Published ahead of print on June 16, 2005, doi:10.1164/rccm.200501-111OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200501-111OC
Asthma Severity and Exposure to Occupational AsthmogensINSERM U472-IFR69, Villejuif; INSERM U578, and Département de Médecine Aiguë Spécialisée, CHU, Grenoble, France; and University of British Columbia, Vancouver, British Columbia, Canada Correspondence and requests for reprints should be addressed to Nicole Le Moual, INSERM U472, 16 avenue Paul Vaillant Couturier, 94807 Villejuif Cedex, France. E-mail: lemoual{at}vjf.inserm.fr
Rationale: Severe asthma is a public health problem with limited information regarding preventable causes. Although occupational exposures have been implicated as important risk factors for asthma and asthma exacerbations, associations between occupational exposures and asthma severity have not been reported. Objective: To examine associations between occupational exposures and asthma severity. Methods: The Epidemiological Study on the Genetics and Environment of Asthma combines a case-control study with a family study of relatives of patients with asthma. Adult patients (n = 148) were recruited in chest clinics and control subjects without asthma (n = 228) were population-based. Occupational exposures to nonasthmogenic irritants and asthmogens (classified as "any asthmogen" including three broad groups: high-molecular-weight agents, low-molecular-weight agents, and mixed environments) were assessed by an asthma-specific job exposure matrix. Asthma severity was defined from an 8-grade clinical score (frequency of attacks, persistent symptoms, and hospitalization). Patients with severe (score  2) and mild asthma were compared with control subjects using nominal logistic regression. Main Results: Significant associations were observed between severe adult-onset asthma and exposure to any occupational asthmogen (odds ratio [OR], 4.0; 95% confidence interval [CI], 2.0–8.1), high-molecular-weight agents (OR, 3.7; CI, 1.3–11.1), low-molecular-weight agents (OR, 4.4; CI, 1.9–10.1), including industrial cleaning agents (OR, 7.2; CI, 1.3–39.9), and mixed environments (OR, 7.5; CI, 2.4–23.5). No significant associations were found between nonasthmogenic irritants and asthma severity, nor between asthmogens and childhood-onset asthma or mild adult-onset asthma. Conclusions: Our results suggested a strong deleterious role of occupational asthmogens in severe asthma. Clinicians should consider occupational exposures in patients with moderate to severe asthma.
Key Words: asthma severity • epidemiology • occupational exposure Asthma prevalence has increased markedly in recent decades and is now a major public health problem (1). Trends for both hospital admission rates and asthma mortality also indicate an increase in severe asthma, to which the majority of asthma costs is attributable (1). It has been suggested that severe asthma may represent a different phenotype compared with mild asthma (2–5) and that adult-onset asthma may also be a separate phenotype (2). Risk factors for asthma severity among adults have been rarely studied (5) and include smoking habits, female sex, body mass index, and possibly hormonal factors (4, 6–9). Given the burden of disease represented by severe asthma, especially in adults, it is particularly important to identify modifiable risk factors for this disorder. Although occupational exposures have been implicated as important modifiable risk factors for asthma, associations between occupational exposures and asthma severity have not been reported (5). An American Thoracic Society statement concluded that occupational exposures may account for approximately 15% of the population burden of adult asthma (10); a recent analysis of data from the U.S. general population estimated that at least 27% of asthma cases among adults may be "work-related" (11). Clinical and workplace studies have shown that, among persons with work-related asthma, continued exposure is associated with a worsening of symptoms (12, 13). Even removal of exposure can leave subjects with persistent asthma (12, 13), with persistence linked to the severity of the disease before removal (13, 14). The absence of population-based studies on the contribution of occupational exposures to severe asthma is likely due, in part, to difficulties in estimating the relevant occupational exposures (10, 15) of the more than 250 identified occupational asthmogens (10, 12, 13), and in evaluating asthma severity in such studies (3–5). In the French Epidemiological Study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness, and atopy (EGEA) survey, considerable work has been done to develop a score for current asthma severity on the basis of clinical indicators (6, 16) and to develop a method for estimating relevant occupational exposure to asthmogens (17, 18) suitable for case-control or population-based studies. The aim of the current analysis was to study the relationship between asthma severity and occupational exposures in the EGEA population using these previously developed methods. We hypothesize that the role of occupational exposure with respect to asthma severity may differ according to asthma phenotype, with a different role for subjects with asthma whose asthma first appeared in childhood (potentially work-aggravated asthma) compared with those whose asthma started in adulthood (potentially occupational asthma) (2). Some of the results have been previously reported in the form of an abstract (19).
The EGEA survey (1991–1995) combines a case-control study with a family study of relatives of patients with asthma. The detailed protocol and descriptive characteristics have been published elsewhere (20–22), and some details are given in the online supplement. Patients with asthma were recruited in chest clinics using a standardized procedure, including verification that all patients had clinically relevant asthma (22, 23). Control subjects were recruited from electoral rolls, a surgery department, and one check-up center (20, 21). The present analyses were performed in 148 adult patients with asthma and 228 control subjects without asthma after exclusion of subjects without a job (n = 62) or with uncertain estimates of exposure (n = 19), with missing values for questions on asthma (n = 6), age of asthma onset (n = 1) or asthma severity (n = 22), and control subjects with asthma (n = 37). Information was recorded for treatment, respiratory symptoms, environment, and smoking by a detailed interviewer-administered international standardized questionnaire (23). Main analyses were performed using a clinical severity score (severity classification I) previously described in detail (6, 7, 16), on the basis of frequency of asthma attacks (from 0 to 3), persistent symptoms between attacks (scored from 0 to 3), and hospitalization (yes/no), all in the past 12 months (Table 1). The total score thus ranged from 0 to 7; a cut-off point of 2 or greater was used to classify cases with a high score as "severe" and cases with a low score as "mild" asthma. This cut-off point was chosen so as to have a similar number of subjects in both groups. In addition, a new severity score (severity classification II) combining the clinical severity score and treatment, as recently suggested in the Global Initiative for Asthma (GINA) guidelines (24), was constructed taking into account clinical severity, asthma attacks in the last year, and treatment (i.e., none, treatment not including inhaled corticosteroids, treatment including inhaled corticosteroids; see Table E1 in the online supplement). Analyses using this new score and using three other approaches to classify cases by markers of severity on the basis of lung function (severity classification III), history of hospitalization (severity classification IV), and using an ordinal logistic regression for the clinical score (severity classification V) were also performed (see the online supplement).
Occupational exposure to each of 18 agents, groups of agents, or environments known to be associated with an increased risk for occupational asthma (referred to here as "asthmogens") and to nonasthmogenic irritants was estimated, using a job exposure matrix method described in detail previously (17). This method is now used in the European Community Respiratory Health Survey (ECRHS). Exposure estimates were derived for the current or most recent job code (25) to examine the association between "current" asthma severity and "current" exposure. Duration of the current or most recent job was also determined from the questionnaire. The asthmogens were classified in three groups as follows: high-molecular-weight agents, low-molecular-weight agents, or mixed environments (Table 1). Nominal logistic regression analyses adjusted for age, sex, and smoking habits were performed to compare patients with mild and severe asthma with nonasthmatic control subjects. Secondary exploratory analyses were also performed, first stratified on whether or not the patient was receiving inhaled corticosteroids, and second to include some other potential determinants of asthma (e.g., duration of employment in the current or most recent job, and body mass index and age of menarche among women). To study the specificity of the associations, both asthmogens and nonasthmogenic irritants were considered. Childhood-onset and adult-onset cases were studied separately. Specific asthmogens were studied when at least five patients had been exposed, as described previously (17).
Subjects were, on average, approximately 43 years old (Table 2). Age of asthma onset did not differ between patients with mild or severe asthma overall (Table 2), nor among those with childhood-onset (  7 years) or adult-onset asthma ( 35 years). All patients with asthma without an asthma attack in the last 12 months received inhaled corticosteroid treatment in the last year. Patients with asthma classified as being "severe" using the asthma severity clinical score (score of 2; Table 1) had more frequent attacks and more symptoms between attacks. However, there were no differences between patients with severe and mild asthma regarding other markers of asthma (Table 2).
Exposure to occupational asthmogens was significantly higher among patients with severe asthma compared with control subjects and patients with mild asthma, whereas the reverse trend was seen for exposure to irritants (highest in control subjects). These relationships differed considerably by sex (Table 2). In patients with childhood-onset asthma, there was no relationship between any current occupational exposure and asthma (patients with mild or severe asthma compared with control subjects; Table 3). When comparing patients with adult-onset mild asthma with control subjects, no significant associations were found between current occupational exposure and asthma (Table 3); however, all odds ratios (ORs) were greater than 1. Severe adult-onset asthma was strongly and significantly associated with asthmogen exposure in the current or most recent job, with an OR of 4 (for any asthmogen). Analyses by broad exposure groups showed consistently higher ORs for severe adult-onset asthma than for mild asthma, with significant associations for the three broad exposure groups (low-molecular-weight agents, high-molecular-weight agents, and mixed environments). For specific asthmogens, significant associations were observed between severe adult-onset asthma and exposure to highly reactive chemicals, industrial cleaning agents, and metal sensitizers, and a significant association was also found for those employed in textile production jobs (Table 3). Because of multiple exposures, exposure to highly reactive chemicals, cleaning agents, and latex were highly correlated and could not be examined in the same model. A model including a four-class variable (not exposed to asthmogens, exposed to latex alone, exposed to highly reactive chemicals alone, exposed to at least cleaning agents) showed significant associations between severe adult-onset asthma and industrial cleaning agents (OR, 8.1; confidence interval, 1.5–44.4) and highly reactive chemicals alone (OR, 4.1; confidence interval, 1.2–13.5), and a nonsignificant association for exposure to latex alone (OR, 2.6; confidence interval, 0.5–14.0). Secondary analyses for severe adult-onset asthma led to similar results when duration of employment or body mass index or early menarche among women was included in the models (data not shown). Analyses stratified by inhaled corticosteroid treatment (not shown) showed that the associations between severe adult-onset asthma and exposure to industrial cleaning agents, textile production jobs, and latex exposure were stronger (and still significant) in patients with asthma not being treated with inhaled corticosteroids (compared with those treated). No differences were found according to treatment for associations with highly reactive chemicals in general (similar OR for treated and untreated subjects) and metal sensitizers (all patients with asthma treated). Similar results were found when four other definitions of asthma severity (see the online supplement) were used: a new severity score (severity classification II) combining treatment and the first clinical score (Table E2), a score based on airflow limitation (severity classification III, Table E3), a score based on ever being hospitalized for asthma (severity classification IV, Table E4), and the first clinical score with a cut-off point of 3 (not shown). Analyses performed in patients only showed significant associations between exposure to asthmogens and asthma severity using both logistic (data not shown) and ordinal logistic regressions (severity classification V, Table E5).
These results indicate that, in the EGEA case-control survey, in patients with well defined asthma, exposure to asthmogens in the current or most recent job was strongly related to asthma severity among patients with adult-onset asthma. The specificity of these results, the lack of association with nonasthmogenic irritants, the strength of the association for asthmogens, and the strength of the association for adult-onset asthma support a causal association between current occupational exposure to asthmogens and severe asthma (as defined here, based on a clinical severity score). The results indicate a strong deleterious role of both low- and high-molecular-weight occupational asthmogens in severe asthma. For mild adult-onset asthma, all ORs were greater than 1, but associations were not significant. The associations were consistent before and after adjustment for other factors previously found to be related to asthma severity in the EGEA study, such as smoking, body mass index, and early menarche. Furthermore, consistent results were observed whatever the asthma severity definition used (as described in the online supplement), including a new composite severity score based on symptoms and treatment.
Occupational Exposures and Asthma Severity One strength of our approach is that we did not rely on self-reported exposure to occupational agents in this analysis. Self-reported exposure is not sufficiently accurate to be used as a sole exposure estimate, and has the potential to generate biased estimates, as previously described (15, 18). Our approach, which combines a job exposure matrix with a standardized review step, has been suggested by some authors (15, 17) to be a more appropriate method, and has been shown to give reliable asthmogen exposure estimates (17, 18). This combined method, which is easy to use, is now used in the ECRHS survey. To limit the errors of classification and increase the specificity (18), subjects with imprecise estimates of exposure were excluded from the present analyses. For this analysis, we focused on occupational exposure in the current or most recent job to correspond to the fact that we based our definition of asthma severity on the past 12 months. In a larger study, complete occupational and asthma histories, taking into account exposure windows according to the timing of asthma onset, are recommended (17, 18). Results for specific asthmogens also need to be interpreted with caution because of the small number of subjects exposed in each category, which induces ORs with wide confidence intervals. Our analyses that examined the association between current exposure to nonasthmogenic irritants and asthma displayed ORs lower than 1, regardless of asthma severity or age of asthma onset. Such low ORs may reflect a true lack of causal association between current irritant exposure and asthma, or possibly a selection bias. For example, subjects with asthma may not choose jobs with exposure to irritants, even at a low level. In the general population from Spain, a higher asthma risk was observed in former cleaners than in current cleaners, suggesting self-selection related to exposure (30). Selection bias could occur through self-selection (the choice of jobs without exposure to irritants, not staying in jobs with exposure to irritants) or as a result of physician advice (31). A follow-up of young subjects with asthma is necessary to estimate the impact of selection bias in association with occupational hazards.
Limitations regarding the Definition of Asthma Severity Asthma severity may include several dimensions, and authors (32) as well as experts of the recent GINA guidelines (24) have pointed out the potential distinction between asthma control (recent symptoms) and asthma severity (treatment needed to control the symptoms). Unfortunately, in this study, asthma severity was not easily distinguished from asthma control because of limited information regarding asthma treatments and lack of data on asthma activity in the past weeks. It could be argued that our findings may reflect a relationship between occupational exposure and "uncontrolled asthma" rather than intrinsic asthma severity. However, when using a score combining clinical items and treatment, the associations between exposure to asthmogens and a severe combined score were very similar to the results obtained with the clinical score alone. This may suggest that asthmogen exposure in adult-onset asthma is related to asthma severity and control. Further studies with more detailed information on asthma severity and control would be helpful to explore this issue. It is also possible that the stronger associations observed with severe asthma in our study may be that severe asthma, as defined here, corresponds to a more specific definition of asthma. For example, in a previous population-based study (18), we found that combining airflow obstruction with "reported asthma" was associated with stronger associations between asthma and occupational exposure; however, in that study, asthma was based solely on self-report of diagnosis, a method known to be highly nonspecific. In contrast, in the EGEA survey, cases were well defined (all were recruited from chest clinics and had either a positive response to all four questions regarding asthma symptoms and diagnosis or a combination of positive responses and a medical record review). Therefore, it is unlikely that increased specificity alone would explain our results. It should be noted that, because this is a case-control epidemiologic survey, it is subject to the limitations of epidemiology in general, and case-control studies in particular. For example, although patients with asthma were recruited in chest clinics with specific criteria (they may represent slightly more severe asthma than the general population), the definition of asthma attacks and symptoms between attacks were still self-reported. It is not possible to determine whether this biased the findings reported here, although the use of exposure estimates based on job titles (and not self-report) would serve to minimize self-report bias. In addition, in case-control studies, the OR may be overestimated when the prevalence of the disease is high. However, the prevalence of asthma is around 10% and less for severe asthma, suggesting that the ORs observed here are not likely overestimated.
Public Health Implications In summary, these results highlight the importance of identifying occupational exposures when investigating asthma in adults. The rate of asthma remission is very low in adults (33). Other research confirms that the best prognosis for occupational asthma is obtained by early removal from causative exposure when asthma is mild (12, 36). Furthermore, it has been shown that asthma severity predicts disability (13) and that changes in working conditions may prevent disability (37). Further studies on risk factors of asthma severity are warranted. Our findings underscore the necessity for clinicians to consider occupational exposures as a risk factor for severe asthma and to recommend preventive measures to limit exposures in patients with both mild and severe asthma. The early identification of occupational risk factors and their reduction at the individual level may be important for the prevention of severe disease (10).
The EGEA Cooperative Group includes the following members: Respiratory epidemiology: INSERM U472, Villejuif: I. Annesi-Maesano, F. Kauffmann (coordinator), M. P. Oryszczyn; INSERM U408, Paris: M. Korobaeff, F. Neukirch. Genetics: INSERM EMI 00-06, Evry: F. Demenais; INSERM U535, Villejuif: M. H. Dizier; INSERM U393, Paris: J. Feingold; CNG, Evry: M. Lathrop. Clinical centers: Grenoble: I. Pin, C. Pison; Lyon: D. Ecochard (deceased), F. Gormand, Y. Pacheco; Marseille: D. Charpin, D. Vervloet; Montpellier: J. Bousquet; Paris Cochin: A. Lockhart, R. Matran (now in Lille); Paris Necker: E. Paty, P. Scheinmann; Paris-Trousseau: A. Grimfeld. Data management: INSERM ex-U155: J. Hochez; INSERM U472: N. Le Moual. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Conflict of Interest Statement: N.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. V.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. F.K. received a grant of Received in original form January 25, 2005; accepted in final form May 17, 2005
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ABSTRACT
METHODS
720,000 in November 2002 for the follow-up and genetic studies of the EGEA cohort. S.M.K does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. 
