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Cartier A, Bernstein IL, Burge PS, Cohn JR, Fabbri LM, Hargreave FE, Malo JL, McKay RT, Salvaggio JE , Guidelines for bronchoprovocation on the investigation of occupational asthma. Report of the Subcommittee on Bronchoprovocation for Occupational Asthma , J Allergy Clin Immunol , 1989 ; 84 : 823-829

Guidelines for Bronchoprovocation on the Investigation of Occupational Asthma

Report of the Subcommittee on Bronchoprovocation for Occupational Asthma

Andre Carrier, MD, Chairman, I. Leonard Bernstein, MD, P. Sherwood Surge, MD, John R. Conn, MO, Leonardo M. Fabbri, MD, Frederick E. Hargreave, MD, Jean-Luc Malo, MD, Roy T. McKay, PhD, and John E. Salvaggio, MD

Asthma can be induced or exacerbated at work by several means. Four work-related disorders, characterized by airflow obstruction and airway hyperresponsiveness, have been described. These include? occupational asthma, byssinosis, the reactive airways dysfunction syndrome, and variable airflow obstruction caused by irritant substances. This committee has elected to focus .only on the topic of occupational asthma, which is defined as asthma that is either induced or exacerbated by exposure to a specific (as opposed to an irritant) agent found at work.

The Committee has decided to exclude discussion of other causes of asthmatic exacerbations at work, which does not mean that these conditions are not important. It may also, as discussed in other sections of this report, be quite difficult to distinguish an irritant effect from a specific bronchospastic response.

A preexisting history of asthma before exposure to the offending agent does not preclude the diagnosis of occupational asthma.

DIAGNOSIS
The diagnosis of occupational asthma, in most cases, needs to be confirmed by objective means. A suggestive history and objective confirmation of the presence of asthma are not always sufficient to establish a firm diagnosis of occupational asthma. Evidence that asthma is caused or exacerbated specifically by work exposure is needed.

The investigation of patients suspected of occupational asthma is complex and should be carried out under the supervision of experienced physicians. The "gold standard" for confirming a diagnosis of occupational asthma in an individual worker is the specific bronchoprovocation test (SBPT). If it is impossible to perform specific bronchoprovocation testing in an individual worker, however, the physician must rely on other means to establish the diagnosis. Combined monitoring of lung function parameters, such as peak expiratory flow rate (PEFR) at the worksite and of nonspecific bronchial hyperresponsiveness (NSBH) have recently been developed and used both in individual case investigations1-3 and in cross-sectional studies of worker cohorts.4-6 The members of this committee believe the latter approaches require further study before they are accepted as definitive and do not actually represent true alternatives to specific bronchoprovocation testing. Monitoring forced expiratory volume in 1 second (FEV1,) before and after the work shift is not an adequate means of diagnosing occupational asthma.7

While specific bronchoprovocation tests have been used increasingly in clinical practice, some of these tests performed with suspected causative agents for which there has been little previous experience are still considered research procedures, and more validation of their sensitivity, specificity, and reproducibility may be needed before they can officially be recommended for general clinical use. However, specificity and reproducibility have been reasonably established for inhalation testing to an agent such as toluene diisocyanate (TDI). The specificity of TDI challenge has been demonstrated by the fact that non-exposed control subjects with asthma with documented bronchial hyperresponsiveness are nonreac-tive to TDI challenge at 15 to 20 ppb.8-9 The reproducibility of the TDI challenge procedure has also been demonstrated.10

Indications. General indications for which bronchoprovocation testing is performed include: the quantitation of bronchial hyperresponsiveness, a correlation of data obtained from occupational history and pulmonary function testing, evaluation of the effects of unknown substances, and the longitudinal assessment of workers. Severe underlying medical or psychological disorders and low baseline lung function are relative contraindications for performing bronchoprovocation tests. It should also be emphasized that SBPTs are usually indicated for evaluation of patients in whom there is diagnostic uncertainty, diagnostic dispute, or for the purpose of research. 
I.	Specific bronchoprovocation tests.
A.	General comments".
•	These tests should be done either in the laboratory or in the workplace. Ideally, monitoring of the exposure to particulates, fumes, and gases should be done before challenge testing in order to know the precise concentration and duration of exposure. Precise control of exposure to a possible causative agent may be impossible in the work place. In the absence of reliable monitoring of exposure to the challenge agent, it may be difficult to distinguish between irritant and specific bronchial responses. Specific bronchoprovocation is potentially dangerous because there is always a potential for triggering severe, life-threatening asthmatic reactions. Therefore, SBPT should be carried out only in specialized centers, under the close supervision of an experienced physician, and only where adequate resus-citative measures are available. However, when the concentration and duration of exposure are well controlled and baseline lung function and other factors are taken into account, nearly all SBPTs can be performed safely.
•	A suitable exposure chamber in the laboratory is required to generate vapors, fumes, and/or dust at subirritant levels. In order that laboratory personnel are not exposed, the chamber must be a closed system, with exhaust ventilated to the outside or to a scrubber system. Ideally, documentation of the concentration of a substance generated in the chamber should be performed before challenge. Special challenge rooms or closed systems have been described and could be used as models.11-13
•	Exposure should be as realistic as possible, approximating that encountered in the workplace.14-19 The generation method chosen for inhalation challenge should be determined on the basis of the physical nature of the test material.
•	Standardized methods have not yet been adopted for performing specific bronchoprovocation challenges to occupational agents. Uniform guidelines should be developed for bronchial challenge to high molecular weight materials that are known to elicit IgE-mediated responses, as reflected by positive skin tests and early or dual asthmatic reactions. Similarly, methods should be developed for low molecular weight chemicals that rarely give positive immediate skin reactions and are often associated with either isolated late or dual-phase asthmatic reactions.
•	A negative SBPT in the laboratory does not necessarily exclude the diagnosis of occupational asthma because false-negative test results can occur.20 This can result from the use of the wrong testing agent or an antiasthmatic drug, taken inadvertently before or during challenge. A patient who had been removed from continuous exposure to a substance in question for several months before challenge may also fail to exhibit a positive bronchial response in the laboratory.6 21 This situation may require that the worker be sent back to work to determine whether asthmatic responses do or do not occur in the occupational setting.

Selection of the challenge concentration can also be an important factor responsible for false-negative test results, especially when there is little information available to select a starting concentration for a chemical suspected of causing occupational asthma. Because the exposure duration in the workplace may last for up to 8 hours, it is possible that a much shorter exposure period in the laboratory could produce false-negative results. Experience with bronchial challenge with diisocyanates has demonstrated a relationship between concentration and the severity of induced bronchospasm.22 In sensitive individuals, a suboptimal concentration might fail to produce a positive response. Bronchial challenge studies with diisocyanates suggest that there is an association between the duration of exposure and the degree of bronchoconstriction observed both at work and in the laboratory.20-23 In general, a false-negative test result could result when the challenge agent is presented to subjects in ways that do not reproduce the occupational situation. Other factors that could produce false-negative results include the method of administration (face-mask vs mouthpiece vs whole-body exposure) and the presence of carrier particles.20

II.	Specific procedure recommendations.
Asthmatic medications should be withheld for as long as possible before the SBPT. It is important to demonstrate stability in lung function during the prechallenge period while the patient is not taking medication to assure that decrements in pulmonary function parameters after challenge are not attributable to sudden withdrawal of asthma medications.
A.	In order to assure the safety of SBPTs, prolonged medical supervision is often required during the procedure.  Prolonged monitoring after a provocative challenge usually necessitates admission to a hospital or clinical research center unit. Thus these tests can often be time-consuming and expensive. Informed consent of the patient must be obtained before initiation of a SBPT.
B.	Oral or inhaled beta-adrenergic drugs should be withheld for at least 8 hours before specific bronchial challenge and during the postchallenge observation period. If possible, sodium cromoglycate and inhaled corticosteroids should not be given for 1 month before the challenge or during the subsequent observation period. However, if these medications are necessary to control the symptoms of asthma, they should be continued. If not, asthma may flare up during the challenge days and could mimic a positive challenge response that could be falsely attributed to exposure to the challenge agent. Therefore in such circumstances, the total daily dose of cromoglycate or corticosteroids should be given at the end of each challenge day, but no sooner than 8 hours before the next exposure, to avoid inhibition by these drugs of specific bronchial responses. Sustained-release theophylline should be withheld for at least 48 hours before challenge, although some patients may be too unstable to omit this medication, as confirmed by large fluctuations in lung function on the control day. In such instances, theophylline may be taken at usual dosages, with theophylline blood levels monitored on each test day. It is possible that theophylline could effectively block an asthmatic response after a specific bronchial challenge in a truly sensitized individual. In circumstances in which theophylline is required, a negative SBPT does not entirely exclude occupational asthma, but a positive challenge test confirms the diagnosis.
C.	To adequately document both an early and late bronchial response to the offending agent, close monitoring of lung function tests should be carried out for at least 8 hours. Additional monitoring may be required, particularly among patients who manifest a history of asthmatic symptoms more than 8 hours after initial exposure.
D.	A control test day, with exposure to a placebo substance, should be carried out to ensure that the patient's FEV, is stable over at least 8 hours and that any possible physiologic changes observed on challenge days are not attributable to normal circadian changes in pulmonary function or changes in effort. When the potential sensitizing agent is a likely irritant, it may be necessary to expose a control subject with asthma with a similar degree of nonspecific bronchial responsiveness under the same conditions, to exclude a nonspecific or irritant bronchial response. This should be carried out only if it is probable that such an exposure will not put the control subject at risk for sensitization to the challenge agent.
E.	It may be necessary to postpone a test when baseline spirometry is too unstable to allow proper interpretation of changes in FEV1.
F.	Baseline FEV1, must be greater than 2 L and should also be greater than 60% to 70% of predicted before a SEPT is initiated. Baseline FEV, must be at least 60% of predicted before a nonspecific bronchoprovocation test is initiated. Subjects with underlying medical conditions that could be decompensated by the provocation of an asthmatic response should be excluded from bronchial challenge testing.
G.	Measurement of FEV, is often the best physiologic index for detection of changes in central and large airways. However, peak expiratory flow rate (PEFR), forced expiratory flow (FEF25%-75%), forced vital capacity (FVC), specific airway conductance (SGaw), and/or other lung function parameters may also be used to monitor the airway response after challenge.
H.	The FEV, should be monitored at 10- to 15-minute intervals for the first hour, 30-minute intervals for the second hour, then hourly for up to 8 hours after the end of exposure. In certain circumstances, inpatient monitoring of FEV1, may be required for 8 to 24 hours after challenge.
I.	A positive bronchial challenge should generally be regarded as a sustained decrease in FEV1, of at least 20% from the initial baseline FEV1, measured before exposure. Several types of bronchoconstrictive responses after specific bronchial challenge have been described,14 including: immediate or early onset, nonimmediate or late onset, dual asthmatic response, and recurrent nocturnal asthma.24,25 There is a need for better characterization of irritant-induced bronchospastic responses.
J.	Whenever possible, exposure in the laboratory to a challenge agent should be monitored. If possible, the exposure should be maintained below irritant levels as well as recommended work place exposure limits, such as the 8-hour Threshold Limit Value (TLV) or Short-Term Exposure Limit (STEL), established by the American Conference for Governmental Industrial Hygienists (ACGIH).
K.	The exposure to the suspected agent should always be done carefully. Incremental exposure (increasing the length of exposure for a given concentration or increasing the concentration for a given period) on different days may be needed to avoid severe asthmatic reactions. This is especially relevant for low molecular weight chemicals that frequently induce only a late response. The first exposure should always be performed at low levels of exposure. In the case of a high molecular weight (HMW) allergen that can be nebulized, the starting concentration used for SBPT should be less than the predetermined endpoint intracutaneous threshold concentration. The starting concentration and duration of exposure of the challenge agent should be further modified by the subject's prechallenge level of NSBH to methacholine or histamine. The FEV1, should be measured 5 to 10 minutes after exposure. If the FEV, drops between 10% and 15%, another 10-minute wait is advised. The exposure can be carefully increased, up to a maximum of 5 minutes on the first day. If the fall in FEV1, is less than 20% and the maximum exposure has not been reached, the duration of exposure may be increased on a second test day. In the case of reactive chemicals in which isolated late reactions are frequent, the maximum total exposure should not be increased rapidly on the same day. Instead, exposure duration to a low molecular weight (LMW) agent ought to be increased on separate challenge days (e.g., 1 minute on day 1, 5 minutes on day 2, 15 minutes on day 3, etc.). The decision in regard to the initial duration of exposure can be modified based on the baseline level of NSBH, as reflected by the subject's PC20 to methacholine or histamine.
L.	Monitoring of NSBH before and after a SBPT can provide additional information. This approach has been particularly useful for diagnosis of bronchial sensitization to LMW chemicals. Indeed, even in the presence of a negative SBPT, a significant increase in responsiveness to histamine or methacholine may suggest that the patient is nevertheless sensitized to the agent.26-28 In this circumstance, a SBPT may become positive after more prolonged exposure to the causative agent at work. However, specific bronchial sensitization to an agent, such as TDI, has been demonstrated by SBPT in the absence of any objective changes in NSBH.29,30 Therefore, a negative histamine or methacholine challenge result cannot be used to exclude occupational asthma.
M.	It is unknown how long a worker should be exposed in the laboratory to an occupationally encountered agent before SBPT is considered negative. There are no adequate data addressing this issue, and exposure may vary among laboratories. For example, exposure to LMW chemicals may induce an asthmatic response after only one breath, but may have to be continued for up to 2 hours or more in others.1, 31, 32 It must be kept in mind that a negative SBPT in the laboratory does not always exclude the diagnosis of occupational asthma. Return to work may be associated with subsequent deterioration of asthma, documented by monitoring of PEFR and NSBH.

III.	Monitoring of NSBH in the workplace.
Nonspecific bronchial hyperresponsiveness is defined as the propensity of the airways to bronchoconstrict on exposure to nonalergic or non-specific stimuli, such as cold air, exercise, irritant fumes, and chemical agonists, such as histamine and Methacholine. -NSBH can be assessed by several means. The histamine and methacholine tests are currently the most frequently used. Results of such tests are usually expressed as the provocative concentration of histamine or Methacholine inducing a 20% fall in FEV1 (PC20).
A.	The place of NSBH assessment in the investigation of occupational asthma remainsto be clarified:
1	The method used to assess NSBH should be well standardized.33-35
2	Intrasubject reproducibility of the method used to measure airway responsiveness needs to be established over selected time intervals in each clinic and should be reevaluated periodically.
3	Asthmatic medication should be stopped appropriately, according to the recommendations of the American Academy of Allergy and Immunology.33 A change in PC20 should be considered significant when it is consistent, reproducible, and greater than the accepted variability of the test (2 standard deviations) and, at the same time, baseline airway caliber is not modified (FEV1, ± 10% of baseline).
4	Although an increase in_NSBH can be seen in conditions other than asthma, it can be used to confirm the presence of asthma in a subject suspected of this diagnosis. It does not, however, confirm the diagnosis of occupational. asthma.
5	There are some data to suggest that monitoring of NSBH at work and off work can be useful to confirm sensitization when combined with monitoring of lung function.1, 2, 36, 37 These reports require further confirmation. Tests that measure NSBH should not be used as preemployment screening tests to exclude potential individuals at risk because there is no evidence that preexisting NSBH is a risk factor for development of respiratory sensitization to occupational agents. Preemployment NSBH tests may be useful, however, in establishing baseline NSBH for comparison with future studies. Conversion of a negative baseline (preemployment) NSBH to a positive test may help to identify workers with possible occupational asthma.

IV.	Monitoring of PEFR in the workplace.
When serial monitoring of PEFR, with or without testing of NSBH, is used to investigate occupational asthma, medication should be kept constant during the whole period of observation. The addition or withdrawal of an-tiinflammatory drugs, such as sodium cromo-glycate and corticosteroids, may greatly affect these results.
A.	Monitoring of PEFR has been proposed by Burge et al.,23 who demonstrated its usefulness. However, it is highly effort dependent and requires the cooperation of the employee, which is not always possible. Fears attributable to job security and compensation issues may hinder full cooperation on the part of some workers. Whenever possible, monitoring of the employee's workplace, using personal or area air-monitoring equipment, should be performed to establish airborne concentrations of the suspected agent as well as other substances present in the atmosphere. It should be emphasized that bronchoconstriction documented only by monitoring of PEFR may not allow a physician to distinguish between asthma induced by irritant vs. specific stimuli. Combined monitoring of NSBH at and away from work may add further information concerning the specificity of the exacerbation.
1.	The PEFR should be measured with acceptable devices.
2.	Peak flow rates should be measured at 2-hour intervals while the patient is awake, over consecutive periods at work and away from work. The best of three readings should be recorded, but results should be reproducible (within 20 L/min of each other). The daily maximum, daily mean, and daily minimum peak flow readings should be plotted. Records should be kept for a minimum period of 2 weeks, but longer periods may be required in individual workers before definite conclusions can be made.
3.	There is a need for developing objective criteria for interpreting data obtained by monitoring of PEFR. To be considered significant, a fall of at least 20% in PEFR, compared to a period away from work, may be necessary to reveal worsening of asthma at work.
4.	Monitoring of PEFR and NSBH should be continued long enough after removal from work and continued long enough after return to work because it may take several days or weeks before any significant changes are seen.

REFERENCES
1. Cartier A, Chan H, Malo J-L, Pineau L, Tse KS, Chan-Yeung M. Occupational asthma caused by eastern white cedar (Thuja occidentals) with demonstration that plicatic acid is present in this wood dust and is the causal agent. J ALLERGY CLIN IMMUNOL 1986;77:639.
2. Cartier A, Pineau L, Malo J-L. Monitoring of maximum expiratory peak flow rates and histamine inhalation tests in the investigation of occupational asthma. Clin Allergy 1984; 14:193.
3. Cockcroft DW, Hoeppner VH, Werner CD. Recurrent nocturnal asthma after bronchoprovocation with Western Red Cedar sawdust: association with acute increase in non-allergic bronchial responsiveness. Clin Allergy 1984;14:61.
4. Malo J-L, Cartier A. Occupational asthma in workers of a pharmaceutical company processing spiramycin. Thorax 1988; 43:371.
5. Bardy J-D, Malo J-L, Sguin P, et al. Occupational asthma and IgE sensitization in a pharmaceutical company processing psyllium. Am Rev Respir Dis 1987;135:I033.
6. Cartier A, Malo J-L, Forest F, et al. Occupational asthma in snow crab-processing workers. J ALLERGY CLIN IMMUNOL 1984:74:261.
7. Burge PS. Single and serial measurements of lung function in the diagnosis of occupational asthma. Eur J Resp Dis 1982;63:47.
8. Mapp CE, Di Giacomo GR, Omini C, Broseghini C, Zedda L, Fabbri LM. Late, but not early, asthmatic reactions induced by toluene diisocyanate are associated with increased airway responsiveness to methacholine. Eur J Respir Dis 1986;69: 276.
9. Chester EH, Martinez-Catinchi FL, Schwartz HJ, et al. Patterns of airway reactivity to asthma produced by exposure to toluene diisocyanate. Chest 1979;75(2nd suppl):229.
10. Mapp CE, Boschetto P, Dal Vecchio L, et al. Protective effect of anti-asthma drugs on late asthmatic reactions and increased responsiveness induced by toluene diisocyanate in sensitized subjects. Am Rev Respir Dis 1987:136:1403.
11. Butcher BT. Inhalation challenge testing with toluene diisocyanate. J ALLERGY CLIN IMMUNOL 1979:64:655.
12. DeLuca S, Caire N, Cloutier Y, Cartier A, Ghezzo H, Malo J-L. Acute exposure to sawdust does not alter airway calibre and responsiveness to histamine in asthmatic subjects. Eur Respir J 1988;1:540.
13. Gerblich AA, Horowitz J, Chester EH, Schwartz HJ, Fleming GM. A proposed standardized method for bronchoprovocation tests in toluene diisocyanate-induced asthma. J ALLERGY CLIN IMMUNOL I979;64:658.
14. Pepys J, Hutchcroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829.
15. Pepys J. Challenge procedures in occupational asthma. Bull NY Acad Med 1981:57:608.
16. Pauli G. Bessot JC, Dietmann-Molard A. L'asthme profes-sionnel: investigation et principals etiologies. Bull Eur Physiopathol Respir 1986:22:399.
17. Chan-Yeung M, Lam S. State of the Art. Occupational asthma. Am Rev Respir Dis 1986:133:666.
18. Chan-Yeung M, Malo-J-L. Occupational asthma. Chest 1987; 91(suppl):l305.
19. Newman Taylor AJ, Venables KM. Clinical and epidemiological methods in investigating occupational asthma. Clin Immunol Allergy 1984;4:3.
20. McKay RT. Bronchoprovocation challenge testing in occupational airways disorders. Sem Respiratory Med 1986;7: 297.
21. Butcher BT, O'Neil CE, Reed MA, Salvaggio JE, Weill H. Development and loss of toluene diisocyanate (TDI) reactivity: immunologic, pharmacologic and provocative inhalation challenge studies. J ALLERGY CLIN IMMUNOL 1982;70:23I.
22. Butcher BT, Salvaggio JE, Weill H, Ziskind MM. Toluene diisocyanate (TDI) pulmonary-disease: immunologic and inhalation challenge studies. J ALLERGY CLIN IMMUNOL 1976; 58:89.
23. Burge PS. O'Brien IM, Harries MG. Peak flow rate records in the diagnosis of occupational asthma due to isocyanates. Thorax 1979;34:317.
24. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthma after exposure to grain dust. Am Rev Respir Dis 1976:114:1011.
25. Siracusa A, Curradi F, Abbritti G. Recurrent nocturnal asthma due to tolylene diisocyanate: a case report. Clin Allergy 1978;8:195.
26. Cartier A, L'Archeveque J, Malo J-L. Exposure to a sensitizing occupational agent can cause a long-lasting increase in bronchial responsiveness to histamine in the absence of significant changes in airway caliber. J ALLERGY CUN IMMUNOL 1986:78:1185.
27. L'Archeveque J, Pineau L, Cartier A, Malo J-L. Changes in airway responsiveness to histamine preceding fluctuations of bronchomotor tone in occupational asthma (abstract). J ALLERGY CLIN IMMUNOL 1985;75(suppl):170.
28. Cartier A, Pineau L, Malo JL. Occupational asthma to tea dust. (Abstract). J ALLERGY CLIN IMMUNOL 1986;77(suppl): 165.
29. Smith AB, Brooks SM, Blanchard J, Bernstein IL, Gallagher J. Absence of airway hyperreactivity to methacholine in a worker sensitized to toluene diisocyanate (TDI). J Occup Med 1980:22:327.
30. Banks DE, Barkman HE Jr, Butcher BT, Hammad YY, Rando RJ, Glindmeyer HW, Jones RN, Weill H. Absence of hyper-responsiveness to methacholine in a worker with methylene diphenyl diisocyanate (MDI)-induced asthma. Chest 1986; 89:389.
31. L'Archeveque J, Malo J-L, Cartier A. Significant changes in non-specific bronchial responsiveness after isolated immediate, but not after late bronchospastic reactions (abstract). J ALLERGY CLIN IMMUNOL 1988;81:244.
32. Zammit-Tabona M, Sherkin M, Kijek K, Chan H, Chan-Yeung M.   Asthma  caused   by  diphenylmethane  diisocyanate   in ,  foundry workers. Clinical, bronchial provocation, and immunologic studies. Am Rev Respir Dis 1983; 128:226.
33. Eggleston PA, Rosenthal RR, Anderson SA, et al. Guidelines for the methodology of exercise challenge testing of asthmatics. J ALLERGY CLIN IMMUNOL 1979;64:642-5.
34. Hargreave FE, Ryan G, Thomson NC, O'Byrne PM, Latimer K, Juniper EF, Dolovich J. Bronchial responsiveness to his-