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Keywords:

  • irritant-induced asthma;
  • occupational asthma;
  • specific inhalation challenge;
  • work-exacerbated asthma;
  • work-related asthma

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

Work-related asthma (WRA) is a relevant problem in several countries, is cause of disability and socioeconomic consequences for both the patient and the society and is probably still underdiagnosed. A correct diagnosis is extremely important to reduce or limit the consequences of the disease. This consensus document was prepared by a EAACI Task Force consisting of an expert panel of allergologists, pneumologists and occupational physicians from different European countries. This document is not intended to address in detail the full diagnostic work-up of WRA, nor to be a formal evidence-based guideline. It is written to provide an operative protocol to allergologists and physicians dealing with asthma useful for identifying the subjects suspected of having WRA to address them to in-depth investigations in a specialized centre. No evidence-based system could be used because of the low grade of evidence of published studies in this area, and instead, ‘key messages’ or ‘suggestions’ are provided based on consensus of the expert panel members.

Abbreviations
FeNO

fractional exhaled nitric oxide

FEV1

forced expiratory volume in 1 second

HMW

high molecular weight

IIOA

irritant-induced occupational asthma

IS

induced sputum

LMW

low molecular weight

MCH

methacholine

MCH PC20

provocative concentration of MCH causing a 20% fall in FEV1

NAEB

nonasthmatic eosinophilic bronchitis

NAIIOA

nonacute irritant-induced occupational asthma

NSBH

nonspecific bronchial hyperresponsiveness

OA

occupational asthma

PEFR

peak expiratory flow rate

RADS

reactive airways dysfunction syndrome

SIC

specific inhalation challenge

WEA

work-exacerbated asthma

WRA

work-related asthma

Work-related asthma (WRA) is cause of disability and socioeconomic consequences for both the patient and the society and is probably underdiagnosed [1]. A correct diagnosis is important to reduce or limit the consequences of the disease [2]. As much as 25% of adult asthmatic patients are estimated to have WRA [3], and thus, the possibility that nonoccupational physicians such as allergologists or pneumologists face WRA in daily practice is high, and they may play a pivotal role in identifying the suspected cases. Nevertheless, the investigation of WRA still remains a difficult issue in the routine of nonoccupational physicians.

The last EAACI document on occupational asthma (OA) has been published in 1992 [4], and despite several other comprehensive documents produced by other societies [2, 5], an operative protocol for WRA assessment in the daily practice of allergologists is still lacking.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

This consensus document was prepared by a EAACI Task Force consisting of an expert panel of allergologists, pneumologists and occupational physicians and was reviewed and accepted by the EAACI Executive Committee.

The literature was reviewed by the panel members, using a Medline search. A meeting was held to review the findings and reach informal consensus. Further consensus was reached by an informal iterative process by input of all panel members into the drafts of the document. The original aim of the Task Force was to advance recommendations using an evidence-based system. However, it was recognized that the quality of evidence of published studies in this area would be graded as low, based on case series and unmatched cohort studies. Therefore, no evidence-based recommendations could be provided, and instead, ‘key messages’ (see Key Messages Box) or ‘suggestions’ are provided based on consensus of the expert panel members (http://www.chestnet.org/education/guidelines/currentguidelines; accessed 13 November 2007).

In November 2010, the expert panel discussed the first written draft version of the document. Key messages, suggestions and changes were included in the draft, and the revised draft was discussed via e-mail communications, to achieve group consensus. All recommendations that received the agreement of all members were included in the final draft.

This document is not intended to address in detail the full diagnostic work-up of WRA, nor to be a formal evidence-based guideline [6]. It is written to provide an operative protocol to allergologists and physicians dealing with asthma useful for identifying the subjects suspected of having WRA to address them to in-depth investigations in a specialized centre.

Definition and classification of work-related asthma

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

Work-related asthma comprises two major entities, that is OA, defined as a type of asthma ‘caused’ by the workplace and work-exacerbated asthma (WEA), which refers to asthma triggered by various work-related factors (e.g. aeroallergens, irritants or exercise) in workers who are known to have pre-existing or concurrent asthma (e.g. asthma that is occurring at the same time but is not caused by workplace exposure) [2] (Fig. 1). OA is currently one of the most common forms of occupational lung disease in many industrialized countries [7, 8].

image

Figure 1. Classification of work-related asthma.

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Two types of OA are distinguished [2]:

  • Allergic, that is OA induced by sensitizers, which appears after a latency period necessary for the worker to acquire sensitization to the causal agent. It encompasses OA caused by most high (HMW) and some low molecular weight (LMW) agents (Table 1) for which an IgE-mediated mechanism has proven, and OA induced by some specific LMW agents in which the allergic mechanisms responsible have not yet been fully characterized.
  • Nonallergic, irritant-induced OA (IIOA). The most definite form of IIOA is the ‘Reactive Airways Dysfunction Syndrome’ (RADS), which occurs as an acute onset of asthma after a single exposure to very high concentrations of an irritating gas, vapour, fume or smoke [9]. A less definite form, because of the paucity of reports and case studies, is IIOA after multiple exposure, where the onset of asthma is not so sudden and follows multiple exposures to high levels of irritants [10]. Allergic OA is the most common type of OA, accounting for more than 90% of cases [11].
Table 1. Causal agents of occupational asthma and occupations at risk (from Ref. [16])
High molecular weight agentsLow molecular weight agents
OccupationAgentOccupationAgent
Baking, milling, pastry makingFlour(s), α-amylase, other enzymes, egg whiteSpray painters, French polishersDiisocyanates
Laboratory animal researchers and techniciansRat, mouse, guinea pig, ferret, etc. proteins, eggElectronic solderersColophony fume
Health-care workersLatexHealth-care workersGlutaraldehyde, methyl/butyl methacrylate
Detergent enzyme manufacturesDetergent protease, amylase, lipase, cellulasePlastic and foam manufacturersDiisocyanates, acid anhydrides, epoxy resins
Tea packers, coffee processorsHerbal teas, green coffee beanWoodworkers, lumberjackRed cedar, iroko, other tropical sawdusts
Sea food processorsPrawn, crab, other (shell) fish proteinsTextile workersReactive dyes
Other food processorsGarlic, egg, enzymesHairdressersPersulphates
Flower and vegetable farmersPollensPharmaceutical manufacturersPenicillins, morphine, cimetidine

The investigation of WRA has a two-sided objective: demonstrating the presence of asthma and confirming its relationship to work (Table 2) [4]. The starting point is a detailed clinical history, which must be confirmed by objective tests that partially differ for allergic and nonallergic OA [12]. Because of the inflammatory basis of WRA, assessment of bronchial inflammation is helpful in the investigation of the disorder [13, 14]. Moreover, because of the strict link between upper and lower airway inflammation, assessment of nasal inflammation is also suggested [15].

Table 2. Investigation of work-related asthma (mod from Ref. [4])
History suggestive of occupational asthma and exposure documentation
Confirmation of bronchial asthma
Confirmation of work-related bronchoconstriction
Confirmation of sensitization to occupational agents
Confirmation of causal role of occupational agents

Assessment and diagnosis of occupational asthma

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

Assessment and diagnosis of allergic occupational asthma

Clinical history

In every adult whose asthma begins or worsens while working, WRA should be considered, and a detailed occupational and medical history should be collected [8, 16, 17]. However, clinical history alone has a low specificity in the diagnosis of OA [18].

Occupational history aims at obtaining information on:

  • past and current worker's job duties;
  • substances and materials used in the work environment;
  • use of protection devices;
  • recent changes in work processes or materials;
  • workplace environmental conditions;
  • date of the last exposure at current job.

Medical history should focus on:

  • Respiratory symptoms (i.e. chest tightness, wheezing, cough and shortness of breath).
  • Associated symptoms:
  • nose and eye symptoms (i.e. nasal congestion, rhinorrhea, sneezing, lachrymation, ocular itching) [19];
  • skin symptoms (i.e. eczema, rash and urticaria);
  • systemic symptoms (i.e. fever, arthralgias and myalgias).
  • Date of symptoms’ onset: after starting current job, or pre-existing and worsened by current job. In patients with symptoms’ onset after starting current job, the presence of OA can be suspected, in those with pre-existing symptoms worsened by current job WEA can be postulated.
  • Duration of employment at current job before symptoms’ onset (‘latency period’), duration of symptoms before diagnosis, information on individual risk factors (atopy, accidental exposures to irritants, pre-existent asthma and/or rhinitis, smoking habit).
  • Relationship of symptoms to work exposure: immediate onset when entering the workplace; delayed onset beginning 4–12 h after starting work or after coming home; immediate onset followed by recovery, with symptoms recurring 4–12 h after initial work exposure (biphasic). Especially in the delayed-onset symptoms, most frequently presenting after exposure to LMW agents (e.g. isocyanates, reactive dyes, persulphates) may not be so obviously work related, and diagnosis may be delayed.
  • Relationship between symptoms and periods at and away from work: at the onset of symptoms, improvement on weekends and holidays, and worsening on return to work, is the rule (positive stop-resume test). As exposure continues, symptoms may become persistent, and thus, a negative stop-resume test should not rule out the possibility of OA.
Exposure assessment

Work-related asthma results from the interactions between host factors and the environment, but at least in OA, there is evidence that exposure levels represent one of the major determinants for the development of the disease [20, 21]. Therefore, the assessment and documentation of exposure is an important step in the diagnostic work-up of WRA. Every physician should be aware of occupations at risk for WRA and of the possible causative agents. An exhaustive list of agents and occupations is available in the EAACI website (http://www.eaaci.net/images/files/Pdf_MsWord/2010/occupational%20allergens%20list_june2010.pdf). A logistic regression model has been proposed to predict the OA hazard of chemicals [22]. Review manufacturer's safety data sheets nearly always provide the necessary information on substances used. Levels of causative agents in the workplace environment or during specific inhalation challenge (SIC) should be measured when possible [23, 24].

The environmental study requires an exhaustive knowledge of all materials, and even intermediate or temporarily used substances, involved up to the final product, are obtained.

Assessment of the state of the agent such as a dust, aerosol, gas or vapour can be important because this can affect its interaction with the body and the way in which it must be analysed. Dermal absorption of chemicals may influence sensitization [25].

The web pages of various organizations publish sampling methods and analytic techniques for a variety of chemicals (http://www.cdc.gov/niosh/nmam/nmammenu.html, http://www.osha.gov/dts/sltc/methods/index.html, http://www.skcinc.com/guides.asp, [26]). Quantification of allergenic proteins requires the use of specific immunoassay techniques, usually inhibition immunoassays able to detect protein concentrations between 100 pg/ml and 1 ng/ml [27-31]. A disadvantage of inhibition methods is that in most cases, there is no international standardization and that it may not be commercially available for many occupational allergens. In other cases such as pollens or fungi spores counts can be performed by optical microscopy based on morphologic criteria or by culture methods.

Basal physiologic assessment and serial measurements of lung function and bronchial hyperresponsiveness

Basal physiologic assessment. Physical examination and lung function testing are mandatory in the work-up of WRA to confirm objectively that the worker has asthma and to rule out other work-related conditions that can be confused with WRA.

Spirometry assesses airflow obstruction and its reversibility after inhalation of a bronchodilator agent [32]. However, many patients with WRA may be completely asymptomatic and have normal pulmonary function when nonexposed to the relevant work agent, therefore the assessment of nonspecific bronchial hyperresponsiveness (NSBH) through direct challenges, such as methacholine (MCH) or histamine, is suggested [2, 33]. Recently, also the use of indirect challenges (e.g. mannitol, adenosine monophosphate) has been shown to be very effective in diagnosing and monitoring asthma in occupational settings [34]. The MCH challenge is a highly sensitive direct challenge with a high negative predictive value, while indirect challenges are highly specific but have a relatively low sensitivity compared with MCH [35]. A basal positive MCH challenge supports the diagnosis of asthma in patients with asthma symptoms [12]. However, the absence of NSBH does not exclude a diagnosis of OA particularly when the subjects are tested after they have been away from work [33]. A recent systematic review [36] has shown, for HMW and LMW agents, a sensitivity of NSBH tests of 79.3% and 63.9%, respectively, and a specificity of 51.3% and 63.9%, respectively, when compared with SIC. Thus, NSBH challenge alone has a relatively high sensitivity and low specificity in predicting the diagnosis of WRA based on SIC. However, adding skin prick tests or specific IgE measurement can enhance sensitivity and specificity and may be an appropriate alternative to SIC in diagnosing OA in appropriate clinical situations when SIC is not available.

Moreover, in patients with a negative SIC, an increase in NSBH after exposure to the specific agent during the challenge (defined as a PC20 MCH decreases between 1.8- and 3.1-fold form pre- to post-SIC) can be considered an early marker of bronchial response to further challenge exposure in the laboratory and/or at the workplace [37, 38].

In individuals with suspected WRA and normal respiratory function, and/or negative MCH challenge, serial measurements of lung function and NSBH have often been used to improve the diagnostic probability [2].

Cross-shift spirometry

Cross-shift spirometry and measurement of FEV1 (i.e. performed during a work-shift) have been used in workers exposed to occupational sensitizers and to detect workers with allergic OA. However, cross-shift changes in FEV1 have a low sensitivity for discriminating subjects with OA from asymptomatic exposed workers [13].

Serial measurements of peak expiratory flow

Since 1979, serial measurements of peak expiratory flow rate (PEFR) have been used as an objective confirmation of the relationship between the workplace and asthmatic symptoms. One important advantage of serial PEFR is the measurement of lung function during a realistic exposure [39].

Cross-shift changes in PEFR have poor sensitivity in diagnosing OA [40]. Recording of PEFR every 2 h is the preferable method, although the four times a day assessment (upon waking, at noon, at the end of the working day and at bedtime) is almost as satisfactory [41]. During each measurement, three PEFR measures should be performed and recorded once all three readings are within 20 l/min [42]. Although the optimal duration of PEFR recording has not been established, a period of 4 weeks, including a period of 2 weeks away from work, is recommended [2]. Recently, Moore et al. [43] suggested a minimum of 2-hourly PEFR measurements on eight working days and three rest days. However, if there is no recording of work-related reduction in PEFR, the diagnosis of WRA cannot confidently be ruled out. Limitations of PEFR monitoring are need of good cooperation, possible falsification, feasibility of measurement away from work and no identification of the causative agent [39].

Serial measurements of nonspecific bronchial responsiveness

Because serial measurements of PEFR have several limitations, serial measurements of NSBH to MCH have been recommended to confirm a diagnosis of OA based on clinical history and monitoring of PEFR [33]. To identify work-related changes in NSBH in workers with suspected OA, it is suggested that a MCH challenge test should be performed at a time the worker is working and reports respiratory symptoms [2].

Immunologic assessment of work-related asthma

Immunologic assessment of WRA aims to support the diagnosis of allergic OA. Skin tests and determination of specific IgE antibodies are necessary to demonstrate the sensitization to occupational allergens. Nevertheless, because sensitization alone does not mean allergy, the demonstration of the link between the specific sensitization and work-related changes in lung function is mandatory for the diagnosis of WRA.

In some cases, basophil activation tests [44, 45] or histamine release [46] has been used to detect an IgE response, but such tests have not been still validated and cannot be used in daily practice. Unfortunately, standardized tests are available only for a few allergens. Consequently, in many cases, patients are provisionally tested with noncommercially available, laboratory-made skin test extracts and IgE tests. Before accepting the results from such tests, proper control tests in nonexposed subjects and in case of new allergens additional challenge tests are required [47, 48]. Then, a positive test outcome can establish a working diagnosis. In addition, a positive test may guide the physician to the identification of a sensitizer among a series of agents. However, lack of standardization limits the value of negative test results. Although it has been shown that high concentrations of flour-specific IgE and clear skin prick test results in symptomatic bakers are good predictors for a positive challenge tests [49], commercial extracts show a wide variation with respect to sensitivities, negative predictive values and test efficiencies [50]. In selected cases (e.g. bovine animal dander), SPTs demonstrated excellent negative predictive value for excluding OA [51]. In spite of these limitations, it is important to select those allergens for testing that may elicit an IgE response (Table 1) (http://www.eaaci.net/images/files/Pdf_MsWord/2010/occupational%20allergens%20list_june2010.pdf).

In recent years, research has focused on specific allergen panels, instead of crude allergens. For instance, in latex allergy, it is possible to distinguish clinically relevant IgE reactivity for rHev b 1, rHev b 3, rHev b 5 or rHev b 6.0 from irrelevant IgE to recombinant latex profilin (rHev b 8) [52]. With this approach, the appropriate allergens for allergenic extracts can be identified [53]. Research to wheat lipid transfer protein Tri a 14 [54] attempts to refine the diagnosis of baker's asthma. The presence of IgE to cross-reactive carbohydrate determinants may bias the diagnosis of wood sensitization. Therefore, it has been suggested to measure such an IgE response to carbohydrate determinants to assess the relevance of individual wood sensitization [55]. Although immunologic assessment cannot replace challenge tests, this approach may result in a more accurate diagnosis of allergic OA in future.

Specific inhalation challenges

Specific inhalation challenge exposes workers with suspected OA to suspected causing agents in a controlled setting to demonstrate a direct relationship between exposure to an occupational agent and asthma [2]. It is considered a reference standard for the diagnosis of OA induced by some sensitizing agents [56]. SICs have some limitation including possibilities of false-negative and false-positive results and lack of usefulness in the diagnosis of nonallergic OA. In addition, SICs are performed in only a few centres provided by specialized facilities and expertise and when a suspected workplace agent has been identified. On the basis of expert opinion and consensus, SIC is suggested when the diagnosis or causative agent remains equivocal in individuals with suspected allergic OA and when the worker's management is dependent upon knowing the exact cause of OA [2, 57].

When a potential causing agent is not identified or exposure cannot be reproduced in the laboratory, SIC can be replaced with a workplace challenge. It consists of monitoring spirometry at the workplace when the subjects perform the task suspected to cause asthma. Nevertheless, this method does not allow to distinguish between OA and WEA.

A 15–20% decrease from baseline FEV1 is generally considered a positive response. When the appropriate agent is applied, and the response is positive in workers with work-related asthmatic symptoms, SIC is considered confirmatory. False-positive responses are not common, but can occur in unstable asthma, in patients with marked airway hyperresponsiveness, or with exposures to irritating levels of an agent. False-negative responses can occur for a number of reasons: exposure to the wrong agent or process, an inadequate concentration or timing of the exposure, a loss of specific airway responsiveness away from exposure or the use of anti-asthma drugs [5, 57].

Assessment of inflammation

The assessment of airway inflammation is recommended in the investigation of WRA and may help to distinguish OA from WEA and allergic vs irritant-induced asthmatic reactions [58]. Induced sputum (IS) is the most used method and may help in: (i) identifying occupational eosinophilic bronchitis with or without asthma [58, 59], (ii) supporting the diagnosis in a complex environment when the workplace sensitizer is unknown and (iii) monitoring airway inflammation before/after SIC. An increase in sputum eosinophil counts >3% after SIC often precedes the occurrence of functional changes on subsequent exposures [60]. The best timing for the collection of IS is likely to be 7–24 h after exposure [15]. Most subjects with allergic OA show an eosinophilic inflammatory response after exposure to the offending agent in the laboratory [58, 61-63] or in the workplace [64, 65]. Neutrophils seem to play a role in OA because of LMW agents and especially isocyanates, but recent findings show that this type of asthma is associated with eosinophilia [66]. Moreover, the increase in sputum neutrophils has not been validated to support or to confirm the diagnosis of OA, as it is also observed after exposure to irritant agents, and in a recent study [67], the levels of sputum neutrophils were not significantly associated with the final diagnosis and specific bronchial reactivity. Subjects with WEA showed no changes [64] or a neutrophilic type of airway inflammation [65, 68]. The addition of sputum cytology to serial PEFR measurements and SIC in the investigation of OA improves diagnosis [62, 65-68]. Therefore, airway inflammation should be evaluated before excluding the subjects from further investigations when the clinical history is highly suggestive, and functional tests and MCH or indirect challenges are negative [14]. Fractional exhaled nitric oxide (FeNO) has been proposed as a surrogate marker of eosinophilic inflammation in asthma [69]. Although the measurement of FeNO has some advantages over the analysis of IS in OA, the interpretation of FeNO is more difficult than sputum differential cell counts because it is less specific and several confounding factors (e.g. use of inhaled or oral corticosteroids, smoking status, prior diagnosis) may influence the results [15]. For specific purposes, for example to discriminate positive and negative SIC [70], sputum eosinophil counts constitute a more reliable tool than FeNO. Nevertheless, FeNO measurement provides valuable information where analysis of sputum is unavailable (e.g. in daily practice) [71] or unsuccessful [72].

Assessment and diagnosis of nonallergic, irritant-induced occupational asthma

Diagnostic criteria for RADS, the acute form of IIOA, initially proposed by Brooks [9] and adopted by ACCP [2], are:

  • absence of pre-existing respiratory disorder, asthma symptomatology or a history of asthma in remission and an exclusion of conditions simulating asthma,
  • onset of asthma occurring after a single exposure or accident to an irritant vapour, gas, fumes or smoke in very high concentrations,
  • onset of asthma symptoms within minutes to hours and <24 h after the exposure,
  • evidence of NSBH or bronchial obstruction persisting for at least 3 months of exposure avoidance,
  • presence or absence of airflow of obstruction confirmed by pulmonary function testing,

The same criteria could be adopted for diagnosis of IIOA after multiple exposures, except for the onset of asthma, which in this form occurs after multiple exposures to an irritant vapour, gas, fumes or smoke in high concentrations [10].

In patients with a suggestive history of IIOA who do not meet all these stringent criteria, some difficulties can arise in the diagnostic work-up. However, it is agreed that at least three general conditions should be fulfilled:

  • a diagnosis of asthma.
  • evidence of single or multiple exposures to high concentration of irritants [73],
  • exclusion of pre-existent asthma.

Difficult diagnosis and misdiagnosis may often occur. In differential diagnosis of IIOA, WEA must be considered (see Chapter 5). In new onset asthma induced by a high-level respiratory irritant, if the involved agent is also a respiratory sensitizers, IIOA and concurrent OA with sensitization could be induced at the same time [74, 75]. Mimicks of asthma resulting from irritant exposures include vocal cord dysfunction [76], hyperventilation and panic attacks. Finally, asthma-like symptoms with NSBH following irritant exposure may subside spontaneously. If NSBH or bronchial obstruction disappears after 3 months of exposure avoidance, a diagnosis of ‘Acute Respiratory Injury’ should be considered [77].

Assessment and diagnosis of work-exacerbated asthma

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

The mechanisms that induce WEA are unknown. The clinical features correspond to WRA symptoms, but there is no specific test providing evidence of a causal relationship [78].

The worsening of asthma symptoms at work [79] and PEFR monitoring [80] do not differentiate OA from WEA. IS seemed to be more relevant, as there was no significant decrease in eosinophils in WEA at the workplace and outside of the workplace [65].

Work-exacerbated asthma has been diagnosed most commonly by self-report of worsened asthma symptoms on the job in workers with pre-existing asthma [79]. Nevertheless, a definite WEA diagnosis should be based on ‘objective indicators’ of worsening of asthma and of deterioration of pulmonary function related to work environment. If there is no documented workplace exposure to agents known to induce OA, WEA could be considered. Conversely, if there is documented exposure to sensitizing agents, SIC should be performed. An argument for differentiating between allergic OA and WEA is the presumed difference in prognosis with continued workplace exposure. In OA, the patients should be removed from the specific exposure as soon as possible. In WEA, the patient might be able to continue working with a close environmental control and optimization of asthma treatment.

Assessment and diagnosis of eosinophilic bronchitis

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

Nonasthmatic eosinophilic bronchitis (NAEB) is an important cause of chronic cough, being present in 10–15% of patients referred for specialist investigation [81]. It is characterized by chronic cough in patients with no symptoms or objective evidence of variable airflow obstruction, normal airway responsiveness and sputum eosinophilia [82]. It can be considered in the spectrum of work-related airway diseases [83] when it develops as a consequence of work exposure (http://www.eaaci.net/images/files/Pdf_MsWord/2010/occupational%20allergens%20list_june2010.pdf, [59]). A diagnosis of NAEB requires the assessment of lower airway inflammation, after other causes of cough have been excluded [82], and the demonstration of the link between the disease and workplace exposure.

According to the most recent findings, the diagnostic criteria proposed by Quirce [59] can be reviewed as follows:

  • Clinical history of isolated persistent cough (lasting more than 3 weeks) presents solely at work or that worsens at work, improving or disappearing after a consistent period off work.
  • Sputum eosinophilia ≥3% either in spontaneous or IS strictly correlated to workplace exposure. Increases in sputum eosinophils related to exposure to the offending agent should be firstly proved by IS performed during a period at work and off work and finally confirmed by SIC. Airway inflammation should ideally be measured by IS analysis [15, 84]. FeNO measurement has also been proposed as alternative [72], but its role in the diagnosis of NAEB has not been formally evaluated [15].
  • Spirometry within normal limits and not significantly affected by exposure to the offending agent.
  • Absence of NSBH both at work and away from work. Patients with NAEB seem to be not responsive to either direct or indirect bronchial challenges [85].
  • Other causes of chronic cough ruled out.

The diagnosis of occupational NAEB requires all the criteria fulfilled and the offending agent identified by means of SPTs or sIgE, when available, and confirmed by SIC. Basophil activation test has recently been proposed as a new tool in the diagnosis of occupational NAEB [86], but its usefulness needs to be further confirmed.

Diagnostic algorithms of work-related asthma

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

The evaluation of WRA requires training and expertise. The role of allergologists and/or of other specialists dealing with asthma is of primary importance in raising the suspicion of WRA from the clinical history, in performing the investigations in their daily practice (Fig. 2) and, if the suspicion is confirmed, in referring the patient to a specialized centre in order to confirm the work-relatedness of asthma and make a definite diagnosis (Fig. 3). Table 3 summarizes the features of methods used in WRA evaluation.

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Figure 2. Investigation of work-related asthma in nonspecialized centres.

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image

Figure 3. Investigation of work-related asthma in specialized centres.

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Table 3. Methods used in work-related asthma evaluation
 AvailabilityEasinessCostsSensitivitySpecificityReproducibilityNotes
Daily practiceSpecialized centresHighLow
  1. OA, occupational asthma; SIC, specific inhalation challenge.

Clinical history/questionnaire    
Skin prick tests   Possible false-negative results (lack of standardized extracts)
Specific IgE determination   Not available for most low molecular weight agents
Mch test   Not specific for OA, unless performed at work/off work
PEF at work/off work   Not specific for OA, interpretation not standardized
Assessment of airway inflammation      Uncertain diagnostic performance
SIC in the laboratory    If negative, diagnosis not ruled out
SIC in the workplace     Difficult to perform for organizational and safety issues

The starting point of WRA evaluation is a thorough clinical and occupational history. Patients who are suspected of WRA should undergo immunologic tests (skin prick tests and/or serum sIgE) for evaluation of sensitization to common allergens, and the functional tests (spirometry, bronchodilation test and/or nonspecific challenge tests with MCH or indirect agents) aimed at confirming or excluding the presence of asthma (Fig. 2). Asthma severity should be assessed according to GINA guidelines [32]. Bronchodilation and NSBH challenge tests should be performed during a period at work. If one or both are positive, the suspicion of WRA is confirmed. If both bronchodilation and NSBH challenges are negative, serial monitoring of PEFR at least during a 2-week period at work and a 2-week period off work should be carried out. If PEFR monitoring shows a relationship between the workplace and asthmatic symptoms, WRA should be suspected, otherwise WRA might be excluded. The detection of sensitization to an occupational allergen in a patient with suspected WRA raises the likelihood of allergic OA, but this diagnosis should be confirmed in a specialized centre. When immunological tests are negative, or not available, but WRA is suspected, the patient should be referred to a specialized centre for further in-depth investigations. Nevertheless, if the clinical history is highly suggestive, airway inflammation may be evaluated [14]. In the presence of bronchial inflammation, a work-related condition should be suspected, and the patient addressed to a specialized centre for the definite diagnosis. In the absence of bronchial inflammation, other possible conditions (e.g. nonasthmatic vocal cord dysfunction or irritable larynx syndrome) should be considered. In patients not currently employed in the suspected job/workplace at the time of examination, before excluding WRA, a comprehensive evaluation by a specialized centre is strongly suggested, to minimize the risk of a missed diagnosis.

Patients with suspected WRA should be addressed to centres and physicians specialized in WRA and equipped with facilities for performing SICs/workplace challenges and related investigations, as illustrated in algorithms 2 (Fig. 3).

Rhinitis in work-related asthma

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

There is evidence of a strict relationship between work-related rhinitis and WRA [87]. In a recent study, at least one work-related rhinitis symptom was reported by 83% of subjects with WEA and 90% of those with OA, of them 73% with OA because of LMW and 99% with HMW-induced OA [88].

Moreover, rhinitis can exert substantial influence on the patients’ quality of life, work productivity and asthma control [89, 90]. Actually, the most important link between rhinitis and asthma is the presence of inflammation of the nasal and bronchial mucosae [15]. Gaga et al. [91] showed eosinophil infiltration in the nasal mucosa of asthmatic patients irrespective of any signs of rhinitis. Allergen provocation of either the nose or the bronchi results in generalized airway inflammation. Moreover, the eosinophilic inflammation of the nasal mucosa exists even in patients with asthma [92] and with OA [93] without nasal symptoms. In addition, the eosinophil count in nasal lavage fluid is good predictor of sputum eosinophilia in subjects with asthma [94].

Thus, monitoring of nasal inflammatory cells may be used to measure the reaction to inhalation of workplace agent during SIC, simultaneously to evaluation of bronchial inflammation. The estimation of cell number and the biochemical examination of the lavage fluid or secretion in the nose allow one to distinguish between the allergic and irritant effects of various substances on the respiratory system [95, 96]. Specific allergic reaction comprises an increase of eosinophils and less pronounced but very characteristic increase in metachromatic cell number, and mediators in nasal mucosa [97]. A simple, reproducible and easy-to-perform method for assessing nasal blown secretions during SICs has been described, and a cut-off value of 4% and/or 1 × 104 eosinophils/ml for a significant postchallenge eosinophil increase, useful for defining a positive nasal response in addition to symptom score, has been identified [98].

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References

Work-related asthma is a frequent condition, but probably, it is still underestimated and underdiagnosed. A correct diagnosis is important for all forms of WRA to undergo the appropriate management and to reduce or limit the consequences. In OA, early diagnosis followed by early removal from exposure is the most important factor that determines a favourable prognosis. Allergologists and other specialists dealing with asthma play a relevant role in identifying suspected cases, raising the suspicion of WRA from the clinical history, performing investigations in daily practice and if the suspicion is confirmed, referring the patient to a specialized centre to confirm the work-relatedness of asthma, and make the definite diagnosis.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Definition and classification of work-related asthma
  5. Assessment and diagnosis of occupational asthma
  6. Assessment and diagnosis of work-exacerbated asthma
  7. Assessment and diagnosis of eosinophilic bronchitis
  8. Diagnostic algorithms of work-related asthma
  9. Rhinitis in work-related asthma
  10. Conclusions
  11. Authors’ contribution
  12. Conflict of interest
  13. References