A compendium of causative agents of occupational asthma

Occupational asthma is a disease characterized by variable airflow limitation and/or hyper-responsiveness associated with inflammation which is attributable to causes and conditions in a particular occupational environment and not to stimuli encountered outside the workplace [1]. Occupational asthma involves IgE-mediated asthma after a latency period, irritant asthma with or without a latency period, including reactive airways dysfunction syndrome (RADS), resulting from high exposure, and asthma due to specific occupational agents with unknown pathomechanisms that may also show a latency period [2, 3] (Figure 1). Occupational asthma needs to be differentiated from work-aggravated asthma, which is characterized by a worsening of pre-existing asthma or increase in airway resistance, asthma medications or frequency and/or severity of asthma attacks arising from causes and conditions attributable to a particular occupational environment and not to stimuli encountered outside the workplace. These workers have a concurrent history of asthma that was not induced by exposure in the workplace. Aggravation is typically due to an occupational irritant (e.g. non-sensitizing fumes) [4]. There are also workers with pre-existing asthma who, after a latent interval, have a worsening of their pre-existing non-occupational asthma after regular daily exposure to agents which cause IgE-mediated allergies. No detailed studies or valid statistics relevant to work-aggravated asthma are available. The current study focuses on the identification of causes of occupational asthma and is based on two recently published reviews, evaluating occupational allergens [5] and irritants [6] in an evidence-based manner.

Appropriate terms were used to search Medline via PubMed (http://​www.​ncbi.​nlm.​nih.​gov/​mesh). The combination of medical subject headings (MeSH) used were as follows

As reported by various authors ([17‐19]), about 15% of adult asthma cases are caused by occupational agents, whether IgE-mediated or irritant occupational asthma or occupational asthma due to unknown pathomechanism. Irritant asthma may arise from high dose, moderate or even low dose exposure with the clinical pictures of RADS and not-so-sudden-onset irritant asthma. The latter, as well as occupational asthma of unknown pathomechanism, mostly show a latency period from the beginning of causative exposure until the appearance of symptoms, which makes these indistinguishable from allergic asthma [20].

Previous reports and reviews have accumulated narrative and experimental evidence for about 300 causative agents, which are often divided into high or low molecular weight groups ([21‐28]). High molecular weight agents typically induce asthma through an IgE-mediated mechanism while the pathomechanism of low molecular weight agents is mostly airway irritation or unknown.

Quirce and Sastre recently summarised the newer causative agents published between 2009 and 2011 [22]. A continuously updated classification of allergenic or irritant occupational asthma agents has been provided by the American Conference of Governmental Industrial Hygienists (ACGIH) [29], the German MAK commission [30], the Health and Safety Executive [31] and the European Community [14]. At present, the new international labelling of working materials hazardous to health (GHS; EU: CLP), which includes airway allergenic and iritative agents, has been put in force and has replaced the hitherto R and S notes with hazard (H) and precautionary statements (P) as well as by new hazard pictograms (European Parliament [14], United Nations [32]).

These reviews and classifications all lack an evidence-based evaluation of identified agents in the clinical literature. An evidence-based evaluation of the literature is of particular importance for case management and diagnostics in clinical practice. Thus, the objective of this work was to provide a scientific compendium of practical relevance, exhaustively listing the agents and worksites known to cause occupational asthma.

From more than 3,000 publications, 1,339 were retrieved from our Medline/PubMed and additional database searches, which refer to 372 individual agents or worksites that have been identified to cause allergic occupational asthma and 184 individual agents or worksites known to cause irritant occupational asthma. Of these 520 individual agents or worksites, 36 occurred in more than one category.

Evidence for causing occupational asthma was found for 78 allergens and for 71 irritants, respectively, with 8 eliciting an allergic as well as an irritative pathomechanism, establishing 141 in total.

The evidence levels for causing occupational asthma of many of the listed agents or worksites are moderate to low since only about a quarter of the identified studies were analytical, primarily because randomised controlled trials are not considered ethical when studying the exposure effects of harmful agents. Therefore, high quality studies are largely absent and the few available studies are frequently small in number of workers studied.

The vast majority are surveys, case series or case reports with evidence levels rated very low. The common diagnostic procedure for occupational asthma in clinical settings is a stepwise approach, including questionnaires about asthma-specific symptoms as well as respiratory and allergy assessments. Self-reported work-related symptoms are relatively sensitive indicators in the diagnosis of occupational asthma but the specificity is low. In approximately one third of the included studies, self-reported asthma symptoms or physician-reported asthma were used as the only diagnostic approach. Lung function, allergy testing and the diagnostic gold standards, serial spirometric or peak flow measurements (sPFT) or specific inhalation challenges, were each applied in only about one third to half of studies.

The level of evidence for single agents also depends on the absolute number of publications. Agents for which the research activity is higher may obtain higher levels in our rating system and, conversely, an absence or a low evidence grade of an occupational agent (e.g. in studies without SIC or lung function testing) does not necessarily exclude its potential for causing occupational asthma.

It is evident that more work is needed to consolidate the gaps, such as the study of potential asthma-inducing agents which have not or only rarely been investigated so far. This current overview provides a basis for such supplementary work and for surveillance programs of endangered workers. The latter may facilitate early diagnosis and the application of appropriate secondary preventive measures, leading to a significant reduction of asthma from identified causative exposure in the workplace.