Occupational asthma due to chemical agents

Preventiun of occupational Occupational

akwgic disc

asthma due to chemical agents

John E. Salvaggio, M.D., Brian T. Butcher, Ph.D., and Carol E. O’Neil, Ph.D. New Orleans, La.

In modem societies, rapid developmentand diversity of industry have created a need for new chemical reagents, many of which have the potential to induce disease. Although there is a tendency to consider these as modem diseases,some have been recognized for many centuries. Inhalation of certain chemical agentscan causeobstructive airway diseaseand severeinterstitial alveolar filling disease. Exposure is usually, although not exclusively, confined to the workplace. Hippocrates, in the fourth century B.C., recognizedand described toxicity in the mining industry. Five centuries later, Pliny referred to the inherent dangersof processing zinc and sulfur and described a bladder-derived mask to protect workers from dust and fumes. In the secondcentury A.D., Galen contributed additional observations on occupational diseasesbut little further progresswas madeuntil the 16th century, when Agricola describedsilicosis and recommendedventilation of mines and useof protective masks. In 1672, Wedel describedminer’s asthmaas “drying up the broncha” and “being blocked by soot smoke.“’ The first systematicstudy of occupational diseasewas by Ramazzini.* In his classic treatise, De Morbis Artificium, published in 1700, he describedmany adversehealth effects resulting from occupational exposureand proposedspecific “cautions” to reduce industrial hazards. Many of the diseaseshe described are still a problem today. For example, in a description of textile workers using flax and hemp Ramazzini stated, ‘&. . . a foul and poisonousdust flies out of these materials, enters the mouth, then the throat and lungs, makes the workmen cough incessantly, and by degreesbrings on asthmatictroubles.“’ Although occupational exposure to chemicals can cause peripheral airway diseases,this article is limited to occupational asthma,which can be defined asreversible airways diseaseresulting from exposure to agents in the work environment.’ Initial symptomscan be seenin three temporal patterns(Fig. 1). In the immediatetype, a rapid decline in forced expiratory volume is seen, usually beginning within 10 to 15 minutes after exposure and returning to normal

Fromthe Clinical ImmunologySection Department of Medicine TulaneUniversityMedicalCenter Reprint*quests:Dr. JohnE. Salvaggio,ClinicalJmmuaology Section, Departmentof Medicine,Tulane University Medical Center, New Orleans, LA 70112.

Abbreviations used

TMA: RAST: TDI: MNL: CAMP: ELISA: PIC:

Trimellitic anhydride Radioallergosorbent test Toluenediisocyanate Mononuclearleukocytes Cyclic adensoinemonophosphate Ensymelinkedimmunosorbent assay Provocative inhalation challenge

within an hour or two. In the delayed or late type of asthmatic response,symptomsdo not begin until severalhours after exposure and may continue for some time. With delayed onsetasthma,there may also be a cyclic responsethat can continue for weeks. Sometimesa dual asthmatic response occurs, which has the characteristics of both immediateand delayed asthmaticreactionsed

MECHANISMS Occupational asthmamay occur by a numberof different mechanisms.The chemical may act asa nonspecific irritant; asan allergen, causingIgE mediatedtype I hypersensitivity; or it may stimulate nonspecific release of pharmacologic mediators. In many cases, the mechanismsremain to be elucidated. Many crude chemicals and compoundsinhaled as gases, liquids, and vapors, are reportedto be nonspecific irritants. These include automobile exhaust, chemical deaners, household disinfectants, hairsprays, tobacco smoke, and sulfur dioxide. A number of chemicals and additives encounteredin the workplace act as allergens, leading to IgE mediatedtype I hypersensitivity. Good examples of agents acting by this mechanismare salts of nickel and platinum5~6;TMA, used as a hardening agent in the plastics industry’; and Bacillus subtilis enzymes, used in detergents8In workers exposed to theseagents,specific IgE antibodies are demonstrablyby skin test or RAST. In most cases,there is a strong association betweenpresenceof the diseaseand atopic statusof workers, although in the case of highly allergenic agents such as enzymes, nonatopic individuals can also develop specific reaginic antibodies. Other immunologic mechanismsmay also be involved in occupational asthma, especially in normtopic individuals. One example is the spectrumof diseasesymptomsoccurring 1053

1054

Salvaggio

et al.

J. ALLERGY

CLIN. IMMUNOL. NOVEMBER 1986

velops as a result of the diseaseremains to be determined. Most indirect evidence indicates, however, that the hyperreactivity developsconcurrently with onset of occupational asthma” and is often demonstrablefor monthsor yearsafter specific reactivity to the inducing agent has ceased.14 ETIOLOGIC AGENTS

1 123456 TIME

AFTER

CHALLENGE

(HOURS) FIG. 1. Types asthma.

of bronchial

response

in occupational

in workers exposed to TMA. Individuals with immediate rhinitis and asthmaticreactions have demonstrablespecific IgE antibodies and skin reactivity to TMA-protein conjugates. In workers with delayed onset respiratory systemic syndrome, specific IgG antibodies levels are highest, suggesting that a type III immune complex mediatedreaction may be involved.9 Other mechanismsmay also be involved. For example, in occupational asthmacausedby TDI, a chemical used in the manufacture of polyurethane foams and plastics, there is no correlation between presenceof isocyanate-specific IgE antibodies and asthma. TDI has, however, has been shown to alter the ability of MNL to produce CAMP in responseto prostaglandin E, or to beta agonists, such as isoproterenol.” There also appearsto be a diminished ability of cells from workers with TDI asthmato produce CAMP in responseto agonists.” With other agents such as platinum salts,” nonspecific histamine release may also be induced. Asthma has also beenreportedin farm workers spraying organic insecticides that have anticholinesteraseactivity, suggestingthat these agents may act by increasing local concentrationsof acetylcholine in airways. I3 As is the casewith nonoccupational asthma,nonspecific bronchial hyperreactivity is also associatedwith occupational asthma. Whether this is a predisposingfactor or de-

The number of chemical agentswith the ability to cause occupational asthmais extensive (Table 1). As new chemicals are introduced into the work environments of highly industrialized societies, this list will certainly continue to grow. Asthma-inducing chemical agentsrange from simple low molecular weight chemicals such as salts of nickel5 or platinum6to complex organic molecules including bacterial enzymes.8 For a chemical agent to be able to induce asthmait must be respirable. Generally, large particles are filtered out in the upper respiratory tract, while small particles are not usually retained in the lungs; thus, particles causing asthma areusually 9.5 to 10 pm in diameter.Low molecular weight chemicals may act as haptens, reacting with body proteins to form completeantigensthat can induce haptenor carrierspecific antibodies. With some highly reactive chemicals, such as isocyanatesor anhydrides, such in vivo reactions may lead to the formation of neoantigensto which antibodies are formed.15,I6Thus, it is likely that the immune response to such inhaled chemicals may be directed against a broad rangeof antigenic specificities ranging from the haptenitself to an altered host protein neoantigen. EPIDEMIOLOGY The prevalenceof occupational asthmavaries widely depending on a numberof factors including the inducing agent and host factors. For some agents, the-asthma-producing potential may be high; for example, occupational asthma has been reported in 57% of workers exposed to platinum salts.” Other agents,however, causeasthmaonly rarely. A more realistic overall figure for incidence of occupational asthmain any given population is probably between2% and 4% of workers. In addition to the etiologic agent, a numberof host factors may play a role in determining whether exposedindividuals develop disease.The history of atopy in IgE-mediated immediate type asthmahas already been mentioned. For example, in workers exposed to B. subfilis enzyme, there is a strong associationbetweenthe diseaseand the atopic status.* Other factors that may be important in the initiation of diseaseinclude presenceof preexisting bronchial hyperreactivity,‘* altered adrenergic tone,19recent or concurrent respiratory viral infections,” or alterations in the integrity of tight junctions of basal membranes2’ Environmental factors can also be important diseasedeterminants. Little is known about dose/durationof exposure and its relation to occupationalasthma.There areindications that short-term, high-dose exposuresthat occur during industrial accidents, including spills or mechanicalfailures in manufacturingequipment, may be inducing factors.zZOther factors that could be important include meteorologic con-

VOLUME NUMBER

Occupational asthma due to chemicals

78 5, PART 2

TABLE I. Chemical

agents causing

occupational

1055

asthma Mechanism

Agent

Organic chemicals Amines (ethylene diamine and phraphenylenediamine) Formaldehyde Diisocyanates Pthalic anhydride Plexiglas dust Sulfone chloramines Sulfone chloramide Trimellitic anhydride Polyvinyl chloride (phthalic anhydride) Carmine (coccus cactus extract) Furan binders (furfurol alcohol resin containing paraformaldehyde Plicatic acid (wood dusts) Colophony (vegetablegums and resins) Plant enzymes (papain) Microbial enzymes(Bacillus subtilis) Bromelin Pancreatin Organic dyes Antibodies and pharmaceuticals Cimetidine Penicillins (ampicillin, benzyl penicillin, 6-amino-penicillic acid) Phenyl glycine acid hydrochloride Piperazine Spiramycin Sulfathiazole powder Sulfathiazine Tetracycline Inorganic chemicals Chromium salts Nickel salts Platinum salts Amprolium hydrochloride Stainless steel fumes (chromium, nickel) Ethylene oxide gas Chloramine Metabisulfites Aluminum soldering flux (amino ethylethanolamine)

Irritant

Pharmacologic

Immunologic

? + 3 0 9 3

+ +

+ +

? 9

? 9

? ?

?

? + + ?

? = Possible mechanism; + = likely mechanism.

ditions, such as extreme humidity and pressureinversions with subsequent build-up of environmental pollutants, and seasonaleffects. To date, little has been done to evaluate the role of theseenvironmental factors in diseaseinduction. DIAGNOSIS

A careful history is of great diagnostic value and should include the patient’s personal medical history plus an indepth occupational history. As Ramazzini suggestedwhen he wrote ‘<. . to these questions, add one other, what is

your occupation.?“,l it is important to obtain a detailed history of occupational exposure. Details of the types of employment, both civilian and military; possible exposure to potential asthma-inducing agentsfrom hobbies or at work; history of diseasein coworkers;and history of improvement during weekendsoff or vacations,can ail provide vital clues. When the worker developsimmediateasthmait is usually easy to identify the occupational nature of the disease;but when symptoms are of the delayed type, it is difficult to associatethem temporally with occupationalexposure. It is

1056 Salvaggio et al.

FIG. 2. Chamber for provocative inhalation challenge testing. A = Intake filter; B = agent injection port; C = splitter vane; D = plenum; E = observation window; F = ports; G = door; H = airlock; I = blower; J = exhaust.

often useful to provide the worker with a portablepeak flow device to take frequent measurementsduring and following the work day. When used in conjunction with a diary of job duties performed,results of simple peakflow measurements often will provide important information regarding the nature of the putative etiologic agent.*’ . LABORATORY TESTING Although no in vitro laboratory testcanreplacea thorough clinical evaluation, some are useful in diagnosis of occupational asthma. Sometests can be performed at the work site, while otherscan only beperformedin the well equipped laboratory. Certain tests are highly sensitive but have low specificity; othershave specificity but lack sensitivity. Other in vivo tests, such asPIC, can provide accuratecause-effect relationships between symptomsand exposure but am not without risk to the patient. It is often useful to determine the atopic status of the worker. This is best done by skin prick testing with a panel of inhalent allergens common to the local area. Such tests are inexpensive, can easily be performed at the work site, and can help identify individuals at high risk of developing disease.Skin testing with the specific agent is often useful when the agent is known or suspectedto act by an IgEmediatedtype I immediate hypersensitivity mechanism.In the caseof low molecular weight chemicals acting as hap tens, it may often be necessaryto conjugate the agent to a

J. ALLERGY

CLIN. IMMUNOL. NOVEMBER 1986

protein carrier for both skin testing and subsequentin vitro testing. In vitro testing, including the RAST or the ELISA, is useful for detectingspecific IgE antibodies, especially when the etiologic agent is toxic or an irritant in vivo. ELISA is also usedto quantitatelevels of other immunoglobulin classspecific antibodies. RAST is usually used with protein antigens or hapten-carrierconjugates,whereasELISA is also suitable with nonprotein antigens. It may also be useful to measuretotal serum IgE antibodies when skin prick testing is not practical or when a specific in vitro assayis not available for antibodiesagainst the antigen in question. Elevated IgE may also interfere with RAST for specific IgE, so that correction factors must be applied. Quantitation of other immunoglobulin levels has, in general, proved of little value; however, when specific IgG or IgM antibodies are present,the potential for complement-dependentimmune complex-mediated disease must be considered. Pharmacologicmechanismsmay be involved in the pathogenesisof chemically induced occupational asthma, either by the simple chemical-controlling releaseof pharmacologic mediatorsin a non-IgE-dependentmanneror by modulating the effect of mediatorson bronchial smooth muscle. Thus, when appropriate, measurementof mediators such as histamine or leukotrienes releasedduring or following a provocative challenge test may be useful. IDENTIRCATION OF THE ETlOLOGlC AGENT With proper controls and accurate dose-responsedata, PIC with suspectedagents is a useful technique for confirming a specific cause-effectrelationship and, by identifying the time course of the reaction, indicating a possible pathogenicmechanism.PIC is a time-consumingprocedure that requires the services of experts in diverse disciplines. It is not entirely without risk and should only be undertaken in specialized centers. When performed properly, the information obtained from this proceduremakesthe risk/henefit ratio favorable.” In somecases,whererisks areminimal and quantitative data are not needed,a simple biologic type of challenge can be attemptedby having the subject return to the work environment or exposing him to similar conditions for a brief period in an uncontrolled mannerz5 For gases,vapors, and dusts, challenge is bestperformed in a special exposure chamber. The services of a qualified environmental engineer are crucial for performanceof the test. The ideal chamberpermits generation of constant and reproducible exposurelevels and allows control of humidity and other environmental factors. The chamberused by our group is shown in Fig. 2. It is madeof stainlesssteel to facilitate cleaning after eachprocedureand includes an airlock at the effluent end to ensure that exposure concentrations remain constant when the worker enters. A window permits continuous observation during challenge and airtight ports allow accessfor pulmonary function measurementand blood collection. Challenge consists of daily exposuresto increasing concentrations of the putative offending agent with frequent lung function measurementsthroughout each day. The challenge

VOLUME76 NUMBER 5,PARTZ

Occupational asthma due to chemicals

1057

is terminated when a significant decrease in forced expiratory volume is observed or when the maximum exposure concentration is reached. When aqueous extracts are deemed more suitable for use in the challenge, the test agent can be delivered via a nebulizer and a dosimeter such as the Rosenthal apparatus.” The initial challenge concentration used is loo-fold more dilute than that eliciting a positive wheal and flare reaction on skin testing.“5 When skin test results are not available, a suitably safe dilution must be chosen empirically. Pul-

4. Pepys J. Types of allergic reaction. Clin Allergy 1973: 3tsuppl):491. 5. McConnell LH, Fink JN, SchlueterDP, Schmidt MG. Asthma causedby nickel sensitivity. Ann Intern Med 1973:78:888. 6. Pepys J, Pickering CAC, Hughes EC. Asthma due to inhaled chemical agents: complex salts of platinum. Clin Allergy 1972;2:391. 7. Zeiss CR. PattersonR, PruzanskyJJ, Miller MM. Rosenberg M, Levitz D. Trimellitic anhydride-inducedairway syndromes: clinical and immunologic studies. J ALLERGYCLIN IMMUNOL

monary function is measuredafter each challenge concen-

8. NewhouseML, Tagg B, Pockock SJ, McEwan AC. An epidemiological study of workers producing enzyme washing powders. Lancet 1970;1:689. 9. PattersonR. Zeiss CR. Roberts M, Pruzansky JJ, Wolonsky P, Chacon R. Human antihapten antibodies in trimellitic anhydride inhalation reactions. lmmunoglobulin classesof antitrimellitic anhydride antibodies and hapten inhibition studies. J Clin Invest 1978;62:97I. 10. Davies RJ, Butcher BT, O’Neil CE, Salvaggio JE. The in vitro effect of toluene diisocyanateon lymphocyte cyclic adenosine monophosphateproductionby isoproterenol,prostaglandinand histamine-a possible mode of asthma. J ALLERGYCLINJMMUNOL1977;60:233. 11. Butcher BT, O’Neil CE, Reed MA, Salvaggio JE, Weill H. Developmentand lossof toluenediisocyanate(TDI) reactivity: immunologic, pharmacologic,and provocative inhalation challenge studies. J ALLERGYCLINIMMUNOL1982;70:231. 12. Parrott JL, Hebert R, Saindelle A, Ruff F. Platinum and platinosis:allergy andhistaminereleasedue to someplatinum salts. Arch Environ Health 1969;19:685. 13. Weiner A. Bronchial asthma due to the organic phosphate insecticides. Ann Allergy 1961;19:397. 14. Chan-Yeung M. Immunologic and nonimmunologic mechanisms in asthma due to western red cedar (Thu@pficura). J ALLERCYCLINIMMUNOL~~~~;~~:~~. 15. Butcher BT, Mapp C, Reed MA, O’Neill CE, Salvaggio JE. Evidence for carrier specificity of IgE antibodies detectedby isocyanate-proteinconjugates in sera of isocyanate sensitive individuals. J ALLERGYCLINIMMUNOL1982;69(suppl):123. 16. Zeiss CR, Levitz D. Chacon R, Wolonsky P, Patterson R, Pruzansky JJ. Quantitation and new antigenic determinant specificity of antibodies induced by inhalation of trimellitic anhydride in man. Int Arch Allergy Appl Immunol 1980; 61:380. 17. Roberts AE. Platinosis-a five year study of the effects of soluble platinum salts on employees in a platinum laboratory and refinary. Arch Ind Hyg 1951;4:549. 18. Lan S, Wong R, Yeung M. Nonspecific bronchial reactivity in occupational asthma. J ALLERGYCLINIMMUNOL~~~O;~~:~~~. 19. Szentivanyi A. The beta adrenergic theory of the atopic abnormality in bronchial asthma. J ALLERGYCLIN IMMLJNOL 1968;42:203. 20. Empey DW, Laitinen LA, Jacobs L, Gold WM. Nadel JA. Mechanisms of bronchial hyperreactivity in normal subjects after respiratory tract infection. Am Rev Respir Dis 1976; 113:131. 21. McFaddenER. Pathogenesisof asthma. J ALLERGYCLINIMMIJNOL1984;73:413. 22. Diem JE, JonesRN, Hendrick DJ, et al. Five year longitudinal study of workers employed in a new toluenediisocyanatemanufacturing plant. Am Rev Respir Dis 1982;126:493. 23. Burge PS, O’Brien TM. Harries MG. Peak flow rate records in the diagnosis of occupational asthma due to colophony. Thorax 1979;34:308.

tration. Increasing. tenfold stronger concentrations are administered every 30 minutes until a 20% decrease of forced expiratory volume occurs or until the strongest concentration is used. When delayed reactionsare suspected,this protocol may need to be modified to avoid a severe reaction. It is

important in both types of challenge to perform placebo exposures, because in someinstanceschallenge with saline solution or distilled water causes significant declines in

timed vital capacity. It is alsoimportant that, wherepossible, the challengesubjectnot be awareof whetherthe testreagent or placebo is being administered, so that invalid respiratory function changes do not occur.

TREATMENT The treatment of choice for occupational asthmais prevention (i.e., removal of the individual from further ex-

posure to the offending agent). When this is not possible, the worker should be counselled regarding the seriousrisks of further exposureand encouragedto relocateto other areas of the factory. When symptoms have developed, treatment is the same as that used for conventional bronchial asthma (i.e., theophylline derivatives, B, agonists, cromolyn, and

inhaled or systemic corticosteroids when needed). INDUSTRIAL HYGIENE Modem industrial hygiene and engineering practices are continually improving the environment in which individuals spendtheir work time, and it is incumbent on manufacturers to ensureconstantcontrol and monitoring of the atmospheric levels of simple chemicals and related agents. Even so, no technology can completely protect the worker from spills or mechanical failures that result in exposure to high concentrations of the chemical, which may be the event responsiblefor inducing disease.**Even where exposuresare kept at low levels, well within governmentmandatedlimits, individuals

who have already developed occupational

asthmaarenot protected,andmay experienceserious,sometimes life-threatening, asthmatic reactions.*’ REFERENCES 1. Clayton GD. Introduction. In: The industrial environmentits evaluation and control. Washington,DC: US Government Printing Office, 1973:1-5. 2. Ramazzini B. De Morbis Artificium Diatriba [Diseases of Workers]. 1913. Translatedby Wright WC. Chicago: University of Chicago Press, 1940. 3. Salvaggio JE. Occupational asthma, overview and mechanisms. J ALLERGYCLMIMUIMUNOL 1979;64:646.

1977;60:96.

Salvaggio et al.

J. ALLERGY

24. Butcher BT, Hammad YY, Hendrick DJ. Occational asthma: identification of the agent. In: Gee B, ed. Occupational lung disease. New York: Churchill Livingstone Inc, 1984: 111-40. 25. Pepys J, Hutchcroft BJ. Bronchial provocation tests in etiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975;112:289. 26. Guidelines for bronchial inhalation challenges with pharma-

CLIN. IMMUNOL. NOVEMBER 1986

cologic and antigenic agents. Am Thorac Sot News, Spring 1980:11-19. 27. Salvaggio JE, ed. Occupational and environmental respiratory disease. In: Patterson R, Task Force Chairman. NIAID Task Force report: asthma and other allergic disease. US Dept of Health, Education, and Welfare, NIH Publication No. 79-387, May 1979.

Occupational allergic lung disease caused by organic agents Jack Pepys, M.D., F.R.C.P., F.R.C.Path. London, United Kingdom

In the United Kingdom about 20% of workers in various occupations have asthma and about 10% of farmers have extrinsic allergic alveolitis.‘” A list of occupational causal agents, although incomplete, is presentedin Table I7 FACTORS INFLUENCING PATTERNS OF ALLERGIC RESPlRATORY DISEASE Immunologic factors Populationsclassified immunologically asatopic and nonatopic according to prick or radioallergosorbent(RAST) test results with a small battery of relevant common allergens responddifferently to exposureto a numberof occupational organic allergens. Even when symptomfree, the atopic subjects are more likely to becomesensitized, for example, to experimental animals,4 bacterial enzymes,* coffee bean dusts,’ insects such as locusts,” and fumes of pyrolyzed pine resin (colophony).3 Respiratory reactions The inhaled organic allergens can causebronchial, asthmatic reactions in atopic and nonatopic subjects”; peribronchial reactions,.that is, pulmonary eosinophilia, especially to Aspergillus fumigatus, in atopic subjects12;and bronchioloalveolar reactions primarily in nonatopic subjects.” These groups of subjects show various immediate and nonimmediatetypes of reactions. Asthmatic reactions. Asthmatic reactions can be immediate, nonimmediate,or combinedas shown by provocation tests and clinical histories. The immediate reactions are mediatedby IgE antibodies and can be blocked by sodium cromoglycate” and also by IgG-STS antibodies, but without such a blocking effect. I4Immediatereactionsto provocation tests, in contrast to nonimmediate ones, are not followed by increasesin bronchial reactivity.” From the Department of Clinical Immunology, University London. Reprint requests: Jack Pepys, M.D., F.R.C.P., F.R.C.Path., Rmcroft Ave., London NW3 7PE, United Kingdom.

1058

of 36

Studies of IgG, antibodies showed that dual bronchial reactions were elicited by provocation tests in patients with both IgE and IgG., antibodies. In contrast, immediate reactions were elicited in those with only IgE antibody and nonimmediate reactions in those with IgG, antibody alone.I6 I7Patientswith IgE and IgG, antibodieshad severe, anaphylactic reactions to egg, whereasthose with only IgE antibody did not react in this way.‘* Nonimmediateasthmaticreactionscan also be elicited by the use of larger challenge dosesin subjectswho apparently have only IgE antibody.@Recurrent nocturnal asthmatic reactions after very limited allergen provocation tests may or may not be accompaniedon the day of the bronchial test by immediate or late reactions after several hours.“. *O.I1 Recurrent reactions are closely related to circadian variations favoring asthmaticresponses,suchasincreasedplasma histamine and decreasedcatecholaminelevels. At the present time there is no evidence to suggest that a particular allergic mechanism is itself responsible for the nocturnal reaction. Pulmonary eosinophilia. In patients with pulmonary eosinophilia, usually those with asthma as seen in allergic bronchopulmonary aspergillosis, both type I allergy mediatedby IgE antibodiesandclassictype III allergy mediated by precipitins are present. They are demonstrableby skin and bronchial tests that elicit dual reactions. IgG-STS antibodies have also been found in one third of the cases.I*.** Extrinsic allergic alveolitis. Extrinsic allergic alveolitis is primarily a disorder of nonatopic subjectsin whom exposureto large amountsof organic allergenshas resulted in the induction of precipitins. Micropolyspora faeni in moldy hay was the first etiologic agent identified, and the list continues to grow (Table II).*3.24The reactionselicited clinically or by bronchial provocation tests are nonimmediate, appearing after several hours. They are also readily blocked by corticosteroids. These findings are suggestiveof a type III reaction, and both IgG-STS antibodies and precipitins can mediate this reaction.25A number of the allergens also activate complementby the alternative pathway.26