Cleaning products and respiratory health outcomes in occupational cleaners: a systematic review and meta-analysis ================================================================================================================= * Olia Archangelidi * Sean Sathiyajit * Dario Consonni * Debbie Jarvis * Sara De Matteis ## Abstract There is consistent evidence of increased respiratory symptoms in occupational cleaners; however, uncertainty remains on type of respiratory health effects, underlying causal agents, mechanisms and respiratory phenotypes. We aimed to conduct a systematic review and if possible, a meta-analysis of the available literature to characterise and quantify the cleaning-related respiratory health effects. We searched MEDLINE and EMBASE databases and included studies that evaluated the association of any respiratory health outcome with exposure to cleaning occupation or products in occupational cleaners. A modified GRADE was used to appraise the quality of included studies. We retrieved 1124 articles, and after applying our inclusion criteria, 39 were selected for the systematic review. We performed a meta-analysis of the 21 studies evaluating asthma which showed a 50% increased pooled relative risk in cleaners (meta-relative risk (RR)=1.50; 95% CI 1.44 to 1.56). Population-based cross-sectional studies showed more stable associations with asthma risk. No evidence of atopic asthma as dominant phenotype emerged. Also, we estimated a 43% increased risk (meta-RR=1.43; 95% CI 1.31 to 1.56) of chronic obstructive pulmonary disease. Evidence for associations with bronchial-hyper-responsiveness, lung function decline, rhinitis, upper and lower respiratory tract symptoms was weaker. In our systematic review and meta-analysis, we found that working as a cleaner is associated with an increased risk of reversible and even irreversible obstructive airway diseases. All studies lacked quantitative exposure assessment to cleaning products; this would help elucidate underlying causal agents and mechanisms. Exposure control and respiratory surveillance among cleaners is warranted to prevent the associated respiratory health burden. Trial registration number: CRD4201705915. * epidemiology * public health * respiratory * meta-analysis * occupational health ### Key messages #### What is already known about this subject? * There is consistent evidence of increased respiratory symptoms in occupational cleaners worldwide. However, uncertainty remains on type of respiratory health effects, underlying causal agents, mechanisms and respiratory phenotypes. #### What are the new findings? * We evaluated a broad range of respiratory health effects and estimated a 50% increased risk of asthma and 43% of chronic obstructive pulmonary disease among occupational cleaners. No evidence for a typical allergic respiratory phenotype emerged, suggesting that continuous exposure to irritant agents might cause both reversible and irreversible airway obstruction. #### How might this impact on policy or clinical practice in the foreseeable future? * Enhanced exposure control and respiratory health surveillance among cleaners is warranted to avoid the associated respiratory health burden. All studies lacked quantitative exposure assessment to cleaning products; inclusion of such measures in prospective studies would help elucidate underlying causal agents and mechanisms. ## Introduction Occupational cleaners represent a significant proportion of the workforce in developed countries (about 4 million just in Europe), and mostly include ‘vulnerable’ social categories: women, migrants and low educated subjects.1 These figures are likely an underestimation given that many in this job sector are self-employed. In the last decade, a consistent and growing evidence of an epidemic of ‘asthma-like’ respiratory symptoms among occupational cleaners has been reported worldwide.2 3 In addition, a recent large population-based study found an increased risk of spirometrically-defined chronic obstructive pulmonary disease (COPD) among cleaners, confirmed in never-smokers.4 Cleaners are exposed to a wide range of airborne agents that might contain either respiratory sensitisers or irritants.5 6 In particular, bleach and disinfectants have been associated with an increased asthma risk. However, most of the evidence is based on self-reported exposure that is likely to be biased towards cleaning agents with pungent odour so the causal agents remain unclear.7 In addition, the underlying mechanistic pathways are uncertain. There is no evidence of a classic IgE-mediated allergic asthma phenotype, so alternative pathways ranging from inflammatory to neurogenic have been proposed. Moreover, it is still largely debated whether persistent exposure to irritant agents in cleaning products could trigger and then sustain chronic airway inflammation with subsequent fixed airway obstruction.5 6 Given the uncertainty of causal agents, underlying mechanisms and type of respiratory health effects, we aimed to conduct a broad systematic review and if applicable a meta-analysis of the literature in order to characterise and quantify the respiratory health effects attributable to occupational exposure to cleaning products. This is an important public health issue, also for the potentially important downstream implications for all end-users of cleaning products during domestic housekeeping, including vulnerable ‘bystanders’ such as children. ## Methods ### Literature search strategy, selection criteria and quality appraisal We conducted the systematic review following the PRISMA guidelines, and we registered the search protocol in PROSPERO (CRD42017059150) on 21 March 2017. We searched the electronic bibliographic databases ‘Ovid MEDLINE(R) 1946 to 2017’ (PubMed) and ‘Embase 1947 to 2017’ on 24 March 2017. The search was then updated to 31 July 2020. OpenGrey database was also screened to retrieve ‘grey literature’ using broad, concise search terms covering the domains of ‘Occupational cleaning’ and ‘Respiratory outcomes’. The search strategy used free-text terms which were adapted for each database in combination with ‘MeSH’ filters where appropriate (online supplementary table S1). All studies examining occupational cleaning and exposure to cleaning products including disinfectants as the exposure and any respiratory disease, symptom or lung function measure as an outcome were eligible for inclusion. Of note, ‘cleaning products’ is used throughout this paper to designate the broader category of cleaning products and disinfectants. Healthcare workers performing cleaning job tasks were also included. To maximise the number of articles, there were no restrictions on the publication date, and PhD theses captured by the grey literature search were also included. Only articles written in English were included. Case reports, editorials, letters and reviews were excluded. Finally, studies on outdoor cleaners (eg, road cleaners) and cleaners working in industrial/factory settings were excluded as they were likely to have been exposed at workplace to other occupational respiratory toxicants (eg, isocyanates, food respiratory allergens, welding fumes, metals, gas, dusts, diesel exhausts and so on) or to use cleaning agents specific for industrial applications (eg, highly alkaline detergents for heavy industrial soiling). The full list of inclusion/exclusion criteria is in online supplementary table S2. Two authors (OA and SS) independently assessed the retrieved references against the inclusion criteria, and in case of disagreement, consensus was achieved by consulting a third reviewer (SDM). Endnote X7.1 was used as reference management software. Given that virtually the entire evidence in occupational epidemiology comes from observational studies, a modified GRADE system8 was used for the quality appraisal of the included articles. In particular, we considered ‘a priori’ as the best study design to assess a causal association a prospective observational cohort instead of a randomised clinical trial because not applicable in this occupational epidemiology context. All the other GRADE criteria were kept as per the original system, including the final scoring classification into high, moderate, low or very low. ### Supplementary data [[oemed-2020-106776supp001.pdf]](pending:yes) ### Statistical methods for meta-analysis To quantify the cleaning-related respiratory health effects, we considered for meta-analyses the studies included in the systematic review that showed a high/moderate quality according to the GRADE scoring. We pooled the main reported effect measures between occupational exposure to cleaning products or cleaning occupation and each respiratory health outcome by using fixed-effects9 or random-effects methods10 as appropriate based on the Higgins I2 statistic. Significant within-studies heterogeneity is typically considered to be present if I2 is ≥50%.11 Also, subgroup analyses by epidemiological study type were performed. Pooled risk effect estimates were presented as meta-relative risks (RRs) and 95% CIs. The meta-analysis was performed using the command ‘metan’ in the statistical software STATA V.15. ## Results From our electronic database search, 1124 articles were retrieved. After removing record duplicates, 712 articles remained eligible for title and abstract screening. Of note, from forward and backward referencing of the removed review articles, we identified three additional records. After abstracts screening, 148 articles remained eligible for full-text article review. After applying our inclusion/exclusion criteria, 39 studies remained to be included in the final qualitative synthesis (figure 1). ![Figure 1](http://oem.bmj.com/https://oem.bmj.com/content/oemed/78/8/604/F1.medium.gif) [Figure 1](http://oem.bmj.com/content/78/8/604/F1) Figure 1 PRISMA flow diagram showing screening and selection of articles related to occupational cleaning and health outcomes resulting from the search in electronic bibliographic databases. Based on our quality appraisal, most of the studies included reached a moderate GRADE score (online supplementary tables S3–S5), the three studies included that were retrieved using OpenGrey scored very low in quality and we decided to not include them in the final systematic review (online supplementary table S6). We managed to perform a quantitative meta-analysis among 21 high/moderate quality studies evaluating asthma risk and three high quality studies on COPD risk with comparable effect measures (figures 2 and 3, respectively). For the other evaluated outcomes, important differences in both exposure and outcome definition (eg, bronchial-hyper-responsiveness (BHR) defined using self-reported symptoms versus standard methacholine challenge test) prevented us from pooling these studies in a meta-analysis. ![Figure 2](http://oem.bmj.com/https://oem.bmj.com/content/oemed/78/8/604/F2.medium.gif) [Figure 2](http://oem.bmj.com/content/78/8/604/F2) Figure 2 Meta-analysis of 21 studies evaluating the association between occupational cleaning exposure and asthma risk. RR, relative risk. ![Figure 3](http://oem.bmj.com/https://oem.bmj.com/content/oemed/78/8/604/F3.medium.gif) [Figure 3](http://oem.bmj.com/content/78/8/604/F3) Figure 3 Meta-analysis of three studies evaluating the association between occupational cleaning exposure and COPD risk. COPD, chronic obstructive pulmonary disease; RR, relative risk. ### Respiratory health outcomes #### Asthma We included in the systematic review 21 studies evaluating associations between asthma and occupational cleaning (and/or exposure to cleaning products) conducted in a broad range of countries (Europe, USA, South America, Canada and New Zealand) in the last two decades (table 1). Thirteen studies were based on general population samples,12–24 and eight were conducted within workforces.25–32 The majority used a cross-sectional design. In terms of outcome definition, ‘adult-onset asthma’ among current or ever cleaners was mainly used as a *proxy* to define ‘occupational asthma’ or the broader category of ‘work-related asthma’ outcomes, based on a self-reported doctor’s diagnosis or asthma symptoms/medications. Of note, studies evaluating work-exacerbated asthma only were not included. Most of the studies used a standard job-title approach as *proxy* for occupational exposure to cleaning products. Six studies assessed exposure to specific agents included in cleaning products by using an expert-based exposure assessment or a semiquantitative job-exposure matrix approach.13 17 18 26 27 33 Evidence of a positive exposure-response relationship emerged by using duration of employment as a cleaner or frequency/intensity/duration of cleaning tasks as *proxys* for exposure. Most of these studies were conducted among hospital cleaners and evaluated frequency and intensity of exposure to disinfectants during cleaning tasks.21 25–27 None actually managed to measure cleaners’ personal exposure to cleaning agents, so no dose-responses based on concentration metrics were evaluated. Both population-based and workforce-based studies found a positive association between occupational cleaning and asthma risk. Among the eight workforce-based studies,25–32 mainly conducted among hospital healthcare workers, risk estimates were more instable because based on smaller samples. Of note, among healthcare workers emerged positive exposure-response trends for asthma risk and exacerbations for frequency of cleaning tasks, especially when applying disinfectants/sterilising agents.25 Exposures to ammonia and bleach showed the highest associations with asthma risk both in workforce-based and population-based studies.19 20 Also, cleaning products in spray format were found more strongly associated with asthma symptoms or asthma exacerbations compared with liquid and powder products. Of note, we did not include in the systematic review a French population-based case-control study that evaluated asthma severity only33 and a cross-sectional study of cleaners in Brazil because a composite outcome of asthma/rhinitis symptoms was evaluated.34 View this table: [Table 1](http://oem.bmj.com/content/78/8/604/T1) Table 1 Summary of epidemiological studies (chronological order) assessing the associations between cleaning occupation, tasks or agents and asthma in population-based and workforce-based studies ### Meta-analysis for asthma outcome Based on our GRADE quality appraisal (online supplementary table S3), we selected 21 studies on asthma with high/moderate quality score for meta-analysis. Where studies reported more than one risk effect estimate for asthma, we selected for quantitative summary the one that best-defined occupational asthma: for example, we favoured the effect estimate for asthma diagnosis after start work among current cleaners over estimates for ever adult asthma diagnosis among ever cleaners. The population-based studies showed a clear increased risk of asthma among cleaners, irrespective of the study design, with the highest pooled risk estimate among cross-sectional studies (meta-RR=1.53; 95% CI 1.36 to 1.72). Workforce studies found positive, but less stable associations (ie, wider CIs), with the highest pooled risk among cross-sectional studies (meta-RR=1.76; 95% CI 1.33 to 2.34). Overall, the pooled meta-analysis of the 21 studies, showed a 50% increased risk for asthma (meta-RR=1.50; 95% CI 1.44 to 1.56; I2=33.7%; p=0.07) (figure 2). Based on the heterogeneity tests between studies, fixed methods were applied to pool the risk estimates. No evidence of publication bias or small-study effects was detected (Egger’s test p=0.23) (online supplementary figure S1). ### Bronchial hyper-responsiveness Among the three studies included in the systematic review that evaluated non-specific BHR as respiratory outcome among occupational cleaners a weak positive association was found (table 2).23 26 35 In particular, only one study found a clear association with BHR even if assessed using a symptoms score questionnaire instead of an objective a specific bronchial challenge test.26 One study found an association in ex-smokers only,22 and one did not find a statistically significant association.35 Two studies included in the systematic review were not included in table 2 because evaluated BHR only in a combined outcome with asthma symptoms.16 22 View this table: [Table 2](http://oem.bmj.com/content/78/8/604/T2) Table 2 Summary of epidemiological studies (chronological order) assessing the associations between cleaning occupation, tasks or agents and BHR and UTRS and LTRS ### Respiratory symptoms Eleven studies (five workforce and six population based) investigated as outcomes lower (LRTS) and upper (URTS) respiratory tract symptoms, such as cough, wheeze or chest tightness, and itchy or runny nose, respectively (table 2).21 24 29 30 35–41 Eight of the 11 studies explored only LRTS and found an increased risk for higher duration of exposure and among those working as cleaners compared with controls. In one study, this increased risk was confined to women although no formal gender interaction was tested,29 while in another study, there was evidence of a positive exposure-response (OR of wheeze of 1.46; 95% CI 1.18 to 1.83 for exposure between 1 and 4 years and of 1.62 (95%CI 1.34 to 1.96) for exposure >4 years.21 One cross-sectional study in Spain showed increased risk of LRTS in cleaners, but failed to reach conventional statistical significance.30 Finally, one study found a significant increase in phlegm (p=0.019) and dyspnoea (p=0.041) suggestive for chronic bronchitis.35 Three studies assessed also associations with URTS. One study showed a doubled risk for eye/nose/throat symptoms;40 the second found associations confined only to medium and not high exposures which were attributed by the authors to the healthy worker effect.36 The third found a significant increase in nasal (p<0.001) and throat symptoms (p<0.05).38 ### Rhinitis Two population-based studies reported the association of cleaning profession with occupational rhinitis as outcome19 42 and one workforce-based assessed associations with the composite outcome rhinitis/asthma34 (table 3); most have shown small and statistically not significant increased risks. Phenotypes of rhinitis were examined by one study that found increased risk of perennial rhinitis among cleaners, especially women (OR=1.70 (1.09 to 2.64).42 Similarly in Brazil, female cleaners only had higher risk of a composite outcome rhinitis/asthma (rhinitis defined as self-reported sneezing or runny or blocked nose, without cold or influenza over the past 12 months).34 Neither of these studies conducted formal tests for gender interaction. Evidence from a cross-sectional study in Spain on current and former cleaners (domestic and non-domestic) showed increased and significant associations with rhinitis only for former domestic cleaners.19 View this table: [Table 3](http://oem.bmj.com/content/78/8/604/T3) Table 3 Summary of epidemiological studies (chronological order) assessing the associations between cleaning occupation, tasks or agents and rhinitis, COPD, lung function and other health outcomes ### COPD Three studies examined the association between occupational cleaning exposure and COPD risk.4 21 43 A significant association of working as a cleaner and having spirometrically-defined COPD (ie, forced expiratory volume in 1 s, FEV1/forced vital capacity, FVC