Asthma is a heterogeneous disease characterized by diverse clinical, physiological and inflammatory attributes (1–3). Various phenotypes for non-work-related asthma have been reported in the literature, with significant efforts directed toward characterizing severe asthma phenotypes (2, 3). However, few studies have investigated work-related asthma phenotypes. Studies that have characterized occupational asthma phenotypes, have focused mainly on the mechanisms (allergic vs. irritant) and etiological agents (high molecular weight—HMW vs. low molecular weight—LMW) (1, 4, 5). Very little is known about work-related asthma phenotypes in health workers (HWs) exposed to cleaning agents (6, 7). Differentiating between various asthma phenotypes in the workplace is important in understanding the heterogeneous nature of the disease to develop appropriate management and preventive strategies (1, 5).

There have been considerable efforts in investigating the burden of asthma among HWs exposed to cleaning agents. In a prospective population-based European study, the prevalence of new-onset asthma (asthma attack or taking asthma medication in the past 12 months) among nurses was reported to be 4.8% (8). Further analysis revealed a slightly higher prevalence of new-onset asthma (currently taking asthma medication, asthma attack or woken up by an attack of shortness of breath in last 12 months) of 6%, most likely due to different asthma definitions used (9). These findings are similar to a US study of HWs (10), which reported an overall prevalence of doctor-diagnosed asthma with onset after entry into the healthcare profession of 6.6%. In this study, nurses (7.3%) had the highest prevalence followed by respiratory therapists (5.6%), occupational therapists (4.5%) and doctors (4.2%). However, a study 2 years later from the same US population reported a much higher prevalence (9.8%) of doctor-diagnosed asthma with onset after entry into the healthcare profession in nurses based on the longest job held (11). Globally, the prevalence of asthma in HWs exposed to cleaning agents ranges between 4.4 and 11.2% (7–13). Very little is known about the burden of asthma among HWs in Africa, except for a study of South African dental HWs (14), in which the prevalence of atopic asthma (6.9%) was higher than non-atopic asthma (5.9%) or work-exacerbated asthma (4%).

Various studies have investigated the host-associated risk factors in adult asthma. Common host risk factors associated with asthma have included age, female sex, seniority, smoking status and atopy (10, 11). A significantly higher risk (RR = 2.9) for new-onset asthma was observed for atopic individuals, those with a parental history of asthma (RR = 2.1) and in non-smokers (RR = 1.8) in the large population-based ECRHS II study of workers across different industries (8). There is inconsistent evidence regarding the association between smoking and asthma in general and occupational asthma in particular (6, 15, 16). Furthermore, very little is known about the risk of smoking in relation to asthma in HWs exposed to cleaning agents (15, 17).

A review on risk factors for non-work-related adult-onset asthma and occupational asthma revealed that host-associated factors (sex, genetics, and atopy) did not differ for these two broad asthma phenotypes, whereas, environmental factors appeared to play a very important role for the occupational asthma phenotype. A later study however identified novel genes implicated in adult asthma related to occupational exposure to LMW agents or irritants (18). Among HWs, women appear to be more affected than men, with the former having a higher prevalence of all asthma phenotypes, including WRA symptoms (3.6 vs. 1.8%), work exacerbated asthma (1.3 vs. 0.3%) and occupational asthma (1.0 vs. 0.1%) than men (19). Similar findings have been reported in the ECRHS II study (8). In the light of these observations, it is likely that the gendered distribution of work plays an important role. Furthermore, female sex hormones have also been implicated in the pathogenesis of asthma and the higher prevalence in women (1).

The aim of this study was to describe asthma phenotypes in health workers exposed to cleaning agents and to identify important host risk factors associated with various asthma-related outcomes, based either on the presence of symptoms, non-specific bronchial hyperresponsiveness or allergic airway inflammation.

In this study of health workers employed in two large tertiary academic hospitals in southern Africa, atopic asthma (6%) was more prevalent than non-atopic asthma (4%). Furthermore, most asthma-related outcomes and work-related symptoms were positively associated with host attributes suggesting a more dominant role for allergic mechanisms underlying asthma and work-related symptoms. More stronger associations were also observed for asthma symptoms when FeNO ≥ 50 ppb (a marker of allergic airway inflammation) was combined with NSBH (BDR or MCT positive). However, the weak positive association between NSBH and FeNO suggests that these two outcomes possibly detect different underlying pathophysiological mechanisms producing different asthma phenotypes. The pathophysiological mechanisms in asthma related to cleaning agents have not been fully elucidated for most agents. Previous studies have suggested the involvement of both allergic and irritant mechanisms although the latter has been generally thought to be the dominant mechanism (6, 33). Furthermore, it is probable that both these mechanisms may enhance each other, in that airway epithelial damage due to irritant exposures can also activate an allergic T helper type 2 (Th2) response and increase the risk of sensitization (6, 33).

The prevalence of current asthma (10%) in this study was similar to a Spanish study (11%) of professional cleaners (including hospital cleaners) (12) but higher than that reported for nurses (6%) in a general population study of 13 European countries (9). The definition of current asthma used in the current study was similar to these two European studies (9, 12). The reported prevalence of asthma among HWs has varied across other studies as has been reported for other occupational groups probably due to differences in asthma definitions used (34). However, in this current study, the prevalence of atopic asthma (6%) was similar to that reported for South African dental HWs (6.9%) and other workplace-based studies of occupational groups (5–6%) (31–33). On the other hand, the prevalence of non-atopic asthma was slightly lower (4%) than for dental HWs (5.9%) and the other occupational groups (6-7%)(1, 14, 32, 33). Furthermore, the 2% prevalence of work-related asthma is on the lower end of the spectrum of prevalence (3–13%) reported from workplace based studies of other occupational groups in South Africa exposed primarily to high molecular weight agents (14, 35, 36).

In this current study, strong associations were observed between sensitization to occupational allergens in health care settings and atopic status. With exception of one non-atopic subject sensitized to OPA, all HWs sensitized to occupational allergens (OPA, chlorhexidine, and NRL) were atopic (p < 0.001). While most studies globally and several South African studies have shown a higher likelihood of atopics being sensitized to high molecular weight agents such as natural rubber latex, species, flour and poultry dust (35–38), this association has not been previously observed for low molecular weight agents such as OPA and chlorhexidine. However, serum specific IgE to OPA and chlorhexidine has been detected in a few studies (39–42). In addition, case reports of asthma due to OPA have also reported a latency period between initial exposure to OPA and the development of symptoms implicating an allergic response caused by OPA (43, 44). Furthermore, animal studies have also suggested that OPA is a respiratory and dermal sensitizer as evidenced by a predominant expression of Th2 cytokines (IL-4, IL-5, and IL-13) in OPA exposed mice (45, 46). Overall, this suggests that the underlying mechanism of asthma in these HWs is probably IgE-mediated. Interestingly, animal studies have also suggested that OPA also has more irritant effects than GTA in both in-vitro and in-vivo tests, so this irritant effect cannot be ruled out completely (45). Future studies are needed to further investigate these effects to obtain a better understanding of the allergic and possibly irritant pathophysiological mechanisms of asthma due to these cleaning agents.

As to be expected, FeNO, generally considered to be a non-invasive marker for eosinophilic airway inflammation, was positively associated with allergic predictors (atopy and history of hay fever) and a history of childhood-onset asthma. Similarly, stronger associations were also observed between asthma symptoms and high FeNO (≥50 ppb) levels. A positive association between FeNO and atopy is well-known and has also been reported in various studies in other settings (47). Furthermore, a positive association [OR_unadj = 3.59, CI: 1.63–7.93; OR_adj (atopy + smoking) = 1.93, CI: 0.85–4.37] was also observed between elevated FeNO (≥25 ppb) and allergic sensitization to OPA/chlorhexidine (data not shown in tables). However, much stronger relationships have been demonstrated in workplace-based studies of South African workers exposed to predominantly high molecular weight agents (37, 48). Predictably, current smoking (GM ratio = 0.76) was negatively associated with FeNO levels in HWs as has been observed in other studies (31, 44).

In this current study, a positive association was observed between female gender and asthma-related outcomes including work-related asthma symptoms and bronchial hyperresponsiveness. New-onset asthma in adulthood has been shown to be more prevalent in women, due to multiple factors including female sex hormones being implicated (1). Furthermore, the high preponderance of women workers in the health care setting, as in the current study in which 78% were women, together with the gendered distribution of work is another contributory factor. Overall, the findings of this study are consistent with other studies of asthma associated with cleaning agents, which have reported an increased risk in women since they are more likely to be exposed to cleaning agents than men in their work (19, 49, 50).

Interestingly, in the current study, a past history of pulmonary tuberculosis (TB) was strongly associated with asthma symptoms, current asthma and work-related asthma. This association persisted even after adjusting for age, gender, smoking, atopy and body mass index. Similar findings have been reported in other South African population-based and workplace-based studies (51). In a study of adults exposed to vapors emanating from a sulfur stockpile fire incident, a previous history of TB (more than 1 year prior to the fire) was an important predictor for chronicity of new onset irritant-induced asthma (52). Due to the cross-sectional nature of the current study, it was not possible to establish a temporal relationship between TB and asthma-related outcomes. Furthermore, it is also possible that the observed association between TB and asthma-related outcomes could be due to common post-TB complications such as chronic obstructive pulmonary disease and bronchiectasis (53).This observation needs further exploration in a larger longitudinal study of these health workers.

In this study, smoking was positively associated with an elevated ASS (≥2 vs. 0–1) as well as with non-atopic asthma. However, smoking was not associated with allergic sensitization due to occupational allergens, NSBH, current asthma, work-related ocular-nasal symptoms, nor with work-related asthma. This is consistent with the current body of evidence of asthma on the lack of association between smoking and occupational asthma (1, 6, 15). While some studies have demonstrated that smoking at baseline increases the risk of incident asthma in adulthood, no significant associations have been reported in a cross-sectional analysis at follow-up (16). Overall, various studies have reported inconsistent findings of the association between smoking and asthma in general and occupational asthma in particular (1, 15). Furthermore, very limited specific information is available on the risk of smoking in relation to asthma in HWs exposed to cleaning agents (15, 17). Zock et al. study of cleaning workers also did not demonstrate any association between smoking and asthma (17). Additional longitudinal studies are needed to better understand the relationship between smoking, occupational allergic sensitization and asthma risk among health workers exposed to cleaning agents.

Despite the major strengths of this study in using multiple objective markers for asthma, it is likely that some limitations could have been present in a study of this nature, since it was a cross-sectional study. Furthermore, some of the asthma indices such as current asthma, ASS and work-related asthma were based on self-reported information from questionnaires. Self-reported symptom information is usually characterized by a high sensitivity but low specificity in identifying individuals with asthma. However, since self-reported asthma information obtained from a standardized questionnaire correlated relatively well with NSBH and FeNO in this study, this suggests that it did not impact significantly on the associations observed, although the temporality could not be ascertained with certainty.

In conclusion, this study has demonstrated that atopic asthma was more prevalent than non-atopic asthma in health workers. Furthermore, most asthma-related outcomes and work-related symptoms were positively associated with allergic attributes suggesting a more dominant role of allergic mechanisms over non-allergic mechanisms. That atopic individuals were more likely to be sensitized to LMW agents such as OPA and chlorhexidine, further suggests an IgE mediated mechanism, probably underlying the asthma reported in this group of HWs. Further studies are needed to confirm the findings that have been reported in this study, which to our knowledge have not been previously reported.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Human Research Ethics Committee (HREC) of the University of Cape Town (HREC Ref: 212/2013), Muhimbili University of Health and Allied Sciences (MUHAS) Institutional Review Board and University of Michigan Medical School Institutional Review Board (HUM00083115). The participants provided their written informed consent to participate in this study.

HM and MJ were responsible for the conceptualization of the study. HM and RB were responsible for the fieldwork. TS conducted the laboratory analysis of the serum samples. HM was responsible for data collection, data management, analysis, and write-up under the supervision of RB and MJ. HM was responsible for preparation of the first draft of the manuscript. All authors contributed to and reviewed the manuscript before submission.

This work was supported by the South African Medical Research Council, Millennium Promise Programme NIH Grant 1D43ES018744-01 (University of Michigan/Fogarty International Center), Allergy Society of South Africa & National Research Foundation of South Africa.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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