Management of occupational asthma: cessation or reduction of exposure? A systematic review of available evidence

Characteristics of included studies

The bibliographic search identified 114 publications, from which we selected 32 original studies pertaining to the outcome of “reduced exposure”. Of these 32 publications, 10 studies met the inclusion criteria and were included in the analysis (table 1) [11–20]. 22 articles were excluded for the following reasons: 1) lack of a comparison group of workers who avoided exposure [21–27]; 2) comparison with asymptomatic workers who remained exposed to the offending agent [28]; 3) serial assessments of the same or a portion of the same cohort of workers with OA due to red cedar dust [13, 29–33], isocyanates [34] or persulphate salts [35]; 4) failure to provide appropriate data on the outcomes of patients who had “reduced exposure” [36–40]; and 5) single case report [41].

Eight of the 10 selected publications involved a longitudinal follow-up of patients recruited from specialised clinics [11–16, 18, 20], although the mode of selection of the participants and their participation rate were not clearly stated in four studies [12–15]. Two studies were retrospective surveys of patients whose functional parameters were not assessed before environmental interventions [17, 19]. The studies included 478 patients with OA (median (interquartile range) sample size of the studies 28 (22–64)); 186 patients (18 (8–26) per study) had reduced exposure and 292 (12 (7–26) per study) had avoided exposure to the causal agent. The most commonly identified causal agents (seven of 10 publications) were low molecular weight agents, including isocyanates [12, 15, 16], colophony [11], red cedar dust [13], platinum salts [17] and persulphate salts [20], while only two studies involved a high molecular weight agent (i.e. natural rubber latex) [18, 19], and one study evaluated patients with OA caused by various agents, of which 90% were low molecular weight agents [14]. The diagnosis of OA was established by a positive specific inhalation test in seven studies [11, 13–16, 18, 20] or the combination of a positive immunological test with functional assessments (i.e. specific inhalation challenge in the laboratory and/or monitoring of peak expiratory flow rates at work) [12, 17], or with a consistent clinical history [19].

The interventions aimed at reducing exposure are summarised in table 1; none of the studies provided quantitative assessments of exposure before or after the intervention. The baseline characteristics of the workers who reduced exposure were compared to those of the workers who ceased exposure in five of the eight prospective follow-up studies [13, 15, 16, 18]. These comparisons provided inconsistent findings across the studies; reduction of exposure being associated either with a lower baseline forced expiratory volume in 1 s (FEV₁) [11], or a younger age and a shorter duration of exposure before intervention [15], or an older age and a longer duration of exposure [16], or less frequent treatment with inhaled corticosteroids [18], or a higher proportion of atopics [13]. The median or mean follow-up periods ranged from 14 to 63 months. Five studies did not compare the duration of follow-up in workers who reduced and those who avoided exposure [12, 14, 16, 17, 19]. The duration of the follow-up did not differ among the two groups in four studies [11, 13, 15, 18], while it was longer for the patients with reduced exposure in one study [20]. Changes in asthma medications during the follow-up period were described in four of 10 studies [15, 16, 18, 20], and only one study reported on the changes in smoking habits [16].

Effects of interventions on asthma symptoms

Nine publications described the outcome of asthma symptoms after reduction (179 patients) or cessation (283 patients) of exposure using the following categorisation: complete resolution (nine studies, 462 patients), improvement (five studies, 164 patients), or worsening (five studies, 119 patients) (table 2) [11–14, 16–20]. Most (six out of nine) of these studies relied on a qualitative assessment of the changes in asthma symptoms, while only three studies used a quantified symptom score [16, 18]. Pisati et al. [16] analysed the changes in asthma status using a score that combined symptoms, medications, and the changes in FEV₁ and NSBHR (table 2). The study by Vandenplas et al. [18] reported the median values of an asthma severity score that was derived from the frequency of asthma symptoms, the need for asthma medications, and hospital admissions, but also provided the proportion of patients who recovered from their asthma, as defined by the absence of symptoms and anti-asthma medication. Munoz et al. [20] graded asthma severity according to the criteria proposed by the Global Initiative for Asthma guidelines.

The meta-analysis of the pooled data (table 3) showed that the reduction of exposure was associated with a lower likelihood of improvement (OR 0.16, 95% CI 0.03–0.91) and recovery (OR 0.30, 95% CI 0.11–0.84) from asthma symptoms and a higher risk of symptom worsening (OR 10.23, 95% CI 2.97–35.28), compared with avoidance of exposure (fig. 1).

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Figure 1–

Forest plot of the comparison of the outcome of asthma symptoms: a) recovery, b) improvement and c) worsening.

Effects of interventions on NSBHR

Five studies evaluated the changes in NSBHR after reduction (44 patients) or cessation (66 patients) of exposure (table 4) [11, 12, 15, 18, 20]. The level of NSBHR was assessed using various methods; the five publications stated the threshold concentration or dose of a pharmacological agent (i.e. acetylcholine, histamine or methacholine) to achieve a specified bronchial response that was considered as reflecting a level of NSBHR in the asthmatic range. Recovery from NSBHR was considered when these threshold concentrations or doses exceeded the cut-off values for asthma at the follow-up assessment (table 4). The magnitude of the change in the concentration or dose of pharmacological agent at follow-up assessment that was considered as being significant was not clearly stated in two studies and was assigned a threshold value of one doubling concentration or dose [11, 12].

The meta-analysis of changes in NSBHR (table 3) revealed that reduction of exposure was associated with a significantly higher risk of NSBHR worsening (OR 5.65, 95% CI 1.11–28.82), compared with cessation of exposure (fig. 2).

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Figure 2–

Forest plot of the comparison of the outcome of nonspecific bronchial hyperresponsiveness (NSBHR): a) recovery, b) improvement and c) worsening.

Socio-economic outcomes

Five of the 10 publications [11, 14, 15, 18, 19] provided some socio-economic information, but the employment status at the follow-up visit was clearly stated in only two studies of workers with OA caused by colophony [11] and natural rubber latex gloves [18]. These studies revealed that the proportion of currently employed workers was significantly higher among those who reduced exposure (eight out of eight in colophony-induced OA and 20 out of 20 in latex-induced OA) as compared to those who avoided exposure (seven out of 20 in colophony-induced OA (p=0.004) and nine out of 16 in latex-induced OA (p=0.003)). The study by Vandenplas et al. [18] reported that a major loss of income was more frequent in subjects with latex-induced OA who ceased exposure to latex (nine out of 16) than in subjects who remained exposed to reduced levels of latex (three out of 20; p=0.023). The median (interquartile range) actual reduction in earnings was 20% (0–51%) from the initial value after avoidance of exposure and 0% (0–16%) (p=0.038) after the reduction of exposure. Asthma-related quality of life at the follow-up visit did not differ between the two groups.

Findings

This meta-analysis of 10 studies including 478 subjects with OA showed that reducing exposure to the causal agent was associated with a lower likelihood of improvement and recovery of asthma symptoms and a higher risk of worsening of symptoms and NSBHR, compared with complete avoidance of exposure. These findings do not provide sufficient evidence for using exposure reduction as a management option in patients with OA and they further support the statements that reduction of exposure “is not always effective” [5] and that “there is little evidence for using this approach” [6]. The systematic review on the management of OA by Beach et al. [7] examined the outcome of symptoms [11, 12, 17, 18, 22, 23, 26, 27, 41], medications [11, 12, 18, 23, 35], FEV₁ [11, 12, 18] and NSBHR [11, 12, 18] after the reduction of exposure in studies published up to 2004. The authors concluded that the majority of the studies on subjects who reduced exposure reported the following: some improvement in asthma symptoms; no clear pattern of changes in medication use; an improvement in FEV₁ over time in less than half of the studies; and that there were insufficient data (improvement in one of three studies) to draw conclusions about the changes in NSBHR. In contrast to Beach et al. [7], we deliberately opted to restrict our review to publications that allowed for a direct comparison between those workers who reduced and those who avoided exposure to the offending agent. Moreover, we analysed the changes in symptoms and NSBHR after the interventions in a simple, categorical manner (i.e. recovery, improvement and worsening) as proposed by Rachiotis et al. [8] in their systematic review of the outcome of OA after avoidance of exposure. Six [22, 23, 26, 27, 35, 41] of the 10 studies [11, 12, 17, 18, 22, 23, 26, 27, 35, 41] on workers with reduced exposure in the review by Beach et al. [7] were excluded from our analysis because they did not match our pre-defined inclusion criteria. However, we analysed six studies [13–16, 19, 20] that were not included in the review of Beach et al. [7]. Noticeably, the cohorts of workers who avoided exposure that were selected in our review did not differ from those examined by Rachiotis et al. [8]. The rates of symptoms and NSBHR recovery after cessation of exposure that were found in our review (38%, 95% CI 29–48%, and 29%, 95% CI 10–59%, respectively) were similar to those reported by Rachiotis et al. [8] (32%, 95% CI 26–38%, and 27%, 95% CI 21–34%).

Very few studies provided analysable information on socio-economic outcomes. Two studies found that the reduction of exposure resulted in a lower rate of unemployment than the avoidance of exposure [11, 18]. Accordingly, it remains uncertain whether reducing exposure results in a lower socio-economic impact than complete avoidance of exposure.

Limitations

A number of methodological weaknesses of this systematic review should be carefully considered before drawing definitive conclusions for clinical practice. First, available studies have a high, though unquantifiable, potential for selection bias since all publications were observational follow-up studies where the rationale for the intervention decision (i.e. reduction versus avoidance of exposure) was largely unknown. Noticeably, the proportion of subjects who avoided exposure was markedly higher compared with those who reduced exposure in most studies involving low molecular weight agents (i.e. 2.3 to 3.2-fold higher) [11–14, 16, 20]. By contrast, reduction of exposure was a more common intervention than avoidance (i.e. 1.2 to 5.0-fold more common) only for workers with OA due to latex [18, 19] and platinum [17]. This suggests that the outcome of reducing exposure has been mainly investigated in some specific work environments and that the observed effects may not be extrapolated to other settings. In addition, it is possible to speculate that subjects with more severe asthma had the tendency to avoid rather than reduce exposure to the causal agent. In the five studies comparing the baseline clinical data of the subjects, there was no clear indication that those who reduced exposure to the causal agent had less severe asthma than those who avoided exposure [11, 13, 15, 16, 18], with the exception of the study by Vandenplas et al. [18], in which the subjects who ceased exposure to latex allergens were more frequently treated with inhaled corticosteroids than those who reduced exposure. Beach et al. [7] compared the baseline FEV₁ in cohorts of subjects with OA who continued or avoided exposure, and concluded that lung function at diagnosis was not associated with exposure status during follow-up. However, it should be acknowledged that prospective randomised controlled trials of the effectiveness of various management approaches will never be conducted due to ethical considerations.

Secondly, information regarding “baseline” workplace exposures, the interventions taken to reduce exposures, and the effectiveness of such interventions, was very limited. None of the included studies relied on quantitative exposure assessments to document reduction of exposure, although quantifying the reduction of exposure may be difficult owing to the day-to-day variability in the level of exposure in most workplaces. Nevertheless, the interventions aimed at reducing exposure to asthmagens, such as the use of personal protective equipment, engineering changes to the workplace or the relocation of the worker to area or job with decreased exposure, were, in most cases, not clearly described. Therefore, it was not possible to take into account the actual magnitude of the reduction in the level of exposure achieved in each cohort. In addition, none of the interventions were based on an a priori definition of what should be a biologically relevant reduction of exposure.

Thirdly, significant between-study heterogeneity was observed for both studied outcomes, with the exception of symptom worsening and changes in the level of NSBHR. Included studies were very heterogeneous in their sample size, methods of assessment and outcome reporting. Therefore, it was not possible to control for potential confounders, such as atopic status, history of asthma pre-existing to the causal exposure, the duration of symptoms before the intervention, and changes in smoking habits and asthma treatment during the follow-up period. There was also considerable within-study heterogeneity since available studies included workers with very different types of exposure to the same agent, for instance workers exposed to various types of isocyanates in different industries [12, 16]. In addition, most of the studies did not use standardised, validated instruments for assessing the severity or control of asthma symptoms and their impact on quality of life.

Finally, the major limitation of this review relates to the low generalisability of its findings. Thus, it was not possible to separately analyse the outcome of the interventions according to the nature of the causal agents since most of the available publications (i.e. eight out of 10 cohorts) involved populations exposed to low molecular weight agents. Furthermore, studies pertaining to high molecular weight agents were restricted to natural rubber latex gloves. For instance, a large majority of the studies reporting on the improvement of asthma symptoms (fig. 1b) [11, 12, 14, 16, 19, 20] and the worsening of symptoms [14, 16, 19, 20] and NSBHR [11, 12, 15, 20] assessed populations with OA due to low molecular weight agents, mainly isocyanates (figs 1c and 2c).

Conclusions

This systematic review of available evidence found that reduction of exposure to agents causing OA is associated with in a less beneficial effect on asthma outcome than complete avoidance. These findings indicate that the reduction of exposure cannot be routinely advocated as an alternative to the cessation of exposure. However, the limited quality of available studies prevents us from drawing definitive conclusions on the effectiveness and safety of reducing exposure to occupational asthmagens. Moreover, the data are not sufficient for a comparison of the socio-economic consequences of these two management approaches to be made. There is a clear need for further investigation of the cost-effectiveness of the different management options of OA caused by various agents, through prospective and large-scale studies based on outcomes that have been validated for the evaluation of asthma and quantitative evaluation of interventions aimed at reducing exposure.