Occupational lung disease: when should I think of it and why is it important?

Sensitiser-induced OA

Sensitiser-induced OA is considered the most common type of OA and is induced by high-molecular-weight (HMW) or low-molecular-weight (LMW) agents. HMW agents are (glyco)proteins of animal, plant or microbial origin, which have ability to cause immunoglobulin (Ig) E mediated sensitisation. LMW agents are synthetic chemicals, metals and other natural agents that are considered to cause immunological reactions, but specific IgE antibodies are often not detected (table 2). Sensitiser-induced OA always requires a period of repeated allergen exposure before the onset of symptoms. During this “latent period” the sensitisation and immunological response develop [3, 6]. The latent period can vary from weeks to years, but the risk is highest for asthma development within the first 2 years of the relevant exposure. Asthma symptoms which improve away from work also increase the diagnostic probability of OA, but the relationship between symptoms and work is not always obvious [6]. Some patients with OA may report that their symptoms occur in the workplace or when performing certain tasks, while others may have more pronounced symptoms in the evening or at night, i.e. outside the workplace. Additionally, non-occupational triggers, like cigarette smoke, exercise and cold air, may worsen the symptoms. Any clear work-related pattern to symptoms generally declines the longer the duration of asthma. These features highlight the importance of considering the possibility of OA, even when the patient is experiencing few symptoms at work and most symptoms outside the workplace. OA caused by HMW agents is more common in people with atopy and almost invariably occurs in conjunction with work-related rhinitis and conjunctivitis. These symptoms may start before, or at the same time as, asthma symptoms. Therefore, any patient with both upper and lower respiratory symptoms associated with work should raise clinical suspicion. LMW agent-induced OA occurs less often with rhinitis, and typically has late asthmatic reactions, when compared with HMW agent-induced asthma [6].

When enquiring about potential airborne causal agents, it is important not only to ask about the patient's occupation, but also about their work tasks and other processes at their workplace. The workers may have “second-hand” or bystander exposure to the asthma-causing agent even if they do not handle the agent themselves. Over 400 sensitising agents are known to cause OA [7]. However, only a few agents cause the majority of OA cases, most commonly flour dust and isocyanates. Types of industry, with their associated causative agents, vary by geographical area and so it is useful to have an understanding of the local area and the common asthmagens to which the local population might be exposed. Table 2 presents common sensitising agents and occupations with a high risk for OA. Safety data sheets (SDS) provided for hazardous chemicals by the manufacturer, distributor or importer, are useful in identifying chemicals that can cause asthma via respiratory sensitisation. In the European Union (EU), respiratory sensitisation is marked with hazard statement EUH334. However, these SDS are not always comprehensive and so in some cases the statement can be missing even if the product contains sensitising agents.

Irritant-induced OA

Irritant-induced OA (IIA) accounts for 4–14% of cases in series and develops after exposures to high concentrations of airborne agents with corrosive or oxidative (irritant) properties, e.g. strong acids and bases (table 2) [3, 8]. The mechanisms of IIA are less well known, but irritants have been demonstrated to induce direct epithelial cell damage and mostly neutrophilic inflammation. IIA may develop after a single massive exposure to irritants (table 2), which usually occur in chemical accidents, fires or other hazardous events. The clinical features are distinctive. There is no latency and respiratory symptoms (e.g. dyspnoea, cough, wheezing, chest tightness) occur within 24 h of exposure. Coughing is typically the most prominent symptom. Patients may experience a burning sensation in the throat or nose and eye irritation in addition to respiratory symptoms [8]. This classical type of irritant-induced asthma was originally labelled as reactive airways dysfunction syndrome (RADS), but latterly, the terms acute or definite irritant-induced asthma have been used [5, 8]. It is unlikely that this diagnosis would be missed as patients would report a clear exposure history. However, it is important that appropriate diagnostic tests are performed to confirm objective evidence of airways disease rather than other sequalae such as breathing pattern dysfunction.

IIA can also develop after repeated symptomatic exposures to a high level of irritants (subacute or probable irritant-induced asthma) [9]. The symptoms experienced are the same as for acute IIA. It may be more common than acute IIA but is likely under-recognised because the relationship between multiple exposures and the onset of symptoms is more difficult to establish [8, 10]. Additionally, in epidemiological studies, chronic or repeated exposure to low-to-moderate levels of irritant substances had increased asthma risk (low-dose or possible irritant-induced asthma) [9]. It is not possible to diagnose this type of irritant-induced asthma with certainty at an individual level, because the association between exposure and the onset of asthma symptoms is difficult to establish [8]. In irritant-induced asthma airway obstruction is generally less reversible than in allergic asthma and a restrictive spirometric pattern, probably representing a manifestation of a small airway disease, may also be observed [8, 11, 12].

A wide variety of inhaled gases, fumes, aerosols and dusts have been associated with irritant-induced asthma (table 2) [8, 10]. Typically, acute irritant-induced asthma is caused by spills of irritating volatile compounds, overheating of materials, accidental fire and mixing of cleaning products. Subacute irritant-induced asthma is most common in industrial operators and maintenance workers performing their usual tasks under poor hygiene conditions. A confined space with reduced ventilation often amplifies the effects of irritant agents. In SDS, chemicals classified as corrosive (Skin Corr 1A or 1 B) or oxidative (Ox Gas, Ox Liq) and hazard statements EUH314 (“causes severe skin burns and eye damage”) and EUH071 (“Corrosive respiratory tract”) may help to identify the causal agent. Occasionally, high-level exposure to isocyanates or other sensitising chemicals may also cause irritant-induced asthma. Incidentally, dusts and fumes with less irritative properties (e.g. dusts in building sites and welding fumes) may cause work-exacerbated asthma but are not considered to cause irritant-induced asthma.

Diagnostic tests for OA

In addition to detailed clinical and occupational history, diagnostic tests of asthma including spirometry with bronchodilator and nonspecific bronchial hyperresponsiveness tests (e.g. methacholine and histamine challenge tests) are useful in the diagnosis of both sensitiser- and irritant-induced OA [2]. When sensitiser-induced OA is suspected, a few specific tests are available to confirm the diagnosis. These tests are most sensitive if they are performed early, before starting maintenance asthma therapy and while the worker is still in the job suspected to cause asthma [6]. Serial peak expiratory flow recording at work and off work can be used to assess airway response to inhaled agents at work if the patient is still exposed to the suspected causal agent at work [13]. Recordings every 2 hours during waking hours for at least 3 weeks are recommended, and specific software can be used in the interpretation. Immunological testing is useful with HMW agents and some LMW agents. Positive skin prick test or elevated specific IgE level to a workplace agent confirms sensitisation. Also, specific inhalation and workplace challenge tests can be used to confirm OA. The diagnosis of IIA is based on suggestive exposure history, time course of symptom onset with respect to the occurrence of exposure and evidence of reversible airflow limitation and/or nonspecific bronchial hyperresponsiveness.

Idiopathic pulmonary fibrosis and asbestosis

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterised radiologically by basal predominant subpleural fibrosis and honeycombing, and histologically by scattered fibroblastic foci in alternating patches of normal and fibrosed lung, both described as usual interstitial pneumonia (UIP) pattern. By definition, IPF has no known cause, but does this just reflect that the underlying mechanisms are yet to be fully understood? A review of the burden of non-malignant respiratory disease found the PAF for occupational exposures in IPF to be greatest for exposures to vapours, gases, dusts and fumes at 26% (95% CI 10–41%), with a pooled odds ratio of 2.0 (95% CI 1.2–3.2). Statistically significant associations were also seen for metal dusts (8% (95% CI 4–13%)), wood dusts (4% (95% CI 2–6%)) and silica (3% (95% CI 2–5%)) [18].

IPF is commoner in men than women (ratio of 1.6) with a median age of 70 years at diagnosis and increased incidence in industrialised areas [28]. These observations, and other ecological variations have generated the hypothesis that a proportion of IPF may be due to unrecognised asbestos (and other) occupational exposures [29]. A multicentre, incident case–control study of men diagnosed with IPF and age-matched male hospital outpatient controls recently assessed lifetime occupational asbestos exposure applying a job exposure matrix. Occupational asbestos exposure was not associated with IPF; however, there was a significant interaction between smoking and exposure for carriers of the minor allele MUC5B rs35705950, highlighting the likely complex relationships between dual exposures and genetics [30].

Asbestosis often mimics IPF radiologically, presenting most commonly with a UIP pattern on high-resolution computed tomography but other ILD patterns are also seen (table 4). The key to diagnosing asbestos-related disease is a careful occupational and exposure history. An understanding of their jobs (including unpaid or part-time work) and the era in which they worked is important, as is a knowledge of the asbestos legislation (particularly whether asbestos was still being imported) in their country of work. Occupational groups at increased risk of asbestos exposure are listed in table 4. Some individuals, for example, construction workers carrying out refurbishment of commercial and domestic buildings may have, unknowingly, encountered asbestos exposure in their jobs. There is a dose response between asbestos exposure and risk of developing asbestosis and the latency is around 20–30 years. Quantification of exposure is challenging because it relies on a knowledge of concentration of exposure. Whilst 25 fibre·mL⁻¹-years (for example, 1 year of exposure at 25 fibres per mL or 5 years of exposure at 5 fibres per mL) has been proposed as a threshold for a greater risk of asbestosis or lung cancer in the Helsinki criteria [31], the reality is that this is difficult to ascertain in practice and not generally of use.

Whilst the presence of pleural plaques indicates asbestos exposure, relatively low exposures are thought to be required to develop plaques. Therefore, it is important not to automatically attribute all ILD in patients with pleural plaques to asbestosis. Conversely, asbestosis can occur in isolation and so a diagnosis of asbestosis should not be excluded based on the absence of plaques alone. The diagnosis of asbestosis is almost always based on history of exposure and compatible radiological and physiological findings. However, very rarely, a biopsy is undertaken and a number of histological features to determine significant asbestos exposure in a patient with interstitial fibrosis based on the Helsinki criteria have been proposed. These include use of electron or light microscopy to identify the presence of asbestos bodies or asbestos fibres in tissue and in bronchoalveolar fluid [31]. There are caveats to such criteria as the distribution of asbestos bodies is not uniform throughout the lung and thus multiple sampling sites may be required to identify their presence. Finally, cigarette smoking is known to increase the risk of asbestosis.

Hypersensitivity pneumonitis

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic ILD arising in susceptible individuals after exposure to inciting antigens, many of which can occur in occupational settings. HP is not always straightforward to diagnose, with no inciting antigen identified in ∼50% of cases. It is estimated that the occupational burden of all HP cases is 19% [18]; therefore, in any case of HP, an occupational aetiological agent should be considered. HP is probably under-recognised due to the challenges of diagnosis, and this, coupled with the marked geographical variation in cases, means the epidemiology can be difficult to describe. More than 300 different agents have been associated with HP and can be broadly defined as microbial agents (bacteria, fungus), animal antigens, and less commonly, chemicals. All of these exposures can occur in occupational settings. Historically, exposure to avian antigens (“bird fancier's lung”) and moulds on hay (“farmer's lung”) were the commonest causes of HP; however, with more recent changes in workplace practices and industrialisation, metalworking fluids used in engineering have emerged as an increasingly common aetiological agent for occupational HP with outbreaks reported [32].

Identification of an occupational cause of HP often requires direct questioning about specific agents known to cause HP. Key features include exposure to a known occupational cause of HP, and a temporal relationship with worsening of symptoms at work and improvement at weekends, on holiday or when working in areas where they are unexposed. Improvement away from work may take several weeks to become evident. The exception to this is cases of acute HP, which occur less frequently but here the symptoms start within a few hours of exposure to the putative agent and a clear exposure pattern is usually evident. Acute HP may be difficult to differentiate from acute bronchitis or pneumonia.

Silicosis

Silica is the earth's most abundant mineral, with respirable crystalline silica (RCS) generated in a wide variety of occupations, including those working in mining, tunnelling, construction, quarries and foundries, and in the manufacturing and cutting of artificial stone. Silicosis refers to a spectrum of diseases that result from RCS exposure, ranging from acute silicosis through to accelerated silicosis, chronic simple silicosis and progressive massive fibrosis (PMF). Acute and chronic silicosis vary both in the clinical presentation and the underlying pathological mechanisms of onset and histology. A dose relationship tends to exist, with acute silicosis occurring in people with high intensity exposure over a relatively short duration (typically within 10 years of exposure, but often within 1–2 years), and the converse applicable to chronic silicosis (exposure usually over more than 10 years). Specific occupational groups are at increased risk of acute silicosis, where grinding and cutting processes result in fractured or cleaved silica particulate release, such as silica flour processing, sandblasting and surface drilling. More recently, accelerated silicosis associated with a rapidly progressive disease amongst artificial stone workers, such as kitchen-fitters, has emerged [33]. Acute silicosis tends to present with fatigue, fevers, dyspnoea and weight loss, with the potential to develop rapidly progressive respiratory failure. Chronic simple silicosis tends to either be diagnosed in asymptomatic people through surveillance and incidental findings on chest radiography, or with mild respiratory symptoms such as cough or mild exertional dyspnoea. However, the concern is progression to PMF where more debilitating respiratory symptoms develop. Silica exposures are associated with tuberculous infection and silicosis is associated with a number of connective tissue diseases and renal disease [34].

Sarcoidosis

Sarcoidosis is a multisystem disease characterised by the presence of non-caseating granulomas. Whilst the underlying cause and mechanism of sarcoidosis remain unclear, it is likely the result of exposure to an environmental trigger in a genetically susceptible individual leading to immune dysfunction [35]. As more than 90% of cases of sarcoidosis involve the lungs (pulmonary sarcoidosis) [36], and seasonal and geographical variation in the onset of sarcoidosis have been recognised, inhalable environmental exposures or antigens are considered a potential underlying cause. It is estimated that ∼30% of the burden of sarcoidosis is occupational [18]. However, the quest for which exposures cause sarcoidosis is longstanding and unanswered, although many causal associations have been suggested, and continue to be investigated [37].

Many studies have described possible occupational associations with sarcoidosis and include silica, pesticide and mould and mildew exposures [37, 38]. The largest individual-level case–control study of lifetime occupational exposures in patients diagnosed with sarcoidosis was the ACCESS study [37], which found that occupational exposures to insecticides, mould and mildew and musty odours were more prevalent amongst sarcoidosis patients. Phenotypes of sarcoidosis are increasingly studied, and recently a case–case study demonstrated that inorganic dusts were associated with pulmonary sarcoidosis, jobs with close human or livestock contact associated with liver and splenic involvement, and reactive chemicals or livestock contact with cardiac sarcoidosis [39].

Sarcoidosis is known as the “great mimic”, meaning that it may behave like many other diseases, leading to diagnostic challenges in clinical practice. Silicosis [40] and chronic beryllium disease (CBD) [41] can present in an identical manner to sarcoidosis and cases may be missed if the occupational and exposure history is not considered. The recent British Thoracic Society clinical statement [42] and American Thoracic Society guidelines [43] recommend that alternative causes of granulomatous disease should be excluded in all new cases of sarcoidosis, including those related to occupation. This will primarily be done by taking a careful occupational history, whilst clinical manifestations of extrapulmonary disease may suggest an alternative underlying diagnosis.

Other granulomatous lung parenchymal diseases

CBD is a granulomatous disease caused by exposure to beryllium metal or its oxide (in the form of fumes or dusts), which are used widely in the aerospace, electronics and defence industries. Exposure can result in development of beryllium sensitisation, diagnosed using a beryllium lymphocyte proliferation test (BeLPT). The diagnosis of CBD requires evidence of non-caseating granulomatous inflammation in lung tissue, a positive BeLPT and radiological changes. The radiological features in the lung are essentially indistinguishable from those of sarcoidosis with lymphadenopathy and interstitial nodules; however, extrapulmonary manifestations such as uveitis and erythema nodosum are not seen. Genetic susceptibility to CBD is strongly linked to HLA-DPB1 alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69) [44].

Hard metal lung disease (HMLD) or giant cell interstitial pneumonitis is another granulomatous ILD. It is caused by exposure to the extremely hard metal formed by compacting (or “sintering”) tungsten carbide and cobalt together. The clinical picture, and latent period of HMLD, are variable with most commonly insidious onset. Radiologically, the appearances are nonspecific and are described in table 4. If a biopsy is obtained, the presence of multinucleated giant cells is diagnostic [45]. Like CBD, HMLD is associated with βGlu69-containing HLA-DP alleles. The prognosis may improve with removal from exposure.

Exposure to the dusts (or fumes) of other metals, such as aluminium, titanium and zirconium, also, very rarely, induces granulomatous lung disease. Following the World Trade Center disaster, an increase in the incidence and prevalence of sarcoid-like granulomatous lung disease was suggested amongst firefighters [46] and case series have described disease amongst exposed local residents [47]. Epidemiological studies of sarcoidosis are methodologically difficult and highly susceptible to detection bias, and no properly designed studies have validated or replicated the results of that initial study. Components of the dust-cloud generated from the World Trade Center may have been responsible, as it contained a complex but poorly characterised mix of calcium salt and metal dust, synthetic organic materials, combustion products, silica and chemicals [48].