects or oral contraceptive use; determinants of major chronic diseases in women, such as breast cancer or cardiovascular disease), and the range of risk factors and health outcome data collected has expanded over time. Information on occupational exposures was collected for the first time in 2009, which was defined as the baseline for the present study. This JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 2/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses investigation was approved by the institutional review board at Brigham and Women’s Hospital, and participants provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Among the 116 429 participants in the NHSII, 98 817 returned at least 1 biennial questionnaire during the follow-up period (2011-2015); of these, 76 331 were still in a nursing job (eFigure in the Supplement). Among these respondents, we selected women without missing data for occupational exposure and pack-years of smoking who had not reported any history of COPD at baseline (2009). Clean and complete data used for this analysis were available in July 2018, and analyses were conducted from September 2018 through August 2019. Occupational Exposure to Disinfectants Information on nursing job types (education or administration, outpatient/other nurses, emergency department or inpatient unit, and operating room) and general disinfection tasks (frequency of use of disinfectants to clean surfaces/medical instruments) was collected by questionnaire in 2009, 2011, and 2013. Information on the use of sprays (for instrument cleaning/disinfection, surface cleaning/disinfection, patient care, air refreshing, or other) was collected in 2011 and 2013. Disinfection tasks were studied using a dichotomous (weekly use of disinfectants to clean surfaces or medical instruments vs less than weekly) and a 3-level (no disinfection task performed weekly, weekly use of disinfectants to clean surfaces only, or weekly use of disinfectants to clean medical instruments regardless of the use of disinfectants to clean surfaces) variable. Frequency of cleaning or disinfection tasks and spray use (never, <1 d/wk, 1-3 d/wk, or 4-7 d/wk) was also examined. Exposure to 7 of the most commonly used disinfectants or cleaning products (formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide, alcohol, quaternary ammonium compounds, and enzymatic cleaners) was evaluated by a nurse-specific job-task-exposure matrix (JTEM), as described in detail elsewhere and in the eAppendix in the Supplement. The JTEM assigned exposure level (low, medium, or high) based on types of nursing jobs and general disinfection tasks. Exposure to specific disinfectants according to the JTEM was thus studied using 3-level variables, with separate models for each disinfectant. Then, because nurses were often classified as exposed to multiple products, we studied exposure to combinations of several specific products evaluated by the JTEM for the products found associated with COPD when studied separately. COPD Incidence In biennial questionnaires, participants were asked to report any condition(s) with which they were diagnosed since the last questionnaire cycle, including emphysema or chronic bronchitis. We used this information to identify incident cases of physician-diagnosed COPD (primary case definition) from 2009 to 2015. Between October 2015 and December 2017, we sent a supplemental questionnaire on COPD to participants who reported a physician’s diagnosis of emphysema or chronic bronchitis in any past biennial questionnaire. Based on information collected on the supplemental questionnaire, we selected participants who reiterated that a physician had diagnosed them as having emphysema, chronic bronchitis, COPD, or any combination of these. This definition (stringent case definition), validated in a random sample of participants with COPD in NHSII (eAppendix in the Supplement), was used in a sensitivity analysis. Statistical Analysis Prospective associations between occupational exposures and COPD incidence were evaluated by using Cox proportional hazards regression models. In each model, occupational exposure was handled as a time-varying variable and was evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. All Cox proportional hazards regression models were stratified by age and calendar year. For race and ethnicity, multiple categories were combined to JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 3/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses create binary general categories. Analyses were adjusted for race (white vs black and other), ethnicity (Hispanic vs non-Hispanic), smoking habits (nonsmoker, ex-smoker, or current smoker), pack-years of smoking, and body mass index (calculated as weight in kilograms divided by height in meters squared into categories of <25.0, 25.0-29.9, and 30.0). Several sensitivity analyses were conducted, further adjusting the models for diet quality as measured by the Alternate Healthy Eating 26 2 Index 2010, divided into quintiles, or for pack-years of smoking and excluding participants with previous comorbidities (cardiovascular diseases and cancer). We performed stratified analyses by smoking status, asthma status, and job change (any change in job type from the 2009 to 2013 questionnaires) and tested interactions in multivariable models. We estimated the population- attributable fraction of weekly use of any disinfectant on COPD risk among female nurses as PAF = pc(1 − 1/AHR), in which PAF is the population-attributable fraction; pc, the prevalence of exposure among cases of COPD; and AHR, the adjusted hazard ratio. A 2-sided P < .05 was considered statistically significant. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc). Results Among the 73 262 women who were eligible for analysis, mean (SD) age at baseline (in 2009) was 54.7 (4.6) years; 70 311 (96.0%) were white, 1235 (1.7%) black, and 1716 (2.3%) other; 1345 (1.8%) were Hispanic and 71 917 (98.2%) non-Hispanic; 4162 (5.7%) were current smokers and 20 631 (28.2%) were former smokers. Regarding cleaning/disinfection tasks, 16 786 (22.9%) of the nurses reported weekly use of disinfectants to clean surfaces only, and 13 899 (19.0%) reported weekly use of disinfectants to clean medical instruments. Very small but statistically significant differences were seen in sociodemographic characteristics according to disinfection tasks (Table 1); in particular, nurses reporting weekly use of disinfectants were younger and more often former or current smokers. Cleaning/Disinfection Tasks and COPD Incidence Based on 368 145 person-years of follow-up from 2009 to 2015, 582 nurses reported incident physician-diagnosed COPD. In multivariable models, no single nursing job type was associated with COPD incidence, although a significant trend toward an increased risk of COPD incidence was observed when classifying jobs according to the level of disinfectant use (Table 2). Weekly use of any disinfectants was positively associated with COPD incidence, with an adjusted hazard ratio (AHR) of 1.35 (95% CI, 1.14-1.59). The corresponding population-attributable fraction (calculated in combination with a prevalence of exposure among cases of COPD of 45%) was 12%. Associations were observed for use of disinfectants both to clean surfaces only (AHR, 1.38; 95% CI, 1.13-1.68) and to clean medical instruments (AHR, 1.31; 95% CI, 1.07-1.61). When we examined the frequency of cleaning/disinfection tasks (Figure), risk of COPD incidence was highest among nurses with the greatest frequency of use (4-7 d/wk). A significant dose-response association was observed for the use of any disinfectants (for frequency of 4-7 d/wk: AHR, 1.43; 95% CI, 1.13-1.80; P for trend < .001) and disinfectants to clean surfaces (for frequency of 4-7 d/wk: AHR, 1.37; 95% CI, 1.09-1.72; P for trend, .003). Weekly use of spray (vs less than weekly) was not significantly associated with COPD incidence. However, when we examined frequency of spray use, a significant trend toward an increased risk of COPD incidence with higher frequency of use was observed (P for trend, .03), with a dose-response association. Results were similar in sensitivity analyses excluding participants with previous comorbidities (cardiovascular diseases and cancer) or in models further adjusted for pack-years of smoking or diet quality (eTable 1 in the Supplement). Moreover, the association between weekly use of any disinfectants and COPD incidence was significant and similar in never smokers (AHR, 1.34; 95% CI, 1.03-1.73; eTable 2 in the Supplement) and ever smokers (AHR, 1.38; 95% CI, 1.11-1.71; P for interaction = .91) and in participants with asthma (AHR, 1.37; 95% CI, 1.02-1.84; eTable 3 in the JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 4/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Supplement) and without asthma (AHR, 1.31; 95% CI, 1.03-1.66; P for interaction = .78). When we examined the types of disinfection tasks, the association between use of disinfectants to clean surfaces only and COPD incidence was more pronounced among ever smokers and participants without asthma, whereas the association between use of disinfectants to clean medical instruments and COPD incidence was more pronounced among never smokers and participants with asthma. Nonetheless, the latter differences by smoking or asthma status were not statistically significant (all P for interaction > .15). The association between weekly use of any disinfectants and COPD incidence was also similar in participants who changed nursing job type between 2009 and 2013 (47 788 [65%]; AHR, 1.41; 95% CI, 1.14-1.73) and participants who did not (25 474 [35%]; AHR, 1.33; 95% CI, 1.00-1.78; P for interaction = .52). In the sensitivity analysis using a more stringent COPD definition (eTable 4 in the Supplement), the association between use of disinfectants to clean surfaces only and COPD incidence was similar (AHR, 1.32; 95% CI, 0.99-1.78; P = .06), although statistical power was no longer significant owing to fewer cases of COPD. In contrast, the association between use of disinfectants to clean instruments and COPD incidence was no longer significant (AHR, 1.14; 95% CI, 0.83-1.56; P = .41). Specific Disinfectants/Cleaning Products Evaluated by JTEM and COPD Incidence In multivariable models using the JTEM estimates (Table 3), no statistically significant association was observed between high-level exposure to enzymatic cleaners (AHR, 1.05; 95% CI, 0.84-1.31) or formaldehyde (AHR, 1.20; 95% CI, 0.92-1.57) and COPD incidence. In contrast, high-level exposure to glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds was significantly associated with increased risk of COPD incidence, with AHRs ranging from 1.25 (95% CI, 1.04-1.51) to 1.36 (95% CI, 1.13-1.64). No significant association was observed when we compared Table 1. Baseline Characteristics of the Study Population According to Disinfectant Use Among 73 262 US Female Nurses Weekly Use of Disinfectants to Clean Surfaces and/or Instruments None Surface Only Instruments Population Characteristics (n = 42 577) (n = 16 786) (n = 13 899) P Value Age, mean (SD), y 55.0 (4.6) 54.5 (4.6) 54.1 (4.6) <.001 Race White 40 908 (96.1) 16 120 (96.0) 13 283 (95.6) Black 746 (1.7) 274 (1.6) 215 (1.5) <.001 Other 923 (2.2) 392 (2.3) 401 (2.9) Ethnicity Hispanic 761 (1.8) 338 (2.0) 246 (1.8) Non-Hispanic 41 816 (98.2) 16 448 (98.0) 13 653 (98.2) Smoking status Never smoker 28 050 (65.9) 11 286 (67.2) 9129 (65.7) Former smoker 12 290 (28.9) 4514 (26.9) 3827 (27.5) <.001 Current smoker 2233 (5.2) 986 (5.9) 943 (6.8) Pack-years of cigarette smoking 13.6 (11.9) 13.4 (11.6) 14.2 (12.3) .05 among ever smokers, mean (SD) BMI at baseline <20.0 1900 (4.6) 750 (4.7) 590 (4.4) 20.0 to 24.9 14 583 (35.5) 5641 (35.2) 4596 (34.5) 25.0 to 29.9 12 512 (30.5) 4878 (30.4) 4270 (32.1) ≥30.0 12 101 (29.4) 4764 (29.7) 3853 (29.0) Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters Job type squared); ED, emergency department. Education or administration 11 085 (26.0) 1431 (8.5) 588 (4.2) Data are presented as number (percentage) unless Outpatient, other nurses 23 714 (55.7) 8945 (53.3) 6768 (48.7) otherwise stated. Values of categorical variables may <.001 ED or inpatient unit 6647 (15.6) 4830 (29.4) 5104 (36.7) not total 100% because of rounding. Operating room 1131 (2.7) 1580 (9.4) 1439 (10.4) There were 2824 missing values (3.8%) for BMI. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 5/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses medium- and low-exposure level (AHRs ranged from 1.18 [95% CI, 0.95-1.46] to 1.32 [95% CI, 0.98- 1.79]) except for glutaraldehyde (AHR, 1.50; 95% CI, 1.18-1.90). When we analyzed combinations of specific products (eTable 5 in the Supplement), no associations with COPD incidence were observed among nurses exposed to alcohol or quaternary ammonium compounds only or to aldehydes (formaldehyde or glutaraldehyde) but not to the other products. In contrast, a significantly increased risk of COPD incidence was observed among nurses exposed to hypochlorite bleach or hydrogen peroxide with or without aldehydes. Discussion This analysis of a cohort of 73 262 US nurses followed up across 6 years showed that occupational exposure to disinfectants was prospectively associated with a higher risk of developing COPD. Self- reported cleaning/disinfection tasks and exposure to several specific disinfectants evaluated by a JTEM, including glutaraldehyde, bleach, hydrogen peroxide, and alcohol and quaternary ammonium compounds, were associated with a 25% to 38% increased risk of COPD incidence. To our knowledge, this is the largest prospective study to date to investigate the association of exposure to cleaning products and disinfectants with COPD incidence. Two large cross-sectional studies in Europe (of 13 499 and 502 649 participants) have reported an increased risk of 17 16 self-reported or spirometry-defined COPD, respectively, among professional cleaners. In a cross- sectional study of US working adults, the highest prevalence of self-reported COPD was found among health care support occupations. In 2018, a prospective analysis of 6235 participants in the European Community Respiratory Health Survey who were followed up for 20 years further showed that women cleaning at home or working as cleaners had accelerated decline in lung function, independently of asthma. These recent findings confirmed older and smaller analyses of population-based studies reporting increased risk of COPD or chronic bronchitis among cleaners or 29,30 health care–related professions. Thus, our longitudinal results are consistent with the few data Table 2. Prospective Association of Job Types and Self-reported Cleaning/Disinfection Tasks With Chronic Obstructive Pulmonary Disease Incidence Among US Female Nurses Age-Adjusted HR Multivariable-Adjusted HR a b Occupational Exposure Person-Years No. of Cases (95% CI) P for Trend (95% CI) P for Trend Job type Education or administration 52 909 85 1 [Reference] 1 [Reference] Outpatient, other nurses 196 143 285 0.99 (0.78-1.26) 1.03 (0.81-1.32) .004 .02 ED or inpatient unit 95 095 168 1.32 (1.01-1.71) 1.24 (0.95-1.62) Operating room 23 998 44 1.36 (0.94-1.96) 1.38 (0.96-1.99) Weekly use of disinfectant None 183 480 276 1 [Reference] 1 [Reference] Any disinfectant 184 665 306 1.35 (1.14-1.59) 1.35 (1.14-1.59) NA NA Surface only 93 443 161 1.35 (1.11-1.65) 1.38 (1.13-1.68) Instruments 91 222 145 1.35 (1.10-1.65) 1.31 (1.07-1.61) Weekly use of sprays No 196 903 214 1 [Reference] 1 [Reference] NA NA Yes 56 702 75 1.31 (1.00-1.70) 1.27 (0.97-1.66) Abbreviations: ED, emergency department; HR, hazard ratio; NA, not applicable. for pack-years of smoking (<0.5%) were excluded from analyses. Observations with a missing values for body mass index (3.8%) were included in the model as a “missing” Exposure was evaluated as the highest exposure level at any of the questionnaire category. cycles before time of diagnosis. Follow-up periods were 2009 to 2015 for job type and use of disinfectants (368 145 person-years; 582 cases) and 2011 to 2015 for use of Job types are classified in increasing order of frequency of disinfectant use, as shown sprays (253 606 person-years; 289 cases). Job type, weekly use of disinfectant, and previously. weekly use of spray were evaluated in separate models. d Use of sprays for patient care, instrument cleaning or disinfection, surface cleaning or Multivariable models were adjusted for age, smoking status and pack-years disinfection, air refreshing, or other. (continuous), race, ethnicity, and body mass index. Observations with missing values JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 6/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses available in the literature and strengthen evidence of a role of exposure to disinfectants in COPD pathogenesis. In addition, our study extends previous findings by examining disinfection tasks and exposure to specific chemicals among health care workers in relation to COPD. This question is of particular importance to provide guidance for the development of prevention strategies. We found that use of several specific disinfectants was associated with higher risk of COPD development; these included hypochlorite bleach (chlorine), hydrogen peroxide, alcohol, and quaternary ammonium compounds (commonly used for low-level disinfection of noncritical items, such as environmental surfaces) and glutaraldehyde (used for high-level disinfection). Several of these exposures often occurred concurrently, and disentangling the role of each product was challenging. When studying combinations of exposure to specific disinfectants, we found the highest risks of COPD incidence among nurses exposed to hypochlorite bleach or hydrogen peroxide and in those combining these Figure. Prospective Association Between Self-reported Frequency of Cleaning/Disinfection Tasks and Chronic Obstructive Pulmonary Disease (COPD) Incidence Among US Female Nurses a b A Any disinfectant B Spray 2.5 2.5 P for trend <.001 P for trend = .03 1.43 1.40 1.38 1.35 1.26 1.12 1.0 1.0 0.7 0.7 Never <1 1-3 4-7 Never <1 1-3 4-7 [Reference] [Reference] Frequency of Use, d/wk Frequency of Use, d/wk No. at risk No. at risk Person-years 105 784 77 709 100 095 83 902 Person-years 143 499 53 404 33 384 23 318 No. of COPD cases 163 113 165 140 No. of COPD cases 147 67 43 32 C Clean surfaces D Clean instruments 2.5 2.5 P for trend = .003 P for trend = .02 1.37 1.35 1.31 1.25 1.16 1.09 1.0 1.0 0.7 0.7 Never <1 1-3 4-7 Never <1 1-3 4-7 [Reference] [Reference] Frequency of Use, d/wk Frequency of Use, d/wk No. at risk No. at risk Person-years 115 245 79 293 95 325 77 627 Person-years 212 850 63 754 55 340 35 546 No. of COPD cases 185 116 152 128 No. of COPD cases 326 110 82 62 Occupational exposure was evaluated as the highest exposure level at any of the indicate 95% CIs. Adjusted hazard ratios (AHRs) with 95% CIs are shown for type of questionnaire cycles before time of diagnosis. The follow-up periods were 2009 to 2015 disinfectant (A and B) and specific use of disinfectant (C and D). for job type and use of disinfectants and 2011 to 2015 for use of sprays. Multivariable a Use of a disinfectant to clean surfaces or instruments. models were adjusted for age, smoking status and pack-years (continuous), race, Use of sprays for patient care, instrument cleaning or disinfection, surface cleaning or ethnicity, and body mass index. Observations with missing values for pack-years of disinfection, air refreshing, or other. smoking (<0.5%) were excluded from analyses. Observations with missing values for body mass index (3.8%) were included in the model as a “missing” category. Error bars JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 7/13 AHR AHR AHR AHR JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses exposures with exposure to aldehydes. Both the chemical properties of specific products and the greater number of products used could explain these elevated risks. Moreover, all of the agents that were associated with COPD incidence when evaluated separately have been described as airway 31-34 irritants. Inhalation of irritant chemicals may cause injury of the airway epithelium and oxidative 35-37 stress and may be associated with neutrophilic inflammation. Oxidative stress is now recognized to have an important role in COPD pathogenesis and to partly result from environmental exposures. In addition, neutrophilic inflammation is seen in most patients with COPD and correlates with disease severity. It is notable that exposure to enzymatic cleaners, which have previously been associated with asthma outcomes but are known to contain sensitizers rather than irritants, was not associated with COPD. Although the associations between exposure to specific disinfectants and COPD incidence must be replicated in independent cohorts and underlying pathophysiological mechanisms must be clarified, there is a biological plausibility that long-term exposure to irritant disinfectants and cleaning agents could contribute to persistent airway damage and COPD pathogenesis. Strengths and Limitations Major strengths of our study include the large population, longitudinal design, and use of a nurse- specific JTEM to evaluate occupational exposure. Previous studies were limited in exposure assessment because they relied only on job titles or self-reported use of general products (sprays or other cleaning products). To evaluate specific exposures in large cohorts, the use of job-exposure matrices is generally favored over self-report. In this population of nurses, we further showed that using a JTEM, which assigns exposure level based not only on nursing job types but also on disinfection tasks, provides better exposure estimates than a job-exposure matrix by reducing 14,24 exposure misclassification. Nursing job types and disinfection tasks were self-reported; however because associations were evaluated prospectively (ie, exposure was evaluated before the report of COPD diagnosis), differential recall bias is unlikely. Moreover, we observed dose-response associations for both self-reported cleaning/disinfection tasks and specific exposures evaluated by the JTEM. Nonetheless, our study had some limitations with regard to exposure assessment. First, the JTEM only evaluated exposure to 7 major products used in US health care settings; exposure to less common products (eg, ortho-phthalaldehyde, peracetic acid, acetic acid, ammonia, phenolics, ethylene oxide, chloramine-T, and “green” products) could not be assessed with this method. Although a previous study using NHSII data found that fewer than 10% of nurses used these products weekly, their potential association with COPD development should be examined in future research. Second, we did not collect information regarding the use of protective equipment during cleaning/ Table 3. Prospective Associations Between Exposure to Specific Disinfectants/Cleaning Products Evaluated by Job-Task-Exposure Matrix and Chronic Obstructive Pulmonary Disease Incidence Among US Female Nurses Multivariable-Adjusted HR a b Occupational Exposure Person-Years No. of Cases (95% CI) Formaldehyde 38 056 62 1.20 (0.92-1.57) Glutaraldehyde 125 281 192 1.25 (1.04-1.51) Hypochlorite bleach 127 879 215 1.36 (1.13-1.64) Hydrogen peroxide 141 504 229 1.29 (1.08-1.54) Alcohol 150 512 245 1.32 (1.10-1.59) Quaternary ammonium compounds 142 722 233 1.33 (1.11-1.60) Enzymatic cleaners 69 447 97 1.05 (0.84-1.31) Abbreviation: HR, hazard ratio. Exposure was evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Associations presented compare high-exposure level vs low-exposure level for each product. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Observations with missing values for body mass index (3.8%) were included in the model as a “missing” category. Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity, and body mass index. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 8/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses disinfection tasks in this large population. However, in a substudy on occupational exposures conducted among NHSII nurses with asthma in 2014, 5% of the participants reported using a face mask or other respiratory protection devices when working with disinfectants, and the use of respiratory protections did not modify the association between disinfectant exposure and poor asthma control. Third, data regarding complete occupational exposure history were not available; indeed, detailed assessment of disinfectant exposure has only been available since 2009. A previous analysis of job changes across 22 years among NHSII participants showed that nurses tend to move to jobs with lower exposure to disinfectants over time. We therefore expect that women who, after more than 30 years working as a nurse, were still exposed to disinfectants in 2009 had already accumulated a long history of exposure. However, we may have underestimated the association between disinfectant exposures and COPD development, because the reference group (nurses currently nonexposed) likely includes women who had been exposed in the past. Fourth, despite the prospective design and exclusion of all women with COPD before baseline, we cannot exclude the possibility that our results may be subject to a healthy worker effect. Indeed, women with respiratory conditions or symptoms that sometimes precede COPD development, such as asthma, may have left exposed jobs before a COPD diagnosis. A previous study of NHSII participants found that women with a history of asthma were more likely to move to jobs involving a lower level of disinfectant exposure during follow-up. Thus, the association between disinfectant exposure and COPD incidence may have been underestimated. Despite this potential bias, significant associations between disinfectant exposures and COPD incidence were found among women both with and without a history of asthma. Another potential limitation was that COPD was defined by questionnaire because lung function measurements were not available in this large, nationwide cohort. However, a previous validation study showed that self-report of physician-diagnosed COPD was a valid marker of medical record evidence of COPD in the Nurses’ Health Study, a related cohort of health professionals (nurses). Despite reduced power, sensitivity analyses using a more stringent COPD definition confirmed the main findings. In addition, the most likely source of misclassification of COPD cases is asthma misdiagnosis ; however, results were confirmed after excluding all participants with a history of asthma. Finally, although COPD diagnosis in clinical practice relies in large part on spirometry, it has been argued that, in epidemiologic studies, spirometry-based definitions may not capture all COPD phenotypes because the disease is increasingly recognized as heterogeneous. Studies with different COPD assessment methods may therefore be useful for a more comprehensive understanding of risk factors. It is thus noteworthy that our findings are consistent with a previous report of an association between cleaning work and spirometry-defined COPD. Reports of an association between cleaning exposures, in particular when evaluated based on job title, and COPD in general population studies may raise concerns regarding potential residual confounding by socioeconomic status. Investigating this association within a population of registered nurses, who likely have a relatively homogeneous education level and socioeconomic status, provides better control for this type of confounding. Moreover, we have carefully addressed potential confounding by smoking by adjusting all models for smoking status and pack-years (time- varying variables) and in analyses stratified by smoking status, which confirmed the finding both among smokers and nonsmokers. Nonetheless, our study population of mainly non-Hispanic white female nurses may limit the generalizability of our results. Additional studies in different populations, including other health care–related professions, among male participants, and among more diverse racial and ethnic groups, are thus needed. Studies collecting information on both occupational and domestic exposure to cleaning products/disinfectants would also be helpful to assess the overall association of these exposures with COPD. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 9/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Conclusions Our findings provide further evidence of an adverse association between disinfectants and cleaning products and respiratory health. A large body of evidence already supports an association between these exposures and asthma ; our additional findings of an association with COPD incidence urges the need for the development of exposure-reduction strategies that remain compatible with 19,20 infection control in health care settings. We estimated that the population-attributable fraction of weekly use of disinfectants on COPD risk among female nurses was 12%; this findings suggests an important contribution of occupational exposure to disinfectants to the burden of COPD among health care workers. Because our study and previous reports found that a wide range of disinfectants/cleaning agents may be associated with poor respiratory outcomes, the development of new approaches to maintain infection control standards in health care settings may be needed. Potential safer alternatives include emerging nonchemical technologies for disinfection (eg, steam, 20,42,43 UV light) or green cleaning, which should be further investigated. Further research is needed to better establish a causal link between exposure to cleaning products and disinfectants and COPD development. Nonetheless, clinicians should be aware of this new risk factor and systematically look for sources of exposure to cleaning products and disinfectants in addition to other occupational exposures in patients with COPD. ARTICLE INFORMATION Accepted for Publication: September 2, 2019. Published: October 18, 2019. doi:10.1001/jamanetworkopen.2019.13563 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Dumas O et al. JAMA Network Open. Corresponding Author: Orianne Dumas, PhD, INSERM U1168, VIMA—Aging and Chronic Diseases, Epidemiological and Public Health Approaches, 16 Ave Paul Vaillant Couturier, 94807 Villejuif CEDEX, France (orianne.dumas@ inserm.fr). Author Affiliations: INSERM U1168, VIMA: Aging and Chronic Diseases, Epidemiological and Public Health Approaches, F-94807, Villejuif, France (Dumas, Varraso, Quinot, Le Moual); University de Versailles St-Quentin-en- Yvelines, UMR-S 1168, F-78180, Montigny le Bretonneux, France (Dumas, Varraso, Quinot, Le Moual); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Boggs, Speizer, Camargo); Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Boggs, Camargo); Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain (Zock); Universitat Pompeu Fabra (UPF), Barcelona, Spain (Zock); CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain (Zock); Respiratory Health Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia (Henneberger). Author Contributions: Dr Dumas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Dumas, Zock, Speizer, Le Moual, Camargo. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Dumas. Critical revision of the manuscript for important intellectual content: Varraso, Boggs, Quinot, Zock, Henneberger, Speizer, Le Moual, Camargo. Statistical analysis: Dumas, Zock. Obtained funding: Le Moual, Camargo. Administrative, technical, or material support: Varraso, Boggs, Quinot, Speizer, Le Moual, Camargo. Supervision: Boggs, Speizer, Camargo. Conflict of Interest Disclosures: Drs Dumas, Varraso, Le Moual, and Camargo and Ms Boggs reported receiving grants from the National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and Prevention (CDC) during the conduct of this study. Dr Zock reported receiving personal fees from Partners HealthCare System, Inc, and being a paid consultant on an NIOSH R01 grant. No other disclosures were reported. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 10/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Funding/Support: This study was supported in part by grants R01 OH-010359 from the CDC (Dr Camargo, principal investigator [PI]) and UM1 CA-176726 from the National Institutes of Health. The research leading to the results presented herein has received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7/2007-2013) (Dr Dumas, PI) under REA grant agreement PCOFUND-GA- 2013-609102 through the PRESTIGE program coordinated by Campus France. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the NIOSH. Additional Contributions: The Nurses’ Health Study II is coordinated at the Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. We thank the participants and staff of the Nurses’ Health Study II for their valuable contributions. REFERENCES 1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 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Int J Hyg Environ Health. 2019;222(5):873-883. doi:10. 1016/j.ijheh.2019.04.001 JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 12/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses 42. Garza JL, Cavallari JM, Wakai S, et al. Traditional and environmentally preferable cleaning product exposure and health symptoms in custodians. Am J Ind Med. 2015;58(9):988-995. doi:10.1002/ajim.22484 43. Goodyear N, Markkanen P, Beato-Melendez C, et al. Cleaning and disinfection in home care: a comparison of 2 commercial products with potentially different consequences for respiratory health. Am J Infect Control. 2018;46 (4):410-416. doi:10.1016/j.ajic.2017.09.033 SUPPLEMENT. eAppendix. Supplemental Methods References. eFigure. Flow Chart of the Study Population eTable 1. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Sensitivity Analyses eTable 2. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Smoking Status eTable 3. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Asthma Status eTable 4. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Using a More Stringent Case Definition eTable 5. Prospective Associations Between Combination of Specific Disinfectants/Cleaning Products Evaluated by the JTEM and COPD Incidence in US Female Nurses JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 13/13 Supplementary Online Content Dumas O, Varraso R, Boggs KM, et al. Association of occupational exposure to disinfectants with incidence of chronic obstructive pulmonary disease among US female nurses. JAMA Netw Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 eAppendix. Supplemental Methods eReferences. eFigure. Flow Chart of the Study Population eTable 1. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Sensitivity Analyses eTable 2. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Smoking Status eTable 3. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Icidence in US Female Nurses, According to Asthma Status eTable 4. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Using a More Stringent Case Definition eTable 5. Prospective Associations Between Combination of Specific Disinfectants/Cleaning Products Evaluated by the JTEM and COPD Incidence in US Female Nurses This supplementary material has been provided by the authors to give readers additional information about their work. ©2019 Dumas O et al. JAMA Network Open. 1 eAppendix. Supplemental Methods Occupational exposure to disinfectants The occupational questionnaire used in our study (2009, 2011, 2013) was adapted to U.S. context from questionnaires used in European studies (European Community Respiratory Health Survey and Epidemiological study on the Genetics and Environment of Asthma), with additions of relevant tasks based on results from a study of asthma among healthcare workers in Texas. Job type and tasks Current nurs in the emergency room, operating room, intensive care unit, other inpatient nurse, outpatient or community, other hospital nursing, nursing outside hospital and nursing education or administration. The two questions regarding the frequency (days/week Thinking about your current job and the use of disinfectants (such as ethylene oxide, hydrogen peroxide, orthophthalaldehyde, formaldehyde, glutaraldehyde and bleach): (a) On how many days per week, on average, do you clean medical instruments with disinfectants? (b) On how many days per week, on average, do you clean surfaces (like floors, tables) at work with disinfectants? (never, <1 day/week, 1-3 days/week, 4- . A specific question was average, do you use spray or aerosol products? (never, <1 day/week, 1-3 days/week, 4- - - never <1 day/week The two questions on disinfecting 4,5 tasks (to clean medical instruments/to clean surfaces) were combined to create a 3-level variable as previously, to define tasks performed weekly: no weekly disinfection tasks; weekly use of disinfectants to clean surfaces only; and weekly use of disinfectants to clean at least medical instruments (regardless of the use of disinfectants to clean surfaces). studied separately because of the low number of NHSII nurses in this category (2.9%). Job-task exposure matrix (JTEM) to evaluate exposure to specific disinfecta nts Exposure to seven major disinfectants/cleaning products was evaluated by the JTEM (formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide, alcohol [ethanol, methanol, isopropanol], quats, and enzymatic cleaners). The development of the JTEM has been described in detail elsewhere. Briefly, it used the responses to the questions described above in a population of 9,073 nurses without asthma (2014-2015), drawn included the 24 possible combinations of 8 types of nursing jobs by 3 categories of cleaning tasks (surfaces only, at least instruments, none). Specific cut- levels for each disinfectant, in a given job or job-task combination. of frequent (weekly) exposure. As the cut-offs chosen were disinfectant-specific, and were relative to the average level of use within each job/task .g. To study combinations of specific products evaluated by the JTEM, we classified exposure to products found associated with COPD when studied separately into 5 mutually exclusive categories: low exposure level for all 7 products evaluated by the JTEM (reference); high exposure level to alcohol or quats only; high exposure level to aldehydes (formaldehyde or glutaraldehyde); high exposure level to hypochlorite bleach or hydrogen peroxide; and high exposure level to both aldehydes and hypochlorite bleach/hydrogen peroxide (eTable 5). COPD In all biennial questionnaires since 1989, information on physician-diagnosed COPD was collected, first -text field, and since 1999 by a specific question on physician- diagnosed chronic bronchitis or emphysema (eFigure 1). In our analyses, incident cases of clinician-diagnosed COPD were identified from 2009 to 2015. All women with any history of COPD at baseline (2009) were excluded (eFigure1). The COPD stringent case definition, used in sensitivity analyses, was based on responses to a supplemental questionnaire on COPD, sent between 2015 and 2017 to all participants who ever reported clinician-diagnosed emphysema or chronic bronchitis in biennial questionnaires (responses collected until July 2018, response rate=76%). The specific questionnaire gathered, among other data, information confirming a ©2019 Dumas O et al. JAMA Network Open. 2 diagnosis. In the current study, the stringent case definition included participants who reiterated on the supplemental questionnaire that a physician had diagnosed her as having chronic bronchitis, emphysema, or COPD. A validation study was previously conducted in to evaluate this epidemiologic definition of COPD. Briefly, in a random sample of participants who reported COPD, we obtained medical records (two pulmonary function tests, two chest films, one chest computed tomography scan, two office or emergency department visits for COPD or asthma, and one hospital discharge summary regarding COPD or asthma), and a physician reviewed them in a blinded fashion. The validation study confirmed 83 newly diagnosed COPD based on this definition. Asthma In all biennial questionnaires since 1991, the participants were asked if they had physician-diagnosed asthma. Supplemental questionnaires on asthma were sent in 1998, 2003 and 2014, to all living women who had reported a physician diagnosis of asthma in earlier biennial questionnaire(s). More detailed information on dates of symptom onset and diagnosis, asthma symptoms, medications and hospitalizations for asthma were collected. Asthma cases (definition 1) were defined as participants who reiterated on at least one of the supplemental questionnaires that they had physician-diagnosed asthma, and reported using an asthma medication since diagnosis. Race/ethnicity Race and ethnicity were considered as potential confounders in our analyses. Race and ethnicity were evaluated by questionnaire (self-report). In the NHSII 1989 questionnaire, participants were asked to report their Because the NHSII population is in large majority white and non-Hispan ©2019 Dumas O et al. JAMA Network Open. 3 eReferences 1. Mirabelli MC, Zock JP, Plana E, et al. Occupational risk factors for asthma among nurses and related healthcare professionals in an international study. Occup Env Med. 2007;64(7):474-479. 2. Donnay C, Denis M-A, Magis R, et al. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occup Env Med. 2011;68(8):611-617. 3. Delclos GL, Gimeno D, Arif AA, et al. Occupational risk factors and asthma among health care professionals. Am J Respir Crit Care Med. 2007;175(7):667-675. 4. Dumas O, Wiley AS, Quinot C, et al. Occupational exposure to disinfectants and asthma control in US nurses. Eur Respir J . 2017;50(4):pii: 1700237. 5. Quinot C, Dumas O, Henneberger PK, et al. Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses. Occup Env Med. 2017;74(2):130-137. 6. Barr RG, Herbstman J, Speizer FE, Camargo CA Jr. Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses. Am J Epidemiol. 2002;155(10):965-971. 7. Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med. 1999;159(21):2582-2588. ©2019 Dumas O et al. JAMA Network Open. 4 Participants with missing data for occupational exposure were older (mean age: 61 years) than included participants (mean age: 55 years p<0.001), but did not differ from included participants for smoking status, body mass index, race, ethnicity or COPD diagnosis. Participants with missing data for pack-years of smoking were less often white (93%) than included participants (96%, p=0.03), but did not differ from included participants for age, body mass index, ethnicity, self-reported use of disinfectants or COPD diagnosis. ©2019 Dumas O et al. JAMA Network Open. 5 eTable 1. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, sensitivity analyses Occupational exposure Model further Model further Model excluding adjusted for pack- adjusted for diet participants with 2 b b, c years of smoking quality previous b,d comorbidities HR 95% CI HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.34 1.14-1.59 1.33 1.13-1.57 1.27 1.07-1.50 Surface only 1.38 1.13-1.68 1.37 1.13-1.67 1.30 1.06-1.60 Instruments 1.31 1.06-1.60 1.29 1.05-1.58 1.23 0.99-1.52 Abbreviations: HR, hazard ratio; CI, confidence interval. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. All models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Diet quality measured by the Alternate Healthy Eating Index 2010 (AHEI-2010), divided into quintiles. Analyses excluding cases of cardiovascular diseases and cancer. Analyses conducted in 346,529 person-years (547 incident COPD cases). ©2019 Dumas O et al. JAMA Network Open. 6 eTable 2. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, according to smoking status Occupational exposure Never smoker Ever smoker P interaction (245,005 person-years, (123,124 person- 238 COPD cases) years, 344 COPD cases) HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.34 1.03-1.73 1.38 1.11-1.71 0.91 Surface only 1.28 0.94-1.74 1.47 1.14-1.91 0.48 Instruments 1.40 1.02-1.92 1.28 0.97-1.68 0.58 Abbreviations: HR, hazard ratio; CI, confidence interval. Models were adjusted for age, race and body mass index (models were not adjusted for ethnicity because of low numbers in stratified analysis); and for pack-years (continuous) of smoking among ever smokers. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. ©2019 Dumas O et al. JAMA Network Open. 7 eTable 3. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, according to asthma status a a Occupational exposure Never asthma Ever asthma P interaction (301,313 person-years, (50,299 person-years, 283 COPD cases) 190 COPD cases) HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.31 1.03-1.66 1.37 1.02-1.84 0.78 Surface only 1.49 1.13-1.97 1.20 0.83-1.73 0.38 Instruments 1.12 0.82-1.52 1.56 1.10-2.23 0.16 Abbreviations: HR, hazard ratio; CI, confidence interval. Models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Ever asthma before baseline (2009), using case definition 1. Participants who reported asthma in main questionnaire but did not meet asthma case definition 1, or who were diagnosed with asthma after 2009, were excluded from the analyses. ©2019 Dumas O et al. JAMA Network Open. 8 eTable 4. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, using a more stringent case definition Person-years No. of Age-adjusted HR Multivariable-adjusted cases HR HR 95% CI HR 95% CI Job type Education or administration 52,827 32 1 - 1 - Outpatient, other nurses 195,946 136 1.13 0.77-1.67 1.17 0.79-1.72 ER or inpatient unit 94,837 69 1.31 0.86-2.00 1.21 0.79-1.85 Operating room 23,928 21 1.54 0.89-2.68 1.47 0.84-2.56 Weekly use of disinfectant None (ref.) 183,292 120 1 - 1 - Any disinfectant 184,245 138 1.25 0.97-1.59 1.24 0.96-1.59 Surface only 93,225 75 1.30 0.97-1.74 1.32 0.99-1.78 Instruments 91,020 63 1.19 0.87-1.61 1.14 0.84-1.56 Abbreviations: HR, hazard ratio; CI, confidence interval; ER, emergency room. Participants who reiterated that a physician had diagnosed her as having emphysema, chronic bronchitis and/or COPD in the supplemental questionnaire (stringent case definition, n=258). Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Observations with missing value for ©2019 Dumas O et al. JAMA Network Open. 9 eTable 5. Prospective associations between combination of specific disinfectants/cleaning products evaluated by the JTEM and COPD incidence in US female nurses a c Exposure combinations (JTEM estimates) Person- No. of Multivariable-adjusted HR years cases HR 95% CI Low exposure level for all products (reference) 111,579 174 1 - 1): High exposure level to alcohol or quats only 11,545 22 1.32 0.84-2.06 2): High exposure level to formaldehyde or 25,472 35 1.21 0.84-1.74 glutaraldehydew 3): High exposure level to hypochlorite bleach or 44,466 84 1.58 1.21-2.06 hydrogen peroxide 4): 2)+3) 105,099 164 1.36 1.08-1.70 Abbreviations: HR, hazard ratio; CI, confidence interval; JTEM Job-Task-Exposure Matrix. Mutually exclusive categories; Exposure evaluated based on the highest exposure level at any of the questionnaire cycles before time of diagnosis. classified as low exposure level for all seven products evaluated by the JTEM. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Observations with missing value for body mass index (3.8%) w ©2019 Dumas O et al. JAMA Network Open. 10 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA Network Open American Medical Association

Association of Occupational Exposure to Disinfectants With Incidence of Chronic Obstructive Pulmonary Disease Among US Female Nurses

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Copyright 2019 Dumas O et al. JAMA Network Open.
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10.1001/jamanetworkopen.2019.13563
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Abstract

Key Points Question Is exposure to disinfectants IMPORTANCE Exposure to disinfectants in health care workers has been associated with respiratory and cleaning products associated with health outcomes, including asthma. Despite the biological plausibility of an association between incidence of chronic obstructive disinfectants (irritant chemicals) and risk of chronic obstructive pulmonary disease (COPD), available pulmonary disease among health data are sparse. care workers? Findings In a cohort study of 73 262 US OBJECTIVE To investigate the association between exposure to disinfectants and COPD incidence female nurses participating in the in a large cohort of US female nurses. Nurses’ Health Study II who were followed up from 2009 to 2015, DESIGN, SETTING, AND PARTICIPANTS The Nurses’ Health Study II is a US prospective cohort occupational exposure to cleaning study of 116 429 female registered nurses from 14 US states who were enrolled in 1989 and followed products and disinfectants was up through questionnaires every 2 years since. The present study included women who were still in significantly associated with a 25% to a nursing job and had no history of COPD in 2009, and used data from the 2009 through 2015 38% increased risk of developing questionnaires. Clean and complete data used for this analysis were available in July 2018, and chronic obstructive pulmonary disease analyses were conducted from September 2018 through August 2019. independent of asthma and smoking. EXPOSURES Occupational exposure to disinfectants, evaluated by questionnaire and a job-task- Meaning This study’s findings suggest exposure matrix (JTEM). that regular use of chemical disinfectants among nurses may be a MAIN OUTCOMES AND MEASURES Incident physician-diagnosed COPD evaluated by risk factor for developing chronic questionnaire. obstructive pulmonary disease. RESULTS Among the 73 262 women included in the analyses, mean (SD) age at baseline was 54.7 Supplemental content and Audio (4.6) years and 70 311 (96.0%) were white, 1235 (1.7%) black, and 1716 (2.3%) other; and 1345 (1.8%) Hispanic, and 71 917 (98.2%) non-Hispanic. Based on 368 145 person-years of follow-up, 582 nurses Author affiliations and article information are listed at the end of this article. reported incident physician-diagnosed COPD. Weekly use of disinfectants to clean surfaces only (16 786 [22.9%] of participants exposed) and to clean medical instruments (13 899 [19.0%] exposed) was associated with COPD incidence, with adjusted hazard ratios of 1.38 (95% CI, 1.13-1.68) for cleaning surfaces only and 1.31 (95% CI, 1.07-1.61) for cleaning medical instruments after adjustment for age, smoking (pack-years), race, ethnicity, and body mass index. High-level exposure, evaluated by the JTEM, to several specific disinfectants (ie, glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds) was significantly associated with COPD incidence, with adjusted hazard ratios ranging from 1.25 (95% CI, 1.04-1.51) to 1.36 (95% CI, 1.13-1.64). Associations were not modified by smoking or asthma status (P for interaction > .15). CONCLUSIONS AND RELEVANCE These longitudinal results suggest that regular use of chemical disinfectants among nurses may be a risk factor for developing COPD. If future studies confirm these (continued) Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 1/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Abstract (continued) results, exposure-reduction strategies that are compatible with infection control in health care settings should be developed. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 Introduction Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality worldwide and among the diseases contributing the most to disability-adjusted life-years. Although tobacco smoke remains the major risk factor for COPD development in the United States and other industrialized countries, occupational exposures contribute substantially to the burden of disease. A growing body of data suggests that 15% to 20% of cases of COPD are attributable to occupational 3,4 exposures. However, despite the general recognition of an association between occupational 2,5 5,6 exposures and COPD, few individual causal agents have been identified. Most studies on occupation and COPD have investigated broad exposure categories (eg, “vapor, gases, dust, or fumes”), which include many agents. Industry-specific studies, which generally provide more insight regarding specific causal agents than population-based studies, have focused on a limited number of occupational settings, which are often occupations with predominantly male workers. Although chemical exposures are an important component of vapor, gases, dust, or fumes and may account 4,8 3 for a large part of COPD risk, their association with COPD remains unclear. Exposure to cleaning products and disinfectants is common at work and at home and remains 9,10 11 more frequent among women. Exposure levels are particularly high in the health care industry, one of the largest employment sectors in the United States and Europe. The respiratory health risks associated with exposure to cleaning products and disinfectants are increasingly recognized. 13-15 Although investigators have primarily focused on asthma, the irritant properties of many chemicals contained in disinfectants support the study of a broader range of respiratory effects. A 16,17 few European studies have reported an increased risk of COPD, accelerated lung function 9 18 decline, and higher rates of death due to COPD among cleaning workers. However, to our knowledge, no study to date has investigated the association of occupational exposure to disinfectants and cleaning products with COPD risk among health care workers, nor has any study suggested specific chemicals that may underlie the association between cleaning jobs and COPD. Determining specific agents associated with adverse health outcomes is crucial in health care settings. Indeed, prevention strategies are often based on avoidance of the causal agent(s); however, adequate levels of disinfection must be maintained in health care settings to protect patients and workers from nosocomial infections. Using data from the Nurses’ Health Study II (NHSII), a large, ongoing, prospective study of US female nurses, we investigated the association between exposure to disinfectants and cleaning products and risk of incident COPD. Methods Population The NHSII began in 1989 when 116 429 female registered nurses from 14 US states, aged 25 to 44 years, completed a questionnaire about their medical history and lifestyle characteristics. Follow-up questionnaires have been sent every 2 years since. The NHSII was initially designed to study women’s health (eg, long-term health effects or oral contraceptive use; determinants of major chronic diseases in women, such as breast cancer or cardiovascular disease), and the range of risk factors and health outcome data collected has expanded over time. Information on occupational exposures was collected for the first time in 2009, which was defined as the baseline for the present study. This JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 2/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses investigation was approved by the institutional review board at Brigham and Women’s Hospital, and participants provided written informed consent. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Among the 116 429 participants in the NHSII, 98 817 returned at least 1 biennial questionnaire during the follow-up period (2011-2015); of these, 76 331 were still in a nursing job (eFigure in the Supplement). Among these respondents, we selected women without missing data for occupational exposure and pack-years of smoking who had not reported any history of COPD at baseline (2009). Clean and complete data used for this analysis were available in July 2018, and analyses were conducted from September 2018 through August 2019. Occupational Exposure to Disinfectants Information on nursing job types (education or administration, outpatient/other nurses, emergency department or inpatient unit, and operating room) and general disinfection tasks (frequency of use of disinfectants to clean surfaces/medical instruments) was collected by questionnaire in 2009, 2011, and 2013. Information on the use of sprays (for instrument cleaning/disinfection, surface cleaning/disinfection, patient care, air refreshing, or other) was collected in 2011 and 2013. Disinfection tasks were studied using a dichotomous (weekly use of disinfectants to clean surfaces or medical instruments vs less than weekly) and a 3-level (no disinfection task performed weekly, weekly use of disinfectants to clean surfaces only, or weekly use of disinfectants to clean medical instruments regardless of the use of disinfectants to clean surfaces) variable. Frequency of cleaning or disinfection tasks and spray use (never, <1 d/wk, 1-3 d/wk, or 4-7 d/wk) was also examined. Exposure to 7 of the most commonly used disinfectants or cleaning products (formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide, alcohol, quaternary ammonium compounds, and enzymatic cleaners) was evaluated by a nurse-specific job-task-exposure matrix (JTEM), as described in detail elsewhere and in the eAppendix in the Supplement. The JTEM assigned exposure level (low, medium, or high) based on types of nursing jobs and general disinfection tasks. Exposure to specific disinfectants according to the JTEM was thus studied using 3-level variables, with separate models for each disinfectant. Then, because nurses were often classified as exposed to multiple products, we studied exposure to combinations of several specific products evaluated by the JTEM for the products found associated with COPD when studied separately. COPD Incidence In biennial questionnaires, participants were asked to report any condition(s) with which they were diagnosed since the last questionnaire cycle, including emphysema or chronic bronchitis. We used this information to identify incident cases of physician-diagnosed COPD (primary case definition) from 2009 to 2015. Between October 2015 and December 2017, we sent a supplemental questionnaire on COPD to participants who reported a physician’s diagnosis of emphysema or chronic bronchitis in any past biennial questionnaire. Based on information collected on the supplemental questionnaire, we selected participants who reiterated that a physician had diagnosed them as having emphysema, chronic bronchitis, COPD, or any combination of these. This definition (stringent case definition), validated in a random sample of participants with COPD in NHSII (eAppendix in the Supplement), was used in a sensitivity analysis. Statistical Analysis Prospective associations between occupational exposures and COPD incidence were evaluated by using Cox proportional hazards regression models. In each model, occupational exposure was handled as a time-varying variable and was evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. All Cox proportional hazards regression models were stratified by age and calendar year. For race and ethnicity, multiple categories were combined to JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 3/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses create binary general categories. Analyses were adjusted for race (white vs black and other), ethnicity (Hispanic vs non-Hispanic), smoking habits (nonsmoker, ex-smoker, or current smoker), pack-years of smoking, and body mass index (calculated as weight in kilograms divided by height in meters squared into categories of <25.0, 25.0-29.9, and 30.0). Several sensitivity analyses were conducted, further adjusting the models for diet quality as measured by the Alternate Healthy Eating 26 2 Index 2010, divided into quintiles, or for pack-years of smoking and excluding participants with previous comorbidities (cardiovascular diseases and cancer). We performed stratified analyses by smoking status, asthma status, and job change (any change in job type from the 2009 to 2013 questionnaires) and tested interactions in multivariable models. We estimated the population- attributable fraction of weekly use of any disinfectant on COPD risk among female nurses as PAF = pc(1 − 1/AHR), in which PAF is the population-attributable fraction; pc, the prevalence of exposure among cases of COPD; and AHR, the adjusted hazard ratio. A 2-sided P < .05 was considered statistically significant. Analyses were conducted using SAS, version 9.4 (SAS Institute Inc). Results Among the 73 262 women who were eligible for analysis, mean (SD) age at baseline (in 2009) was 54.7 (4.6) years; 70 311 (96.0%) were white, 1235 (1.7%) black, and 1716 (2.3%) other; 1345 (1.8%) were Hispanic and 71 917 (98.2%) non-Hispanic; 4162 (5.7%) were current smokers and 20 631 (28.2%) were former smokers. Regarding cleaning/disinfection tasks, 16 786 (22.9%) of the nurses reported weekly use of disinfectants to clean surfaces only, and 13 899 (19.0%) reported weekly use of disinfectants to clean medical instruments. Very small but statistically significant differences were seen in sociodemographic characteristics according to disinfection tasks (Table 1); in particular, nurses reporting weekly use of disinfectants were younger and more often former or current smokers. Cleaning/Disinfection Tasks and COPD Incidence Based on 368 145 person-years of follow-up from 2009 to 2015, 582 nurses reported incident physician-diagnosed COPD. In multivariable models, no single nursing job type was associated with COPD incidence, although a significant trend toward an increased risk of COPD incidence was observed when classifying jobs according to the level of disinfectant use (Table 2). Weekly use of any disinfectants was positively associated with COPD incidence, with an adjusted hazard ratio (AHR) of 1.35 (95% CI, 1.14-1.59). The corresponding population-attributable fraction (calculated in combination with a prevalence of exposure among cases of COPD of 45%) was 12%. Associations were observed for use of disinfectants both to clean surfaces only (AHR, 1.38; 95% CI, 1.13-1.68) and to clean medical instruments (AHR, 1.31; 95% CI, 1.07-1.61). When we examined the frequency of cleaning/disinfection tasks (Figure), risk of COPD incidence was highest among nurses with the greatest frequency of use (4-7 d/wk). A significant dose-response association was observed for the use of any disinfectants (for frequency of 4-7 d/wk: AHR, 1.43; 95% CI, 1.13-1.80; P for trend < .001) and disinfectants to clean surfaces (for frequency of 4-7 d/wk: AHR, 1.37; 95% CI, 1.09-1.72; P for trend, .003). Weekly use of spray (vs less than weekly) was not significantly associated with COPD incidence. However, when we examined frequency of spray use, a significant trend toward an increased risk of COPD incidence with higher frequency of use was observed (P for trend, .03), with a dose-response association. Results were similar in sensitivity analyses excluding participants with previous comorbidities (cardiovascular diseases and cancer) or in models further adjusted for pack-years of smoking or diet quality (eTable 1 in the Supplement). Moreover, the association between weekly use of any disinfectants and COPD incidence was significant and similar in never smokers (AHR, 1.34; 95% CI, 1.03-1.73; eTable 2 in the Supplement) and ever smokers (AHR, 1.38; 95% CI, 1.11-1.71; P for interaction = .91) and in participants with asthma (AHR, 1.37; 95% CI, 1.02-1.84; eTable 3 in the JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 4/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Supplement) and without asthma (AHR, 1.31; 95% CI, 1.03-1.66; P for interaction = .78). When we examined the types of disinfection tasks, the association between use of disinfectants to clean surfaces only and COPD incidence was more pronounced among ever smokers and participants without asthma, whereas the association between use of disinfectants to clean medical instruments and COPD incidence was more pronounced among never smokers and participants with asthma. Nonetheless, the latter differences by smoking or asthma status were not statistically significant (all P for interaction > .15). The association between weekly use of any disinfectants and COPD incidence was also similar in participants who changed nursing job type between 2009 and 2013 (47 788 [65%]; AHR, 1.41; 95% CI, 1.14-1.73) and participants who did not (25 474 [35%]; AHR, 1.33; 95% CI, 1.00-1.78; P for interaction = .52). In the sensitivity analysis using a more stringent COPD definition (eTable 4 in the Supplement), the association between use of disinfectants to clean surfaces only and COPD incidence was similar (AHR, 1.32; 95% CI, 0.99-1.78; P = .06), although statistical power was no longer significant owing to fewer cases of COPD. In contrast, the association between use of disinfectants to clean instruments and COPD incidence was no longer significant (AHR, 1.14; 95% CI, 0.83-1.56; P = .41). Specific Disinfectants/Cleaning Products Evaluated by JTEM and COPD Incidence In multivariable models using the JTEM estimates (Table 3), no statistically significant association was observed between high-level exposure to enzymatic cleaners (AHR, 1.05; 95% CI, 0.84-1.31) or formaldehyde (AHR, 1.20; 95% CI, 0.92-1.57) and COPD incidence. In contrast, high-level exposure to glutaraldehyde, bleach, hydrogen peroxide, alcohol, and quaternary ammonium compounds was significantly associated with increased risk of COPD incidence, with AHRs ranging from 1.25 (95% CI, 1.04-1.51) to 1.36 (95% CI, 1.13-1.64). No significant association was observed when we compared Table 1. Baseline Characteristics of the Study Population According to Disinfectant Use Among 73 262 US Female Nurses Weekly Use of Disinfectants to Clean Surfaces and/or Instruments None Surface Only Instruments Population Characteristics (n = 42 577) (n = 16 786) (n = 13 899) P Value Age, mean (SD), y 55.0 (4.6) 54.5 (4.6) 54.1 (4.6) <.001 Race White 40 908 (96.1) 16 120 (96.0) 13 283 (95.6) Black 746 (1.7) 274 (1.6) 215 (1.5) <.001 Other 923 (2.2) 392 (2.3) 401 (2.9) Ethnicity Hispanic 761 (1.8) 338 (2.0) 246 (1.8) Non-Hispanic 41 816 (98.2) 16 448 (98.0) 13 653 (98.2) Smoking status Never smoker 28 050 (65.9) 11 286 (67.2) 9129 (65.7) Former smoker 12 290 (28.9) 4514 (26.9) 3827 (27.5) <.001 Current smoker 2233 (5.2) 986 (5.9) 943 (6.8) Pack-years of cigarette smoking 13.6 (11.9) 13.4 (11.6) 14.2 (12.3) .05 among ever smokers, mean (SD) BMI at baseline <20.0 1900 (4.6) 750 (4.7) 590 (4.4) 20.0 to 24.9 14 583 (35.5) 5641 (35.2) 4596 (34.5) 25.0 to 29.9 12 512 (30.5) 4878 (30.4) 4270 (32.1) ≥30.0 12 101 (29.4) 4764 (29.7) 3853 (29.0) Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters Job type squared); ED, emergency department. Education or administration 11 085 (26.0) 1431 (8.5) 588 (4.2) Data are presented as number (percentage) unless Outpatient, other nurses 23 714 (55.7) 8945 (53.3) 6768 (48.7) otherwise stated. Values of categorical variables may <.001 ED or inpatient unit 6647 (15.6) 4830 (29.4) 5104 (36.7) not total 100% because of rounding. Operating room 1131 (2.7) 1580 (9.4) 1439 (10.4) There were 2824 missing values (3.8%) for BMI. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 5/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses medium- and low-exposure level (AHRs ranged from 1.18 [95% CI, 0.95-1.46] to 1.32 [95% CI, 0.98- 1.79]) except for glutaraldehyde (AHR, 1.50; 95% CI, 1.18-1.90). When we analyzed combinations of specific products (eTable 5 in the Supplement), no associations with COPD incidence were observed among nurses exposed to alcohol or quaternary ammonium compounds only or to aldehydes (formaldehyde or glutaraldehyde) but not to the other products. In contrast, a significantly increased risk of COPD incidence was observed among nurses exposed to hypochlorite bleach or hydrogen peroxide with or without aldehydes. Discussion This analysis of a cohort of 73 262 US nurses followed up across 6 years showed that occupational exposure to disinfectants was prospectively associated with a higher risk of developing COPD. Self- reported cleaning/disinfection tasks and exposure to several specific disinfectants evaluated by a JTEM, including glutaraldehyde, bleach, hydrogen peroxide, and alcohol and quaternary ammonium compounds, were associated with a 25% to 38% increased risk of COPD incidence. To our knowledge, this is the largest prospective study to date to investigate the association of exposure to cleaning products and disinfectants with COPD incidence. Two large cross-sectional studies in Europe (of 13 499 and 502 649 participants) have reported an increased risk of 17 16 self-reported or spirometry-defined COPD, respectively, among professional cleaners. In a cross- sectional study of US working adults, the highest prevalence of self-reported COPD was found among health care support occupations. In 2018, a prospective analysis of 6235 participants in the European Community Respiratory Health Survey who were followed up for 20 years further showed that women cleaning at home or working as cleaners had accelerated decline in lung function, independently of asthma. These recent findings confirmed older and smaller analyses of population-based studies reporting increased risk of COPD or chronic bronchitis among cleaners or 29,30 health care–related professions. Thus, our longitudinal results are consistent with the few data Table 2. Prospective Association of Job Types and Self-reported Cleaning/Disinfection Tasks With Chronic Obstructive Pulmonary Disease Incidence Among US Female Nurses Age-Adjusted HR Multivariable-Adjusted HR a b Occupational Exposure Person-Years No. of Cases (95% CI) P for Trend (95% CI) P for Trend Job type Education or administration 52 909 85 1 [Reference] 1 [Reference] Outpatient, other nurses 196 143 285 0.99 (0.78-1.26) 1.03 (0.81-1.32) .004 .02 ED or inpatient unit 95 095 168 1.32 (1.01-1.71) 1.24 (0.95-1.62) Operating room 23 998 44 1.36 (0.94-1.96) 1.38 (0.96-1.99) Weekly use of disinfectant None 183 480 276 1 [Reference] 1 [Reference] Any disinfectant 184 665 306 1.35 (1.14-1.59) 1.35 (1.14-1.59) NA NA Surface only 93 443 161 1.35 (1.11-1.65) 1.38 (1.13-1.68) Instruments 91 222 145 1.35 (1.10-1.65) 1.31 (1.07-1.61) Weekly use of sprays No 196 903 214 1 [Reference] 1 [Reference] NA NA Yes 56 702 75 1.31 (1.00-1.70) 1.27 (0.97-1.66) Abbreviations: ED, emergency department; HR, hazard ratio; NA, not applicable. for pack-years of smoking (<0.5%) were excluded from analyses. Observations with a missing values for body mass index (3.8%) were included in the model as a “missing” Exposure was evaluated as the highest exposure level at any of the questionnaire category. cycles before time of diagnosis. Follow-up periods were 2009 to 2015 for job type and use of disinfectants (368 145 person-years; 582 cases) and 2011 to 2015 for use of Job types are classified in increasing order of frequency of disinfectant use, as shown sprays (253 606 person-years; 289 cases). Job type, weekly use of disinfectant, and previously. weekly use of spray were evaluated in separate models. d Use of sprays for patient care, instrument cleaning or disinfection, surface cleaning or Multivariable models were adjusted for age, smoking status and pack-years disinfection, air refreshing, or other. (continuous), race, ethnicity, and body mass index. Observations with missing values JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 6/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses available in the literature and strengthen evidence of a role of exposure to disinfectants in COPD pathogenesis. In addition, our study extends previous findings by examining disinfection tasks and exposure to specific chemicals among health care workers in relation to COPD. This question is of particular importance to provide guidance for the development of prevention strategies. We found that use of several specific disinfectants was associated with higher risk of COPD development; these included hypochlorite bleach (chlorine), hydrogen peroxide, alcohol, and quaternary ammonium compounds (commonly used for low-level disinfection of noncritical items, such as environmental surfaces) and glutaraldehyde (used for high-level disinfection). Several of these exposures often occurred concurrently, and disentangling the role of each product was challenging. When studying combinations of exposure to specific disinfectants, we found the highest risks of COPD incidence among nurses exposed to hypochlorite bleach or hydrogen peroxide and in those combining these Figure. Prospective Association Between Self-reported Frequency of Cleaning/Disinfection Tasks and Chronic Obstructive Pulmonary Disease (COPD) Incidence Among US Female Nurses a b A Any disinfectant B Spray 2.5 2.5 P for trend <.001 P for trend = .03 1.43 1.40 1.38 1.35 1.26 1.12 1.0 1.0 0.7 0.7 Never <1 1-3 4-7 Never <1 1-3 4-7 [Reference] [Reference] Frequency of Use, d/wk Frequency of Use, d/wk No. at risk No. at risk Person-years 105 784 77 709 100 095 83 902 Person-years 143 499 53 404 33 384 23 318 No. of COPD cases 163 113 165 140 No. of COPD cases 147 67 43 32 C Clean surfaces D Clean instruments 2.5 2.5 P for trend = .003 P for trend = .02 1.37 1.35 1.31 1.25 1.16 1.09 1.0 1.0 0.7 0.7 Never <1 1-3 4-7 Never <1 1-3 4-7 [Reference] [Reference] Frequency of Use, d/wk Frequency of Use, d/wk No. at risk No. at risk Person-years 115 245 79 293 95 325 77 627 Person-years 212 850 63 754 55 340 35 546 No. of COPD cases 185 116 152 128 No. of COPD cases 326 110 82 62 Occupational exposure was evaluated as the highest exposure level at any of the indicate 95% CIs. Adjusted hazard ratios (AHRs) with 95% CIs are shown for type of questionnaire cycles before time of diagnosis. The follow-up periods were 2009 to 2015 disinfectant (A and B) and specific use of disinfectant (C and D). for job type and use of disinfectants and 2011 to 2015 for use of sprays. Multivariable a Use of a disinfectant to clean surfaces or instruments. models were adjusted for age, smoking status and pack-years (continuous), race, Use of sprays for patient care, instrument cleaning or disinfection, surface cleaning or ethnicity, and body mass index. Observations with missing values for pack-years of disinfection, air refreshing, or other. smoking (<0.5%) were excluded from analyses. Observations with missing values for body mass index (3.8%) were included in the model as a “missing” category. Error bars JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 7/13 AHR AHR AHR AHR JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses exposures with exposure to aldehydes. Both the chemical properties of specific products and the greater number of products used could explain these elevated risks. Moreover, all of the agents that were associated with COPD incidence when evaluated separately have been described as airway 31-34 irritants. Inhalation of irritant chemicals may cause injury of the airway epithelium and oxidative 35-37 stress and may be associated with neutrophilic inflammation. Oxidative stress is now recognized to have an important role in COPD pathogenesis and to partly result from environmental exposures. In addition, neutrophilic inflammation is seen in most patients with COPD and correlates with disease severity. It is notable that exposure to enzymatic cleaners, which have previously been associated with asthma outcomes but are known to contain sensitizers rather than irritants, was not associated with COPD. Although the associations between exposure to specific disinfectants and COPD incidence must be replicated in independent cohorts and underlying pathophysiological mechanisms must be clarified, there is a biological plausibility that long-term exposure to irritant disinfectants and cleaning agents could contribute to persistent airway damage and COPD pathogenesis. Strengths and Limitations Major strengths of our study include the large population, longitudinal design, and use of a nurse- specific JTEM to evaluate occupational exposure. Previous studies were limited in exposure assessment because they relied only on job titles or self-reported use of general products (sprays or other cleaning products). To evaluate specific exposures in large cohorts, the use of job-exposure matrices is generally favored over self-report. In this population of nurses, we further showed that using a JTEM, which assigns exposure level based not only on nursing job types but also on disinfection tasks, provides better exposure estimates than a job-exposure matrix by reducing 14,24 exposure misclassification. Nursing job types and disinfection tasks were self-reported; however because associations were evaluated prospectively (ie, exposure was evaluated before the report of COPD diagnosis), differential recall bias is unlikely. Moreover, we observed dose-response associations for both self-reported cleaning/disinfection tasks and specific exposures evaluated by the JTEM. Nonetheless, our study had some limitations with regard to exposure assessment. First, the JTEM only evaluated exposure to 7 major products used in US health care settings; exposure to less common products (eg, ortho-phthalaldehyde, peracetic acid, acetic acid, ammonia, phenolics, ethylene oxide, chloramine-T, and “green” products) could not be assessed with this method. Although a previous study using NHSII data found that fewer than 10% of nurses used these products weekly, their potential association with COPD development should be examined in future research. Second, we did not collect information regarding the use of protective equipment during cleaning/ Table 3. Prospective Associations Between Exposure to Specific Disinfectants/Cleaning Products Evaluated by Job-Task-Exposure Matrix and Chronic Obstructive Pulmonary Disease Incidence Among US Female Nurses Multivariable-Adjusted HR a b Occupational Exposure Person-Years No. of Cases (95% CI) Formaldehyde 38 056 62 1.20 (0.92-1.57) Glutaraldehyde 125 281 192 1.25 (1.04-1.51) Hypochlorite bleach 127 879 215 1.36 (1.13-1.64) Hydrogen peroxide 141 504 229 1.29 (1.08-1.54) Alcohol 150 512 245 1.32 (1.10-1.59) Quaternary ammonium compounds 142 722 233 1.33 (1.11-1.60) Enzymatic cleaners 69 447 97 1.05 (0.84-1.31) Abbreviation: HR, hazard ratio. Exposure was evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Associations presented compare high-exposure level vs low-exposure level for each product. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Observations with missing values for body mass index (3.8%) were included in the model as a “missing” category. Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity, and body mass index. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 8/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses disinfection tasks in this large population. However, in a substudy on occupational exposures conducted among NHSII nurses with asthma in 2014, 5% of the participants reported using a face mask or other respiratory protection devices when working with disinfectants, and the use of respiratory protections did not modify the association between disinfectant exposure and poor asthma control. Third, data regarding complete occupational exposure history were not available; indeed, detailed assessment of disinfectant exposure has only been available since 2009. A previous analysis of job changes across 22 years among NHSII participants showed that nurses tend to move to jobs with lower exposure to disinfectants over time. We therefore expect that women who, after more than 30 years working as a nurse, were still exposed to disinfectants in 2009 had already accumulated a long history of exposure. However, we may have underestimated the association between disinfectant exposures and COPD development, because the reference group (nurses currently nonexposed) likely includes women who had been exposed in the past. Fourth, despite the prospective design and exclusion of all women with COPD before baseline, we cannot exclude the possibility that our results may be subject to a healthy worker effect. Indeed, women with respiratory conditions or symptoms that sometimes precede COPD development, such as asthma, may have left exposed jobs before a COPD diagnosis. A previous study of NHSII participants found that women with a history of asthma were more likely to move to jobs involving a lower level of disinfectant exposure during follow-up. Thus, the association between disinfectant exposure and COPD incidence may have been underestimated. Despite this potential bias, significant associations between disinfectant exposures and COPD incidence were found among women both with and without a history of asthma. Another potential limitation was that COPD was defined by questionnaire because lung function measurements were not available in this large, nationwide cohort. However, a previous validation study showed that self-report of physician-diagnosed COPD was a valid marker of medical record evidence of COPD in the Nurses’ Health Study, a related cohort of health professionals (nurses). Despite reduced power, sensitivity analyses using a more stringent COPD definition confirmed the main findings. In addition, the most likely source of misclassification of COPD cases is asthma misdiagnosis ; however, results were confirmed after excluding all participants with a history of asthma. Finally, although COPD diagnosis in clinical practice relies in large part on spirometry, it has been argued that, in epidemiologic studies, spirometry-based definitions may not capture all COPD phenotypes because the disease is increasingly recognized as heterogeneous. Studies with different COPD assessment methods may therefore be useful for a more comprehensive understanding of risk factors. It is thus noteworthy that our findings are consistent with a previous report of an association between cleaning work and spirometry-defined COPD. Reports of an association between cleaning exposures, in particular when evaluated based on job title, and COPD in general population studies may raise concerns regarding potential residual confounding by socioeconomic status. Investigating this association within a population of registered nurses, who likely have a relatively homogeneous education level and socioeconomic status, provides better control for this type of confounding. Moreover, we have carefully addressed potential confounding by smoking by adjusting all models for smoking status and pack-years (time- varying variables) and in analyses stratified by smoking status, which confirmed the finding both among smokers and nonsmokers. Nonetheless, our study population of mainly non-Hispanic white female nurses may limit the generalizability of our results. Additional studies in different populations, including other health care–related professions, among male participants, and among more diverse racial and ethnic groups, are thus needed. Studies collecting information on both occupational and domestic exposure to cleaning products/disinfectants would also be helpful to assess the overall association of these exposures with COPD. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 9/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Conclusions Our findings provide further evidence of an adverse association between disinfectants and cleaning products and respiratory health. A large body of evidence already supports an association between these exposures and asthma ; our additional findings of an association with COPD incidence urges the need for the development of exposure-reduction strategies that remain compatible with 19,20 infection control in health care settings. We estimated that the population-attributable fraction of weekly use of disinfectants on COPD risk among female nurses was 12%; this findings suggests an important contribution of occupational exposure to disinfectants to the burden of COPD among health care workers. Because our study and previous reports found that a wide range of disinfectants/cleaning agents may be associated with poor respiratory outcomes, the development of new approaches to maintain infection control standards in health care settings may be needed. Potential safer alternatives include emerging nonchemical technologies for disinfection (eg, steam, 20,42,43 UV light) or green cleaning, which should be further investigated. Further research is needed to better establish a causal link between exposure to cleaning products and disinfectants and COPD development. Nonetheless, clinicians should be aware of this new risk factor and systematically look for sources of exposure to cleaning products and disinfectants in addition to other occupational exposures in patients with COPD. ARTICLE INFORMATION Accepted for Publication: September 2, 2019. Published: October 18, 2019. doi:10.1001/jamanetworkopen.2019.13563 Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Dumas O et al. JAMA Network Open. Corresponding Author: Orianne Dumas, PhD, INSERM U1168, VIMA—Aging and Chronic Diseases, Epidemiological and Public Health Approaches, 16 Ave Paul Vaillant Couturier, 94807 Villejuif CEDEX, France (orianne.dumas@ inserm.fr). Author Affiliations: INSERM U1168, VIMA: Aging and Chronic Diseases, Epidemiological and Public Health Approaches, F-94807, Villejuif, France (Dumas, Varraso, Quinot, Le Moual); University de Versailles St-Quentin-en- Yvelines, UMR-S 1168, F-78180, Montigny le Bretonneux, France (Dumas, Varraso, Quinot, Le Moual); Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts (Boggs, Speizer, Camargo); Department of Emergency Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts (Boggs, Camargo); Barcelona Institute for Global Health (ISGlobal), Barcelona, Spain (Zock); Universitat Pompeu Fabra (UPF), Barcelona, Spain (Zock); CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain (Zock); Respiratory Health Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia (Henneberger). Author Contributions: Dr Dumas had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Dumas, Zock, Speizer, Le Moual, Camargo. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Dumas. Critical revision of the manuscript for important intellectual content: Varraso, Boggs, Quinot, Zock, Henneberger, Speizer, Le Moual, Camargo. Statistical analysis: Dumas, Zock. Obtained funding: Le Moual, Camargo. Administrative, technical, or material support: Varraso, Boggs, Quinot, Speizer, Le Moual, Camargo. Supervision: Boggs, Speizer, Camargo. Conflict of Interest Disclosures: Drs Dumas, Varraso, Le Moual, and Camargo and Ms Boggs reported receiving grants from the National Institute for Occupational Safety and Health (NIOSH) of the Centers for Disease Control and Prevention (CDC) during the conduct of this study. Dr Zock reported receiving personal fees from Partners HealthCare System, Inc, and being a paid consultant on an NIOSH R01 grant. No other disclosures were reported. JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 10/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses Funding/Support: This study was supported in part by grants R01 OH-010359 from the CDC (Dr Camargo, principal investigator [PI]) and UM1 CA-176726 from the National Institutes of Health. The research leading to the results presented herein has received funding from the People Program (Marie Curie Actions) of the European Union’s Seventh Framework Program (FP7/2007-2013) (Dr Dumas, PI) under REA grant agreement PCOFUND-GA- 2013-609102 through the PRESTIGE program coordinated by Campus France. Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the NIOSH. Additional Contributions: The Nurses’ Health Study II is coordinated at the Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. We thank the participants and staff of the Nurses’ Health Study II for their valuable contributions. REFERENCES 1. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 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Int J Hyg Environ Health. 2019;222(5):873-883. doi:10. 1016/j.ijheh.2019.04.001 JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 12/13 JAMA Network Open | Occupational Health Occupational Exposure to Disinfectants and COPD Among US Female Nurses 42. Garza JL, Cavallari JM, Wakai S, et al. Traditional and environmentally preferable cleaning product exposure and health symptoms in custodians. Am J Ind Med. 2015;58(9):988-995. doi:10.1002/ajim.22484 43. Goodyear N, Markkanen P, Beato-Melendez C, et al. Cleaning and disinfection in home care: a comparison of 2 commercial products with potentially different consequences for respiratory health. Am J Infect Control. 2018;46 (4):410-416. doi:10.1016/j.ajic.2017.09.033 SUPPLEMENT. eAppendix. Supplemental Methods References. eFigure. Flow Chart of the Study Population eTable 1. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Sensitivity Analyses eTable 2. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Smoking Status eTable 3. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Asthma Status eTable 4. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Using a More Stringent Case Definition eTable 5. Prospective Associations Between Combination of Specific Disinfectants/Cleaning Products Evaluated by the JTEM and COPD Incidence in US Female Nurses JAMA Network Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 (Reprinted) October 18, 2019 13/13 Supplementary Online Content Dumas O, Varraso R, Boggs KM, et al. Association of occupational exposure to disinfectants with incidence of chronic obstructive pulmonary disease among US female nurses. JAMA Netw Open. 2019;2(10):e1913563. doi:10.1001/jamanetworkopen.2019.13563 eAppendix. Supplemental Methods eReferences. eFigure. Flow Chart of the Study Population eTable 1. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Sensitivity Analyses eTable 2. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, According to Smoking Status eTable 3. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Icidence in US Female Nurses, According to Asthma Status eTable 4. Prospective Association Between Self-reported Cleaning/Disinfection Tasks and COPD Incidence in US Female Nurses, Using a More Stringent Case Definition eTable 5. Prospective Associations Between Combination of Specific Disinfectants/Cleaning Products Evaluated by the JTEM and COPD Incidence in US Female Nurses This supplementary material has been provided by the authors to give readers additional information about their work. ©2019 Dumas O et al. JAMA Network Open. 1 eAppendix. Supplemental Methods Occupational exposure to disinfectants The occupational questionnaire used in our study (2009, 2011, 2013) was adapted to U.S. context from questionnaires used in European studies (European Community Respiratory Health Survey and Epidemiological study on the Genetics and Environment of Asthma), with additions of relevant tasks based on results from a study of asthma among healthcare workers in Texas. Job type and tasks Current nurs in the emergency room, operating room, intensive care unit, other inpatient nurse, outpatient or community, other hospital nursing, nursing outside hospital and nursing education or administration. The two questions regarding the frequency (days/week Thinking about your current job and the use of disinfectants (such as ethylene oxide, hydrogen peroxide, orthophthalaldehyde, formaldehyde, glutaraldehyde and bleach): (a) On how many days per week, on average, do you clean medical instruments with disinfectants? (b) On how many days per week, on average, do you clean surfaces (like floors, tables) at work with disinfectants? (never, <1 day/week, 1-3 days/week, 4- . A specific question was average, do you use spray or aerosol products? (never, <1 day/week, 1-3 days/week, 4- - - never <1 day/week The two questions on disinfecting 4,5 tasks (to clean medical instruments/to clean surfaces) were combined to create a 3-level variable as previously, to define tasks performed weekly: no weekly disinfection tasks; weekly use of disinfectants to clean surfaces only; and weekly use of disinfectants to clean at least medical instruments (regardless of the use of disinfectants to clean surfaces). studied separately because of the low number of NHSII nurses in this category (2.9%). Job-task exposure matrix (JTEM) to evaluate exposure to specific disinfecta nts Exposure to seven major disinfectants/cleaning products was evaluated by the JTEM (formaldehyde, glutaraldehyde, hypochlorite bleach, hydrogen peroxide, alcohol [ethanol, methanol, isopropanol], quats, and enzymatic cleaners). The development of the JTEM has been described in detail elsewhere. Briefly, it used the responses to the questions described above in a population of 9,073 nurses without asthma (2014-2015), drawn included the 24 possible combinations of 8 types of nursing jobs by 3 categories of cleaning tasks (surfaces only, at least instruments, none). Specific cut- levels for each disinfectant, in a given job or job-task combination. of frequent (weekly) exposure. As the cut-offs chosen were disinfectant-specific, and were relative to the average level of use within each job/task .g. To study combinations of specific products evaluated by the JTEM, we classified exposure to products found associated with COPD when studied separately into 5 mutually exclusive categories: low exposure level for all 7 products evaluated by the JTEM (reference); high exposure level to alcohol or quats only; high exposure level to aldehydes (formaldehyde or glutaraldehyde); high exposure level to hypochlorite bleach or hydrogen peroxide; and high exposure level to both aldehydes and hypochlorite bleach/hydrogen peroxide (eTable 5). COPD In all biennial questionnaires since 1989, information on physician-diagnosed COPD was collected, first -text field, and since 1999 by a specific question on physician- diagnosed chronic bronchitis or emphysema (eFigure 1). In our analyses, incident cases of clinician-diagnosed COPD were identified from 2009 to 2015. All women with any history of COPD at baseline (2009) were excluded (eFigure1). The COPD stringent case definition, used in sensitivity analyses, was based on responses to a supplemental questionnaire on COPD, sent between 2015 and 2017 to all participants who ever reported clinician-diagnosed emphysema or chronic bronchitis in biennial questionnaires (responses collected until July 2018, response rate=76%). The specific questionnaire gathered, among other data, information confirming a ©2019 Dumas O et al. JAMA Network Open. 2 diagnosis. In the current study, the stringent case definition included participants who reiterated on the supplemental questionnaire that a physician had diagnosed her as having chronic bronchitis, emphysema, or COPD. A validation study was previously conducted in to evaluate this epidemiologic definition of COPD. Briefly, in a random sample of participants who reported COPD, we obtained medical records (two pulmonary function tests, two chest films, one chest computed tomography scan, two office or emergency department visits for COPD or asthma, and one hospital discharge summary regarding COPD or asthma), and a physician reviewed them in a blinded fashion. The validation study confirmed 83 newly diagnosed COPD based on this definition. Asthma In all biennial questionnaires since 1991, the participants were asked if they had physician-diagnosed asthma. Supplemental questionnaires on asthma were sent in 1998, 2003 and 2014, to all living women who had reported a physician diagnosis of asthma in earlier biennial questionnaire(s). More detailed information on dates of symptom onset and diagnosis, asthma symptoms, medications and hospitalizations for asthma were collected. Asthma cases (definition 1) were defined as participants who reiterated on at least one of the supplemental questionnaires that they had physician-diagnosed asthma, and reported using an asthma medication since diagnosis. Race/ethnicity Race and ethnicity were considered as potential confounders in our analyses. Race and ethnicity were evaluated by questionnaire (self-report). In the NHSII 1989 questionnaire, participants were asked to report their Because the NHSII population is in large majority white and non-Hispan ©2019 Dumas O et al. JAMA Network Open. 3 eReferences 1. Mirabelli MC, Zock JP, Plana E, et al. Occupational risk factors for asthma among nurses and related healthcare professionals in an international study. Occup Env Med. 2007;64(7):474-479. 2. Donnay C, Denis M-A, Magis R, et al. Under-estimation of self-reported occupational exposure by questionnaire in hospital workers. Occup Env Med. 2011;68(8):611-617. 3. Delclos GL, Gimeno D, Arif AA, et al. Occupational risk factors and asthma among health care professionals. Am J Respir Crit Care Med. 2007;175(7):667-675. 4. Dumas O, Wiley AS, Quinot C, et al. Occupational exposure to disinfectants and asthma control in US nurses. Eur Respir J . 2017;50(4):pii: 1700237. 5. Quinot C, Dumas O, Henneberger PK, et al. Development of a job-task-exposure matrix to assess occupational exposure to disinfectants among US nurses. Occup Env Med. 2017;74(2):130-137. 6. Barr RG, Herbstman J, Speizer FE, Camargo CA Jr. Validation of self-reported chronic obstructive pulmonary disease in a cohort study of nurses. Am J Epidemiol. 2002;155(10):965-971. 7. Camargo CA Jr, Weiss ST, Zhang S, Willett WC, Speizer FE. Prospective study of body mass index, weight change, and risk of adult-onset asthma in women. Arch Intern Med. 1999;159(21):2582-2588. ©2019 Dumas O et al. JAMA Network Open. 4 Participants with missing data for occupational exposure were older (mean age: 61 years) than included participants (mean age: 55 years p<0.001), but did not differ from included participants for smoking status, body mass index, race, ethnicity or COPD diagnosis. Participants with missing data for pack-years of smoking were less often white (93%) than included participants (96%, p=0.03), but did not differ from included participants for age, body mass index, ethnicity, self-reported use of disinfectants or COPD diagnosis. ©2019 Dumas O et al. JAMA Network Open. 5 eTable 1. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, sensitivity analyses Occupational exposure Model further Model further Model excluding adjusted for pack- adjusted for diet participants with 2 b b, c years of smoking quality previous b,d comorbidities HR 95% CI HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.34 1.14-1.59 1.33 1.13-1.57 1.27 1.07-1.50 Surface only 1.38 1.13-1.68 1.37 1.13-1.67 1.30 1.06-1.60 Instruments 1.31 1.06-1.60 1.29 1.05-1.58 1.23 0.99-1.52 Abbreviations: HR, hazard ratio; CI, confidence interval. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. All models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Diet quality measured by the Alternate Healthy Eating Index 2010 (AHEI-2010), divided into quintiles. Analyses excluding cases of cardiovascular diseases and cancer. Analyses conducted in 346,529 person-years (547 incident COPD cases). ©2019 Dumas O et al. JAMA Network Open. 6 eTable 2. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, according to smoking status Occupational exposure Never smoker Ever smoker P interaction (245,005 person-years, (123,124 person- 238 COPD cases) years, 344 COPD cases) HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.34 1.03-1.73 1.38 1.11-1.71 0.91 Surface only 1.28 0.94-1.74 1.47 1.14-1.91 0.48 Instruments 1.40 1.02-1.92 1.28 0.97-1.68 0.58 Abbreviations: HR, hazard ratio; CI, confidence interval. Models were adjusted for age, race and body mass index (models were not adjusted for ethnicity because of low numbers in stratified analysis); and for pack-years (continuous) of smoking among ever smokers. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. ©2019 Dumas O et al. JAMA Network Open. 7 eTable 3. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, according to asthma status a a Occupational exposure Never asthma Ever asthma P interaction (301,313 person-years, (50,299 person-years, 283 COPD cases) 190 COPD cases) HR 95% CI HR 95% CI Weekly use of disinfectant None (ref.) 1 - 1 - Any disinfectant 1.31 1.03-1.66 1.37 1.02-1.84 0.78 Surface only 1.49 1.13-1.97 1.20 0.83-1.73 0.38 Instruments 1.12 0.82-1.52 1.56 1.10-2.23 0.16 Abbreviations: HR, hazard ratio; CI, confidence interval. Models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Ever asthma before baseline (2009), using case definition 1. Participants who reported asthma in main questionnaire but did not meet asthma case definition 1, or who were diagnosed with asthma after 2009, were excluded from the analyses. ©2019 Dumas O et al. JAMA Network Open. 8 eTable 4. Prospective association between self-reported cleaning/disinfection tasks and COPD incidence in US female nurses, using a more stringent case definition Person-years No. of Age-adjusted HR Multivariable-adjusted cases HR HR 95% CI HR 95% CI Job type Education or administration 52,827 32 1 - 1 - Outpatient, other nurses 195,946 136 1.13 0.77-1.67 1.17 0.79-1.72 ER or inpatient unit 94,837 69 1.31 0.86-2.00 1.21 0.79-1.85 Operating room 23,928 21 1.54 0.89-2.68 1.47 0.84-2.56 Weekly use of disinfectant None (ref.) 183,292 120 1 - 1 - Any disinfectant 184,245 138 1.25 0.97-1.59 1.24 0.96-1.59 Surface only 93,225 75 1.30 0.97-1.74 1.32 0.99-1.78 Instruments 91,020 63 1.19 0.87-1.61 1.14 0.84-1.56 Abbreviations: HR, hazard ratio; CI, confidence interval; ER, emergency room. Participants who reiterated that a physician had diagnosed her as having emphysema, chronic bronchitis and/or COPD in the supplemental questionnaire (stringent case definition, n=258). Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Exposure evaluated as the highest exposure level at any of the questionnaire cycles before time of diagnosis. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Observations with missing value for ©2019 Dumas O et al. JAMA Network Open. 9 eTable 5. Prospective associations between combination of specific disinfectants/cleaning products evaluated by the JTEM and COPD incidence in US female nurses a c Exposure combinations (JTEM estimates) Person- No. of Multivariable-adjusted HR years cases HR 95% CI Low exposure level for all products (reference) 111,579 174 1 - 1): High exposure level to alcohol or quats only 11,545 22 1.32 0.84-2.06 2): High exposure level to formaldehyde or 25,472 35 1.21 0.84-1.74 glutaraldehydew 3): High exposure level to hypochlorite bleach or 44,466 84 1.58 1.21-2.06 hydrogen peroxide 4): 2)+3) 105,099 164 1.36 1.08-1.70 Abbreviations: HR, hazard ratio; CI, confidence interval; JTEM Job-Task-Exposure Matrix. Mutually exclusive categories; Exposure evaluated based on the highest exposure level at any of the questionnaire cycles before time of diagnosis. classified as low exposure level for all seven products evaluated by the JTEM. Observations with missing values for pack-years of smoking (<0.5%) were excluded from analyses. Multivariable models were adjusted for age, smoking status and pack-years (continuous), race, ethnicity and body mass index. Observations with missing value for body mass index (3.8%) w ©2019 Dumas O et al. JAMA Network Open. 10

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JAMA Network OpenAmerican Medical Association

Published: Oct 18, 2019

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