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Disease Summaries

Diagnosis of Occupational Asthma

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Posted: August 2005

Santiago Quirce, MD, PhD
Fundación Jiménez Díaz
Servicio de Alergia
Universidad Autonoma de Madrid
Spain

Joaquín Sastre, MD, PhD
Fundación Jiménez Díaz
Servicio de Alergia
Universidad Autonoma de Madrid
Spain

 

Introduction

Occupational allergy refers to those disorders or conditions that are caused by exposure to allergenic substances in the work environment. The allergic diseases that may be contracted as a consequence of exposure to sensitizing agents in the workplace are rhinitis, conjunctivitis, asthma, hypersensitivity pneumonitis and skin diseases, such as contact urticaria and contact dermatitis. Different immunologic mechanisms may underlie these disorders. Occupational rhinitis and occupational asthma (OA) are usually due to an allergic response to high or low molecular weight antigens, either through the interaction with specific IgE antibodies or by other immune mechanisms. These allergic events lead to chronic and acute airway inflammation. Less commonly, OA can result from high level irritant exposures at work.

OA is now the most common work-related respiratory disorder in many industrialized countries. A study carried out in the USA showed that among adults with asthma treated in general practice settings, about 1 in 10 patients has a work history strongly suggestive of a potential relationship between exposure and disease (1). In Europe, the proportion of asthma among young adults attributed to occupation was 5-10%, and 0.2% to 0.5% of young adults have asthma that may be related to workplace exposure (2).

The frequency of OA, however, varies among types of industries, and it is dependent on physiochemical properties of the inhaled agent, level and duration of exposure, host factors and industrial hygiene practices. About 300 agents encountered in the workplace have been reported to induce OA in susceptible individuals. These agents can be divided into three major categories based on their pathogenesis: high-molecular weight (HMW) agents, low-molecular weight (LMW) agents and irritants (3). The type of exposure to these agents very often determines the type of asthma (Fig. 1).

Definition and classification of OA

OA is a disease characterized by variable airflow limitation and/or airway hyperresponsiveness due to causes and conditions attributable to a particular environment and not to stimuli encountered outside the workplace. Two types of OA are distinguished (4):

Immunological OA. This type is characterized by a latency period (interval between onset of exposure and symptoms) that may vary from a few weeks to several years.

Non-immunological OA. This category includes asthma that occurs after single (reactive airways dysfunction syndrome or RADS) (5) or multiple (irritant-induced asthma) exposures to irritants at high concentrations (6).

Importance of diagnosing OA

The diagnosis of OA should be performed using objective methods (7). Complete cessation of exposure to the offending agent, which usually implies removal of the affected person from work, is the mainstay in the treatment of OA. Thus, proper management of a patient in whom OA is suspected depends on the establishment of a definite diagnosis. It is important that the worker not be advised to leave the job until adequate investigations have been performed. Early referral and medical evaluation is needed because the diagnosis may be very difficult to establish in patients who have left work and cannot return (8).

When examining a patient with suspected OA, several aspects have to be considered. OA caused by an occupational allergen needs to be distinguished from the coincidental onset of asthma unrelated to work. In addition, other causes of asthma-like symptoms should be included in the differential diagnosis. Work-aggravation of underlying or pre-existing asthma due to exposure to known asthma triggers at work is one of the most common and conflicting differential diagnoses of true OA. In the case of work-aggravated asthma, work-related changes in airway caliber may occur, but usually there is no worsening of bronchial responsiveness to methacholine after the exposure (8).

In the diagnosis of OA, a combination of various functional, environmental, and immunological methods should be used in a stepwise fashion (3, 9, 10). Although the place of measurements of indices of airway inflammation in sputum in clinical practice has not been fully established, it may be of interest in the investigation of OA (10).

In most cases of OA, the culprit agent can be identified. Ascertaining environmental and specific occupational causes of OA can significantly alter the clinical outcome for the affected patient. Therefore, appropriate clinical and immunological investigations should be carried out to diagnose the disease and to identify the offending agent (Fig. 2). The main aspects that need to be considered in the diagnosis of OA are:

  1. Clinical features (bedside);
  2. Exposure assessment (workplace);
  3. Immunologic responses (molecular);
  4. Physiologic assessment (functional);
    • Bronchial hyperresponsiveness,
    • Serial measurements of lung function,
    • Specific inhalation challenges, and
  5. Inflammatory component (cellular).

1. Clinical features

Clinical symptoms
The clinical history is a key element of the investigation of OA, and it usually provides crucial information on the diagnosis of asthma and the likelihood of its work-relatedness. Moreover, the clinical history provides a rational basis for the selection and timing of additional diagnostic procedures (9). Several important questions should be included in the history, such as: circumstances of the onset of asthma symptoms, severity and persistence of asthma, the temporal relationships between exposures at work and disease exacerbation, the clinical course of asthma, as well as known triggers and intercurrent factors. OA should be suspected in every adult with new-onset asthma. The suspicion is increased if the patient reports worsening of asthma symptoms on working days compared with weekends or holidays. This worsening may occur within minutes of the onset of exposure at work (immediate asthmatic responses) or after several hours. Sometimes the symptoms occur in the evening or at night after leaving work (late asthmatic responses). The patient may also exhibit both immediate and late (dual or biphasic) asthmatic responses. The clinical history has been found to have high sensitivity (87%) but low specificity (22%) for the diagnosis of OA caused by several agents (11). Similar results have been found in the diagnosis of latex-induced asthma (12).

It is usually considered that the patient with OA is symptomatic at work and shows a marked improvement during weekends and holidays. However, this well-defined pattern occurs mainly at the onset of the disease. After prolonged exposure, the patient's disease tends to show a more insidious course. In this situation, the patient may have predominant nocturnal symptoms, may react not only to the occupational agents but also to nonspecific irritants found outside the workplace, and at a final stage, the patient may lose the pattern of reversibility away from work. Then, the suspicion of the work-relatedness of asthma may be much more difficult. A common misconception is the assumption that if asthma symptoms do not improve away from work, the asthma is not work-related. Exposure of an asthmatic patient to an agent that is known to cause OA should be considered sufficient grounds to investigate the possible implication of that agent in the asthmatic symptoms.

The medical history should also identify risk factors. Atopic subjects are at a higher risk of developing OA due to HMW agents (e.g. animal and vegetable allergens) (3). Therefore, the atopic status should be investigated in all individuals with suspected OA by performing skin prick tests to a panel of common aeroallergens. In addition, atopic patients with OA may also experience asthma exacerbations from exposure to common aeroallergens away from work. The smoking history of the patient is also important since cigarette smokers are at a increased risk of sensitization and of asthma caused by an IgE-mediated mechanism. Tobacco smoke acts synergistically with atopy to increase the risk of the disease.

Findings from the physical examination in patients with OA are often normal. When present, they are not different from other types of asthma and can support the diagnosis. The clinical history and physical examination should also note the presence of associated allergic disorders, such as rhinitis, sinusitis, conjunctivitis, urticaria, and dermatitis. Nose and ocular allergic symptoms usually precede and accompany immunological OA. Specific questions on possible food allergy symptoms should be asked, since certain causative agents of OA may also cause food allergy after being ingested by some patients (e.g. egg and shellfish proteins, soybean flour, etc).

Several factors may reinforce the suspicion of work-related asthma:

  • Recognition of high-risk jobs,
  • Co-existence of allergic symptoms in other organs: rhinitis, conjunctivitis, urticaria,
  • Co-workers affected,
  • Special events related with symptoms onset (new products used, new tasks, change in work practices, accidental exposures),
  • Absence of response to conventional asthma therapy, and
  • Personal risk factors (atopy, cigarette smoking, rhinitis).

Occupational history
A comprehensive occupational history is critical to identify patients with possible OA. The main goals in collecting the occupational history are:

  • To generate a list of past and current jobs, especially those that coincide with or precede the onset of asthma symptoms,
  • To summarize past and present work tasks and exposures, and
  • To assess the likelihood that asthma and the work environment are linked.

Potential exposures should be listed for routine and sporadic tasks. The occupational and environmental history should assess the intensity (duration and concentration), peak concentrations and frequency of the exposures. Symptoms of mucosal or skin irritation and perception of odor may help with quantitative exposure estimates. The list of substances found in the workplace can be compared with comprehensive lists of agents known to cause occupational asthma (13-15). However, the absence of a suspected substance on such lists does not exclude the diagnosis of OA, since new occupational allergens are described each year. It is also worth obtaining, whenever feasible, previous occupational health records. Data on previous spirometry, methacholine inhalation challenges, blood studies and chest x-rays may be particularly useful in assessing the course and severity of the disease.

In some patients, OA may develop after sensitization to a single environmental agent, whereas in other patients the airways disease might be caused by sensitization to a number of inhaled allergens. One example of a complex environment containing many potential allergens is a bakery or confectionery (cereal flour, soybean flour, fungal enzymes, storage mites, moulds, egg proteins, etc). Even in the context of a specific exposure, there can be several potential allergens (e.g. natural rubber latex) that may induce and trigger the allergic inflammatory reaction in the airways.

The diagnosis of irritant-induced OA depends entirely on the clinical and occupational/environmental history, along with documentation of decreases in airway caliber and objective evidence of nonspecific bronchial hyperresponsiveness (6, 16).

2. Exposure assessment

When the clinical history raises the suspicion of work-relatedness, further action should be taken. The first step would be a more detailed investigation of the exposure(s) in the workplace. The assessment of environmental exposures begins with a focused occupational and environmental history, as previously described. This may be sufficient in many instances to identify the substance that is causing the asthma symptoms. Sometimes, however, this history may have to be complemented by a work site visit and air sampling. A walk-through visit to the workplace may be of great help to understand the type, characteristics and extent of the exposure. Additional information can be obtained by requesting patients to provide labels from substances present at work and material safety data sheets for chemical in the workplace, that may help to clarify the presence of work sensitizers or irritants (9). Industrial hygiene data, if available, usually includes a process review and exposure assessment and air monitoring data, and can be extremely useful in identifying relevant exposures.

The physicochemical properties of the inhaled substance, duration and intensity of exposure, and conditions of use are important elements in the development of respiratory sensitization. Several studies have been able to demonstrate the presence of exposure-sensitization and exposure-symptoms relationships to several occupational allergens (17). The intensity of exposure necessary for initial sensitization is probably higher than that required to provoke symptoms in the sensitized subject.

Air sampling may be useful in selected cases of OA. The measurements of specific occupational agents should focus on relevant substances in the work environment that are suspected of causing asthma. Bioaerosol monitoring should target the identification of specific allergens in the work environment that may cause or exacerbate asthma. This type of monitoring is especially indicated when the etiology is unclear and may provide objective data that can help in the diagnosis of OA. Collection of aerosols can be performed by either high-volume or personal sampling pumps. Unfortunately, few health-based exposure standards have been developed for exposure to aeroallergens in the air (18). The air samples can be used to culture microorganisms, determine the concentration of endotoxins, assay for suspected chemicals, and to perform immunoassays (e.g. RAST or ELISA) for specific allergens.

3. Immunologic assessment

Many agents causing OA possess allergenic properties. Immunologic tests that measure IgE responses are valuable when integrated with other data. The main limitation of the immunologic assessment is that the demonstration of IgE antibodies to a specific allergen indicates sensitization, but sensitization can occur in exposed persons who do not have asthma or other allergic symptoms.

High-molecular weight agents
Most HMW agents are complex mixtures of polypeptides that act as complete antigens and stimulate IgE synthesis (e.g. animal allergens, flour, latex, etc). In some instances, relatively pure proteins or peptides (e.g. enzymes) and more recently purified and recombinant allergens are available as clinical tools. Skin prick testing is commonly used to identify sensitization to HMW allergens because it is safe, specific and more sensitive than most in vitro assays. However, a positive response on skin testing only confirms exposure and sensitization. Some individuals can react positively on skin tests and not demonstrate allergen-induced asthma. Few occupational allergen extracts are commercially available for skin testing, most of which are not standardized, and some of the available extracts may not be of adequate potency and reliability. Combining positive skin prick testing with nonspecific bronchial hyperresponsiveness can be an effective way of documenting IgE-dependent OA, at least to some HMW allergens (19).

It is also possible to use in vitro tests, such as the radioallergosorbent test (RAST) or enzyme-linked immunoassay (ELISA), for the detection of allergen-specific IgE antibodies. However, skin tests are usually more sensitive for early detection of sensitization than in vitro tests. In some circumstances, the specificity of IgE measurements to occupational agents can be hampered by allergenic cross-reactivities with common aeroallergens or panallergens such as profilin (20).

HMW allergens are also amenable to more detailed immunologic studies, such as electrophoretic methods in combination with immunoblotting, crossed radioimmunoelectrophoresis and other methods, that allow identification and characterization of the allergenic components. The identification of specific causative allergens of OA may allow ascertainment of different allergenic components from the same allergenic source under different conditions of exposure (e.g. OA caused from soybean flour versus soybean-induced epidemic asthma) (21). Using immunologic inhibition studies, it may also be possible to demonstrate allergenic cross-reactivity between different antigens, which may or may not be clinically relevant (22).

Low-molecular weight agents
Some LMW chemicals, such as acid anhydrides, platinum salts, persulfates, and reactive dyes may act as haptens and stimulate IgE production by combining with endogenous proteins to form a hapten-protein conjugate. However, many LMW agents, including isocyanates, plicatic acid and glutaraldehyde, may cause OA but induce specific IgE antibodies in only a minority of affected workers. In other cases, specific IgE antibodies have not been found (e.g. acrylates). Skin testing does not adequately assess the response to LMW antigens. Thus, skin tests are almost useless for most LMW agents, but they are good diagnostic tools in workers sensitized to complex platinum salts, and in some instances, in patients exposed to other metallic salts (22) and to persulfates. Although protein-conjugates of some reactive chemicals, such as diisocyanates and acid anhydrides, can be readily obtained, optimal ligand:protein binding ratios have not been defined (9). Serologic tests have limited utility in the diagnosis of isocyanate-induced asthma, but they are preferred to skin tests in the diagnosis of OA due to acid anhydrides.

Cell-mediated hypersensitivity may be directly involved in mediating the inflammatory response in the airways leading to OA caused by certain LMW agents (23, 24). However, the use of assays of allergen-specific, cell-mediated immune responses, have been studied only to a very limited extent and as yet have no clinical application. 

4. Physiologic assessment

Diagnosis of asthma
Asthma diagnosis should be confirmed before the investigation of occupational causes. The diagnosis of asthma requires both relevant symptoms and the presence of airflow limitation that is partially or completely reversible either spontaneously or after treatment. The clinical confirmation of asthma should demonstrate significant improvement of the FEV 1 (>12%) following administration of a bronchodilator.

Differential diagnoses, e.g. hypersensitivity pneumonitis, bronchiolitis, vocal cord dysfunction, non-asthmatic cough, pneumoconiosis, and congestive heart failure, need to be considered.

Bronchial hyperresponsiveness
In the absence of airflow limitation, it is necessary to confirm the presence of bronchial hyperresponsiveness to methacholine or histamine (PC20≤ 16 mg/ml) within 24 hours of typical workplace symptoms. The absence of bronchial hyperresponsiveness when the patient has been working for at least two weeks virtually rules out OA (8). If bronchial hyperresponsiveness is demonstrated, further testing is required to confirm the work-relatedness of asthma. Bronchial hyperresponsiveness to pharmacologic agents usually increases in a patient with immunological OA upon re-exposure to the offending agent (9). The degree of bronchial hyperresponsiveness is also useful to select an appropriate starting dose in bronchial challenges with specific agents.

Serial recording of pulmonary function tests
Prolonged recording of peak expiratory flow (PEF) or spirometry for periods at work and off work is a valuable diagnostic tool in OA as it has been found to be both sensitive and specific, although possibly not satisfactory enough to warrant using it alone (25). The patient should be instructed in the correct use of the portable PEF meter or spirometer, and be asked to perform readings at least four times a day during several working weeks and at for least 2 weeks off work. Patients should also keep a diary record of symptoms, medication use and work activities. Regularly used asthma medications should be maintained at a steady dose during the monitoring period. Diurnal variability of at least 20% is suggestive of asthma, and if such variability occurs relatively more often on working days than days off work, this is indicative of an occupational effect. Visual analysis of graphs of PEF records by experienced readers provides the most satisfactory method to interpret these measurements. A position statement on self-monitoring of PEF in the investigation of OA has been published (26).

Prolonged PEF monitoring has limitations, as it requires the cooperation and understanding of subjects to carry out the measurements themselves and to record readings and the time reliably. Therefore, the main pitfall of this method is patient compliance and possible malingering of results (27). This problem may be overcome either by using computerized peak flow meters or by serial measurements of bronchial hyperresponsiveness to pharmacologic agents when the patient is at work and away from work. Bronchial hyperresponsiveness usually heightens after a period of exposure to the offending occupational sensitizer and lessens progressively after the worker's exposure has ceased (9). The effect of workplace exposure on bronchial hyperresponsiveness may last for several weeks.

Specific inhalation challenge tests
Specific inhalation challenge (SIC) tests have been proposed as the "gold standard" in the diagnosis of OA. Whenever feasible, SIC may be done relatively early in the diagnostic work-up. These tests are especially indicated in studying new causes of OA, when the diagnosis of OA remains in doubt, and in determining the precise causative agent, as well as for research on mechanisms of OA. Sophisticated equipment and trained personnel are necessary to perform these challenge tests in order to assure safety for patients and to supply reliable results. SIC must be carefully controlled to provide exposure to an appropriate level of the sensitizing agent, with pulmonary function monitoring for at least 12 hours on a control day and on an active exposure day. SIC tests may induce isolated early, isolated late, dual, or atypical asthmatic reactions. If the type of occupational exposure cannot be reproduced in the laboratory or if the patient is exposed to several occupational agents, a workplace challenge should be carried out with close supervision and serial monitoring of spirometric parameters. SIC procedures have been thoroughly reviewed (28, 29). More recently, SIC with purified occupational allergens is being used (30). Defining the precise causative allergen (and not only the allergenic source) in OA has implications from a pathogenic and clinical standpoint. If an individual is shown to have a specific response to a particular allergen, avoidance from this component and not total removal from all exposures might be possible.

Specific bronchial reactivity and non-specific bronchial hyperresponsiveness may decline or disappear after cessation of exposure in the workplace in patients with OA, leading to falsely negative SIC tests. An absence of significant changes in airway caliber during SIC test but with an increase in bronchial hyperresponsiveness to pharmacologic agents after the challenge may precede the development of an asthmatic reaction to a second SIC (31, 32). Thus, the sensitivity of SIC may be improved by performing methacholine or histamine tests on the day before and after SIC (Fig. 3). Moreover, the post-challenge increase in bronchial hyperresponsiveness may be useful to differentiate an asthmatic reaction due to specific mechanisms from bronchoconstriction triggered by an irritant effect.

5. Assessment of inflammatory parameters

Exposure to allergens or chemical sensitizers in the workplace often induces eosinophilic inflammation in sensitized subjects, although in some cases neutrophilia has been reported (33). Although bronchial hyperresponsiveness may provide indirect evidence of airway inflammation, this functional parameter and noninvasive markers of airway inflammation are non-overlapping dimensions (Fig. 4). Moreover, some patients may develop eosinophilic bronchitis without asthma, which is a condition presenting with chronic cough and characterized by sputum eosinophilia like asthma, but unlike asthma the patients have no evidence of variable airflow obstruction and bronchial hyperresponsiveness (34, 35). Thus, the investigation of OA should be complemented with the assessment of the inflammatory component, such as induced sputum parameters.

Induced sputum can be a useful, noninvasive, tool to investigate OA if the subject is still at work, to support the evidence related to the occurrence of an asthmatic reaction following SIC and to differentiate between truly OA from aggravation of asthma due to irritants. An increase in induced sputum eosinophils was found at 6 and 24 hours after a positive plicatic acid challenge in red cedar asthma (36), but increases in exhaled nitric oxide did not correlate with a positive challenge. Significant increases in induced sputum eosinophils have been found in patients with OA from various agents during periods of work exposure compared with periods off work (22, 37). Moreover, it has been reported that changes in both sputum eosinophil counts and bronchial responsiveness to methacholine are satisfactory predictors of a significant bronchial responsiveness to occupational agents in SIC (33). Nevertheless, whether sputum analysis is a useful tool in evaluating the integrated effect of inflammation on the functional and clinical consequences of OA is still unclear.

The advantages and disadvantages of diagnostic methods for OA are shown in table I (modified from reference 3).

Summary

  • The cornerstone for the diagnosis of occupational asthma is evidence of a causal relationship between exposure to the offending agent and both clinical symptoms and physiological changes.

  • The clinical history should include detailed questioning of the circumstances of the onset and severity of asthma symptoms, temporal patterns between occupational exposures and disease exacerbations, and course of the disease. However, the clinical history is more reliable at excluding than at confirming the diagnosis of OA.

  • The assessment of occupational exposure is an important step in the evaluation of the contribution of the workplace to a patient's asthma. Information from the worksite can be obtained through a walk-through visit and consulting industrial hygiene data and material safety data sheets. In special circumstances, air-sampling monitoring with area or personal sampling pumps can be performed by qualified personnel.

  • Serial monitoring of PEF or spirometry for periods at work and off work has been found to be both sensitive and specific in the diagnosis of OA. The main pitfall of this method is patient's compliance and possible malingering of results. This problem may be overcome either by using computerized PEF meters or by measuring bronchial hyperresponsiveness when the patient is at work and off work.

  • For agents that act through an IgE-mediated mechanism, skin testing or serologic measurement of specific IgE antibodies can be used to assess sensitization, provided a suitable preparation of allergen is available. Most occupational antigens are not standardized and information of sensitivity and specificity of prick or intradermal tests is not available.

  • Specific inhalation challenges are the "gold standard" in the diagnosis of OA. These tests are indicated in studying new causes of OA and in determining the precise etiologic agent, as well as for research on mechanisms of OA. Sophisticated equipment and trained personnel are necessary to perform these challenge tests.

  • Induced sputum can be a useful, noninvasive, tool to support the evidence related to the occurrence of an asthmatic reaction following specific inhalation challenge and to differentiate between truly occupational asthma from aggravation of asthma due to irritants.

References

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  22. Sastre J, Fernández-Nieto M, Marañón F, Fernández-Caldas E, Pelta R, Quirce S. Allergenic cross-reactivity between nickel and chromium salts in electroplating-induced asthma. J Allergy Clin Immunol 2001;108:650-1.
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  30. Quirce S, Fernández-Nieto M, Polo F, Sastre J. Soybean trypsin inhibitor is an occupational inhalant allergen. J Allergy Clin Immunol (in press).
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Figure 1. Evaluation of the worker with suspected occupational asthma should consider the type of exposure (allergens, chemical sensitizers, irritants) since exposure to these agents very often determines the type of asthma.

Figure 2. Stepwise approach for the clinical investigation of occupational asthma.

Figure 3. SIC to glutaraldehyde on test day 1 did not induce significant changes in FEV1, but methacholine inhalation test became positive (PC20 0.74 mg/ml). Re-exposure to glutaraldehyde on test day 2 elicited an immediate asthmatic response. Arrow: salbutamol inhalation (from reference 32).

Figure 4. Exposure of a sensitized person to an occupational allergen or chemical sensitizer may cause airway inflammation (usually eosinophilic bronchitis) that leads to bronchial hyperresponsiveness. Subsequent exposure to non-irritating levels of this allergen or sensitizer provokes intermittent airflow limitation (bronchoconstriction). All these pathophysiological components of occupational asthma should be investigated because, although linked, they are not overlapping dimensions.

 

Table I. Advantages and disadvantages of diagnostic methods for OA (modified from 3).

METHOD

ADVANTAGES

DISADVANTAGES

Questionnaire

Simple, sensitive

Low specificity

Immunologic testing

Simple, sensitive

Valid only for some agents;
identifies sensitization not disease;
lack of standardized extracts

Bronchial responsiveness to methacholine or histamine

Simple, sensitive

Not specific for asthma or OA;
OA not ruled out by a negative test

Serial PEF monitoring at work and away from work

Relatively simple, affordable

Depends on patient's cooperation;
no standardized interpretation

Specific inhalation challenge in the laboratory

If positive, confirmatory

If negative, diagnosis not ruled out;
few specialized centers; expensive

Workplace challenge with serial FEV 1 measurements

If negative under usual work conditions, rules out diagnosis

A positive test may be due to irritation;
requires collaboration (worker and employer)

Induced sputum parameters

Assess inflammation
Specificity of reaction

Different types of inflammation
Research tool, not validated