Contribution of host factors and workplace exposure to the outcome of occupational asthma

Piero Maestrelli, Vivi Schlünssen, Paola Mason, Torben Sigsgaard, on behalf of the ERS Task Force on the Management of Work-related Asthma

Abstract

The outcome of occupational asthma after diagnosis is often poor. The identification of factors associated with a worse outcome may help in the management of the disease, determining its prognosis and assessing the permanent impairment attributable to occupational exposure.

The aim of this systematic review was to provide the available evidence from the medical literature to answer the question: “What is the contribution of host factors and workplace exposure to the risk of a bad outcome of occupational asthma?”

A systematic literature search was conducted in March 2010. We retrieved 177 abstracts. Of these, 67 were assessed as potentially relevant. After full text evaluation, 35 articles that were actually relevant for the question were included in the analysis.

The information obtained was sufficient to establish that older age, high-molecular-weight agents, impaired lung function and longer duration of exposure to the offending agent at the time of diagnosis had a negative role on the outcome of occupational asthma. Atopy and smoking at diagnosis did not seem to influence the outcome of occupational asthma. A limited number of studies considered sex and the pattern of asthmatic reaction on specific inhalation challenge and their findings were contradictory.

The outcome of occupational asthma after diagnosis is often poor. The identification of factors associated with a worse outcome may help in planning appropriate management of the disease, determining its prognosis and in assessing the permanent impairment attributable to occupational exposure. The issue of risk factors associated with the outcome of occupational asthma was considered by recent guidelines but not in a systematic manner. The American College of Chest Physicians (ACCP) [1], the British Occupational Health Research Foundation (BOHRF) [2] and the Agency for Healthcare Research and Quality (AHRQ) [3] agreed that longer symptomatic exposure is related to a worse outcome of occupational asthma. BOHRF concluded that better lung function at diagnosis is related to a better outcome of occupational asthma [2].

The aim of this systematic review was to provide the available evidence from medical literature to answer the key question: “What is the contribution of host factors and workplace exposure to the risk of a bad outcome of occupational asthma?” We considered eight risk factors, in order to determine their respective influence on the prognosis of occupational asthmas: 1) lung function at the time of diagnosis; 2) duration of exposure to the offending agent; 3) atopic status; 4) smoking status at diagnosis; 5) sex; 6) age; 7) type of causing agent; and 8) the pattern of asthmatic reaction on specific inhalation challenge (SIC).

METHODS

Appropriate search terms were adapted to search Medline via PubMed (table 1).

View this table:
Table 1. Terms used for the PubMed search

The final literature search with PubMed was conducted in March 2010. Additional papers were retrieved by cross-referencing. The abstract of each title was independently screened by two occupational medicine specialists for consistency with the aim of the search (P. Mason and V. Schlünssen). The full text of potentially relevant articles was examined according to pre-determined criteria using standardised forms. Two reviewers independently assessed each article. The quality of the studies relevant to the key question was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) grading system (from 1++, highest quality, to 4, lowest quality). Disagreement among reviewers was resolved by discussion and/or consulting a third party, if needed. The heterogeneity of the studies prevented the use of sophisticated analytical methods. Nonetheless, in the synopsis of the data we were able to sufficiently homogenise the information provided and use it for the formulation of statements graded according to the Royal College of General Practitioners (RCGP) three-star system. The evidence and clinical relevance of the recommendations were classified according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system adapted by the American Thoracic Society [4]. The methods are extensively described in the paper by Baur et al. [5]. Search results, as well as the list of considered articles, are included in the evidence tables and are presented in table O3 in the supplementary material in the paper by Baur et al. [5].

RESULTS

148 titles were identified in the systematic literature search. An additional 29 titles that were not included in the search were obtained by cross-referencing the review article by Rachiotis et al. [6]. In total, 177 abstracts were considered. Of these, 67 were assessed as potentially relevant for the key question. After full text evaluation, we selected 36 papers that were actually relevant for the key question. The study by Ameille et al. [7] was subsequently excluded as the findings were based on results from two papers that were already included [8, 9]. The evidence table of the 35 papers is included in the study by Baur et al. [5] (supplementary material, table O3). For each investigated factor, the number of subjects in the positive and negative studies was calculated by adding the number of subjects at follow-up in each study that considered the investigated factor included in the review by Rachiotis et al. [6] and in the extended literature search.

Lung function impairment at diagnosis

Among the 18 articles reviewed, 15 studies detected a significant relationship between low indices of lung function at baseline (nonspecific bronchial hyperresponsiveness (NSBHR): n=10; forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC): n=9; SIC: n=2) and a worse asthma outcome at follow-up (table 2). One study found that increased bronchial hyperresponsiveness (BHR) at baseline favours a good outcome at follow-up [24]. In contrast, five studies did not find associations between low indices of lung function at baseline (NSBHR: n=4; FEV1 or FVC: n=4) and a worse asthma outcome at follow-up. If the evaluation was restricted to well-conducted studies (grading 2+ and 2++), the number of studies reporting a significant relationship between low indices of lung function at baseline and a worse asthma outcome at follow-up was six versus two studies that reported no relationship (table 2).

View this table:
Table 2. Lung function impairment at diagnosis and outcome of occupational asthma

Duration of occupational exposure

In addition to the study by Rachiotis et al. [6], which includes 14 papers related to the duration of occupational exposure before diagnosis, we evaluated seven papers that detected a significant relationship between duration of exposure and outcome of occupational asthma [11, 13, 14, 21, 2628]. In contrast, four articles did not find a relationship between duration of exposure and outcome of occupational asthma [24, 2931]. If the evaluation is restricted to well-conducted studies (2+, 2++ or 1-), two studies found a positive association compared to three which did not find any association (table 3). However, the number of subjects in the positive studies (excluding those with grade 3 evidence) largely exceed (>3,000) the number of subjects in the negative studies (∼500).

View this table:
Table 3. Duration of occupational exposure and outcome of occupational asthma

Atopy

None of the articles reported a relationship between atopy and outcome of occupational asthma (table 4).

View this table:
Table 4. Effect of atopy on outcome of occupational asthma

Smoking at diagnosis

11 articles did not find a significant relationship between smoking at diagnosis and outcome of occupational asthma [12, 16, 18, 20, 2224, 28, 29, 31, 39]. This group includes most of the studies with better (2+) grading. In contrast, four articles reported a relationship between smoking and worse outcome of occupational asthma (table 5) [10, 13, 32, 38].

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Table 5. Effect of smoking at diagnosis on outcome of occupational asthma

Sex

Two papers found no significant relationship between sex and outcome of occupational asthma [21, 31]. However, two other studies found a significant relationship between sex and outcome of occupational asthma [20, 39]. Malo et al. [20] found female sex to favour good prognosis, while Gassert et al. [39] found male sex to favour good prognosis (table 6).

View this table:
Table 6. Effect of sex on outcome of occupational asthma

Age at diagnosis

The papers selected by the systematic review were already included in the study by Rachiotis et al. [6], which identified an effect of age on asthma outcome (table 7). The number of subjects (∼1,700) evaluated in the papers reporting an association between older age at diagnosis and worse outcome of occupational asthma (excluding those with grade 3 evidence) largely exceeds, the number of subjects (∼500) included in the studies that did not find such a relationship.

View this table:
Table 7. Effect of age at diagnosis on outcome of occupational asthma

Type of causative agent

Three studies [19, 34, 39] and the study by Rachiotis et al. [6] found a significant relationship between type of agent and outcome of occupational asthma. Gassert et al. [39] found occupational asthma from the industrial sector to have a worse outcome compared to other sectors. Rachiotis et al. [6] and Perfetti et al. [34] found that patients who are exposed to high-molecular-weight agents are more likely to have persistent BHR. Four studies found no relationship between the type of agent and outcome of occupational asthma [11, 20, 28, 35]. The number of studies is limited, but the body of data supporting a positive relationship in the studies graded 2+ or 1- is substantial compared to data revealing no relationship (∼2,000 versus ∼500 subjects) (table 8).

View this table:
Table 8. Effect of type of causing agent on outcome of occupational asthma

Pattern of asthmatic reaction on specific inhalation challenge: late versus early

Three papers did not find any significant relationship between type of response and outcome of occupational asthma [11, 29, 35]; the grading of these articles is generally low. However, two studies have found late response to worsen the outcome of occupational asthma [22, 40], and Cote et al. [12] detected a relationship with the severity of either early or late asthmatic reactions (table 9).

View this table:
Table 9. Pattern of asthmatic reaction on specific inhalation challenge (late versus early) and outcome of occupational asthma

DISCUSSION

The information retrieved from the systematic literature search was sufficient to establish the role of lung function at the time of diagnosis, duration of exposure to the offending agent, atopic status, smoking status at diagnosis, age and type of causative agent on the outcome of occupational asthma. In contrast, a limited number of studies considered sex and the pattern of asthmatic reaction on SIC, and their findings were contradictory.

The following statements summarise the results of our systematic analysis (refer to table O3 in the Task Force report [5]). The evidence was graded according to the RCGP three-star system.

1) There is a substantial body of data that indicates that lower lung volumes, higher NSBHR or stronger asthmatic response to specific inhalation challenge at diagnosis are risk factors for a bad occupational asthma outcome (moderate evidence: **).

The statement is based on 18 articles; seven had SIGN grade 2+ or 2++ (table 2) [8, 9, 12, 18, 20, 24, 25]. This statement is in agreement with the conclusions of BOHRF [2]. The issue was not considered by ACCP [1] or AHRQ [3].

2) There is a substantial body of data that suggests that a longer symptomatic exposure relates to a worse outcome of occupational asthma (moderate evidence: **).

The statement is based on 26 articles, 10 with SIGN grade 2+, 2++ or 1- (table 3) [6, 9, 18, 20, 21, 25, 28, 29, 31, 33]. This statement is in agreement with the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

3) There is no relationship between atopy and the outcome of occupational asthma (strong evidence: ***).

The statement is based on 10 articles, five with SIGN grade 2+ (table 4) [12, 18, 28, 29, 31]. Atopy was not included in the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

4) Smoking at the time of diagnosis is not related to the outcome of occupational asthma. Although it is well established that smoking cessation is beneficial for the prognosis of asthma per se, smoking at the time for diagnosis of occupational asthma does not seems to have a major impact on the prognosis (moderate evidence: **).

The statement is based on 15 articles, seven with SIGN grade 2+ (table 5) [12, 18, 20, 24, 28, 29, 31]. Smoking was not included in the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

5) There is a limited body of data that considered sex in the outcome of occupational asthma and the evidence is contradictory (contradictory evidence: *).

The statement is based on four articles, two with SIGN grade 2+ (table 6) [20, 31]. Sex was not included in the conclusions of ACCP [1], BOHR [2] and AHRQ [3].

6) There is a sufficient body of data that indicates that an older age of the patients is associated with poorer prognosis of occupational asthma (moderate evidence: **).

The statement is based on six articles, three with SIGN grade 2+ or 1- (table 7) [6, 25, 28]. Age was not included in the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

7) There is a substantial body of data that indicates an effect of the type of causing agents on occupational asthma outcome. High-molecular-weight agents seem to cause longer duration of NSBHR compared to low-molecular-weight allergens (moderate evidence: **).

The statement is based on eight articles, three with SIGN grade 2+ or 1- (table 8) [6, 20, 28]. This statement is in agreement with the conclusions of ACCP [1]. The issue was not included in the conclusions of BOHRF [2] or AHRQ [3].

8) From the low number of papers it is not clear whether the pattern of asthmatic response affects the prognosis for occupational asthma (limited evidence: *).

The statement is based on six articles, three with SIGN grade 2+ (table 9) [12, 29, 40]. The issue was not included in the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

The statements on lung function at diagnosis and duration of exposure to the offending agent before diagnosis are based on a significant number of studies. However, the strength of evidence remains moderate since there is some inconsistency in the results. The conclusion of BOHRF [2] that “the likelihood of improvement or resolution of symptoms or of preventing deterioration is greater in workers who have a relatively normal lung function at the time of diagnosis” is in agreement with our statement. The issue was not considered by ACCP [1] or AHRQ [3].

All recent guidelines have concluded that the probability of a better outcome of occupational asthma is greater in those who have a shorter duration of symptomatic period before diagnosis, and avoid exposure to the offending agent after the diagnosis.

Although it is well established that atopy is a risk factor for occupational asthma due to high-molecular-weight agents, whereas it is not so for low-molecular-weight causes of occupational asthma, the analysis of data indicated that once occupational asthma has developed, being atopic does not modify the prognosis of the disease irrespective of the nature of the occupational agent. The evidence that the outcome of occupational asthma is not related to the presence of atopy is strong, since the literature is concordant on this conclusion. However, it should be considered that among the studies evaluated, there was an imbalance in favour of occupational asthma due to low-molecular-weight agents. Atopy was not included in the conclusions of ACCP [1], BOHRF [2] and AHRQ [3].

There was evidence, albeit moderate, that being a smoker at the time of diagnosis of occupational asthma did not influence the prognosis of the disease. This may be surprising considering that asthmatic smokers have an accelerated decline in lung function and poorer response to corticosteroid treatment compared to nonsmokers. Probably the effect of other variables, in particular on persistence or cessation of exposure to the causing agent, on the course of the disease is sufficiently strong to obscure that of cigarette smoke in the small cohorts examined in the studies on occupational asthma. Since pathophysiology and treatment of occupational asthma are comparable to those of non-occupational asthma, it is reasonable to offer the option of smoking cessation to smoking workers when the diagnosis of occupational asthma is made.

There is evidence that older age is related to poorer prognosis of occupational asthma. It remains to be seen whether age is a risk factor per se or that the effect is seen because older workers had been exposed to the workplace environment for longer. Neither smoking habit nor age were considered in previous guidelines by the ACCP [1], BOHRF [2] and AHRQ [3]. The ACCP [1] adopted the findings of Rachiotis et al. [6] and stated that the prevalence of persisting NSBHR was significantly higher among those with occupational asthma caused by high-molecular-weight agents compared with those with occupational asthma from low-molecular-weight agents. These conclusions have been confirmed by our extended analysis. The relationship between type of causal agent (high molecular weight versus low molecular weight) and outcome of occupational asthma should be taken cautiously, since Rachiotis et al. [6] found that patients exposed to high-molecular-weight agents are more likely to have persistent NSBHR, but the recovery rate after cessation of exposure did not differ in the two groups. The type of causing agent was not considered by BOHRF [2] and AHRQ [3].

Future aspects

More research is needed in order to assess the prognostic value of sex and type of asthmatic response to specific bronchial challenge test at diagnosis. Furthermore, knowledge on the level of exposure is needed in order to assess the effect of duration of exposure in a more qualified way. Finally, most research on risk factors for a bad outcome is performed on a limited number of exposures, i.e. isocyanates and Western red cedar. It is crucial to include other exposures in the research field as well.

In conclusion, based on this systematic review some recommendations can be made regarding risk factors for a bad outcome of occupational asthma (table 10).

View this table:
Table 10. Recommendations

Acknowledgments

The members of the Task Force are as follows: X. Baur (Chair; Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany), T. Sigsgaard (Co-Chair; Århus University, Institute of Environmental and Occupational Medicine, School of Public Health, Århus, Denmark), T.B. Aasen (Haukeland University Hospital, Bergen, Norway), P.S. Burge (Dept of Respiratory Medicine, Heart of England NHS Foundation Trust, Birmingham, UK), H. Dressel (Städt. Klinikum München GmbH, Klinikum Neuperlach Zentrum für Akutgeriatrie und Frührehabilitation, Munich, Germany), D. Heederik (Environmental Epidemiology Division, Institute for Risk Assessment Sciences (IRAS), University of Utrecht, Utrecht, the Netherlands), P.K. Henneberger (National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, USA), P. Maestrelli (Dept of Environmental Medicine and Public Health, University of Padova, Padua, Italy), C.A. Redlich (Yale Occupational/Environmental, New Haven, CT, USA), J. Rooyackers (Netherlands Expertise Center for Occupational Respiratory Disorders – NECORD IRAS NKAL, Utrecht, the Netherlands), V. Schlünssen (Århus University, Århus, Denmark), O. Vandenplas (Dept of Chest Medicine, Mont-Godinne Hospital, Université Catholique de Louvain, Yvoir, Belgium), and D. Wilken (Institute for Occupational and Maritime Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany).

Footnotes

  • Support Statement

    The work of the Task Force on the Management of Work-related Asthma was funded by the European Respiratory Society.

  • Statement of Interest

    V. V. Schlünssen received a fee for speaking at a scientific meeting by GlaxoSmithKline Pharma A/S in 2011.

  • Provenance

    Submitted article, peer reviewed.

  • Received June 7, 2011.
  • Accepted July 26, 2011.

REFERENCES

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