- Email: [email protected]
Occupational allergic lung disease caused by organic agents
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
VOLUME NUMBER
Occupational
78 5. PART 2
TABLE I. Occupational
organic
allergic
Animal sources Birds Feathers,excreta Insects Bees Carmine (dye extracted from Coccus cactus) Locusts Mites/weevils Silkworms Mammals Danders, urinary proteins Pancreaticenzyme supplements Seafood Crabs, oysters; Prawns Vegetablesources Bromelain (pineapple enzyme) Castor oil bean Coffee (green coffee dust) Colophony (pine resin) Cotton, flax, hemp dust Devil’s tongue root Grain/flour (barley, corn, oats, rye, wheat) Gums (acacia, arabic, karaya) Mushrooms Papain (proteolytic enzyme) Psyllium Soya bean oil Soya bean flour Tea Tobacco woods African zebra wood Californian redwood Central American walnut lroko Tanganyika aningre Quillaja bark Westernred cedar *Indicatesprobablemechanism. t Indicatespostulatedmechanism.
1059
allergens Possible
Allergen
lung disease
Occupational
environment
Immunologic
Poultry industry; upholstery and bedding workers; pet shop workers
+*
Beekeepers Clothing manufacture
+ ?t
Pesticideresearch Domestics;cleaners, grain handlers Silk producers
+ + ?I
Veterinarians;laboratory workers
+
Distributors of theseenzymesused in the managementof cystic fibrosis
c
mechanism
Pharmacologic
+
Crab processors;culture oyster workers; Prawn processors
+
Pineappleprocessors;meat tenderizers
+
Vegetableoil manufacture;dock workers Plantation workers; coffee processors Tin-lead solderers(used as flux); hot-melt glue workers Textile workers Producersof the Japanesefood, Konnyaku Farmers;grain handlers; bakers
+ + ?
?
9
17
+ +
?
Printing industry
+
Workersprocessingmushroom soup powder Pharmaceuticindustry; meat tenderizer
+
Producersof the laxative Metamucil This is an additive in polyvinylchloride and has been shown to be contributory to “meat wrappers asthma” Food industry Plantation workers; tea packagers Tobacco harvesters;cigarette and tobacco workers
? ?
Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners,
lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers
Other
+
3
?
+ ?t + + + ? ? ? + +
? Continued
1060 Pepys
J. ALLERGY
CLIN. IMMUNOL. NOVEMBER 1986
TABLE I -Continued Possible Allergen
Microbial sources Enzymes from Bacillus subtilis
Mold contaminants Penicillium casei Tricophyton rubrum
Pharmaceuticals Penicillins
Occupational
environment
Immunologic
Enzyme detergentindustry; brewing, baking, silk and leather industries Many industries, especially farmers, grain workers Cheesewashers Chiropodists
+
Antibiotic manufacture
?t
Histologic featuresarecompatiblewith a type IV reaction, but type IV skin test reactionshave seldombeenelicited to date. The pathology of the diseaseis granulomatouspneumonitis, consisting of patchy bronchiolar and alveolar wall infiltration with epithelioid, lymphoid, and giant cells, the latter with characteristiccytoplasmic clefts. Granulomaformation is a feature of type IV allergy but can also be produced by insoluble antigen-antibody complexesZ7and by particulate antigens.28 The clinical findings consist of dyspnea (which may be very severe),fever, malaise, and myalgia, and frequently a rapid loss of weight. There is a restrictive ventilatory defect and a decreasein gas exchange and lung compliance. Radiographsmay show micronodular to nodular shadowing of the upper lobes and, if progressive, fibrosis and cystic changesappear. The circumstancesof exposure play an important part in its production. Intensive exposure is usually necessaryfor sensitizationof nonatopic individuals. Intermittent exposure of sensitized subjects is followed by acute episodesafter several hours. Regular exposure results in an insidiously developing disease,whereasbronchial challengeunder controlled conditions elicits typical acute episodes. It is not uncommonfor subjectswho have beenexposed,apparently without symptomsand evenfor very long periods, to develop the diseasewhen reexposedafter a short or even lengthy period of nonexposure. ORGANIC ALLERGENS Control of occupational respiratory allergy dependson identification of the sourcesand the nature of the allergens (e.g., physical features such as size and chemical, biochemical, and biologic properties). Vegetable dusts. Aerobiologic studies using Cascadeimpactorsfor microscopicexamination and the Andersensampler (Andersen Samplers, Inc., Atlanta, Ga.) for cultural identification can provide detailed and quantitative analyses of the ambientand inspired air.29Nonviable or nonculturable spores are no less important allergens. The hazards arise mainly from the handling of moldy as opposed to clean grain, straw, hay, etc.‘” For example, actinomycetesand bacteria (lob/m’) in the air surrounding undisturbed moist
mechanism Pharmacologic
Other
? + +
barley number 6.92 but rise to 1800 during loading; total fungi increasefrom 1 to more than 1000.*pThis high spore count sensitizes nonatopic individuals, producing allergic alveolitis. Investigating the presenceof precipitins against the suspectedagent would be especially useful, but this requires clinical or provocation test confirmation. On the other hand, atopic individuals can be sensitized by only small amounts of organic allergens. Many of the organic particles and particularly the spores of thermophilic actinomycetessuch as Micropolyspora faeni (Faenia rectivirg&z) are 2 to 4 pm in diameter, a size conducive for penetration to and retention in the peripheral gas-exhanging parts of the lung. Grain and storage dusts. Bronchial disorders causedby grain dust appear to be related to cigarette smoking, and more problems arise from inhalation of flour.’ Among the flora of vegetabledusts causing respiratory allergy are the storagemites.“. ” Wood dust products. The sawdust of Westernred cedar causesasthmain about 5% of workersJ3and this condition provides an excellent study model. Provocation tests with the active allergen in the wood dust, plicatic acid (molecular weight 400 daltons), elicited immediate, dual, or isolated late reactions in different subjects.“’ Bronchial hyperreactivity to nonspecific agents increased after late asthmatic reactionswere elicited. RAST test results demonstratedthat specific IgE antibodies were presentin 40% of the patients. Bronchial hyperreactivity tendsto disappearon cessationof exposure, indicating that this symptom is related to exposure, sensitization, and disease.‘4In addition to this immunologic evidence,plicatic acid has nonspecific properties in that it is a histamine liberator” and activates the classic complementpathway.‘” Wider implications for the role of the low molecularweight organic acid plicatic acid in Westernred cedar are shown by the allergenicity of abietic acid in pine resin (colophony) in the production of asthma in 20% of workers using this material as a soft solder in the electronics industry” The fumes of the pyrolyzed resin are potently allergenic in those subjects in whom vigorous immediate, nonimmediate,and dual reactionscan beelicited by inhaling as little as one to three breaths of fumes such as that en-
VOLUME NUMBER
Occupational allergic lung disease
78 5, PART 2
1061
TABLE II. Causes of extrinsic (allergic) alveolitis Disease
Farmers’ lung Bagassosis Mushroom workers’ lung Ventilation pneumonitis Humidifier fever Maple bark pneumonitis Sequoiosis Wood-pulp pneumonitis Suberosis Malt worker’s lung Cheeseworker’s lung Wheat weevil lung Bird Breeder’s (fanciers) lung Rat handler’s lung Silk culturer’s lung
Source of antigen
Moldy hay, grain, etc. Moldy sugar cane, bagasse Mushroom compost Heating and air conditioning systems Humidification systems Moldy maple bark Moldy redwood sawdust Moldy wood dust Moldy oak bark Moldy barley Molds or mites on cheese Infested wheat Pigeon, budgerigar, etc. excreta Rat urine Silk worms
countered at work. Some affected workers develop asthmatic reactionsin pine forests, presumablyfrom the fragrant resin. It is probable that other types of wood and wood products causesimilar reactions. Animal allergens. It is increasingly recognizedthat there are large amounts of allergens in the excreta of animals. For example, the urine of rats, mice, and other laboratory and farm animals contain potent allergens.‘.” Such knowledge makesit possible to control the main sourceof alleygens for a particular species. Insect allergens. Allergens in the excreta of mite species (e.g., Dermatophagoides sp.yRneed to be studied further in regard to sources of antigen and may lead to more informative test materials. Fungal allergens. A clinical syndromeof humidifier fever with most of the featuresof extrinsic allergic alveolitis can result from the inhalation of aerosolsof contaminatedwater used for humidification purposes.X9-42 The suspectedcause is free-living amoebasthat flourish in contaminatedwater.4’ Humidifier fever and ventilation pneumonitis attributed to thermophilic actinomycete spores44are examples of oftenunrecognized sources of organic antigens in occupational and other environments. CONCLUSION Investigation of occupational respiratory allergy caused by organic and other agentsrequires clinical, ancillary, and laboratory personnel with proper training in the field for effective treatment,prevention, and control. Efforts require supportfrom regulatory authorities who determinethe availability of clinical and laboratory resources. REFERENCES 1. DaviesRJ, Blainey AD, Pepys J. Occupational asthma. In: MiddletonJr E, ReedCE, Ellis EF, eds.Allergy: principles andpractice.St Louis:The CV MosbyCo, 1983:1037. 2. Keskinen H. Epidermiology of occupational lung diseases:
asthmain allergicalveolitis.In: KerrJW,Ganderson MA, eds.
Causal agent
M. faeni, F. rectivirgula Thermoactinomyces sacchari Actinobifida dichotomica M. faeni Acanthamoeba spp. etc Cryptostroma corticale Aureobasidium pullulans Alternaria sp . Penicillium frequentans Aspergillus clavatus, A. fumigatus P. casei, Acarus siro Sitophilus granarius
Serum and excretory proteins Serum and urinary proteins Larval urine
Proceedingsof the Eleventh International Congressof Allergology and Clinical Immunology. London: Macmillan Press Ltd, 1983:403. 3. Burge PS. Occupational asthma, rhinitis and alveolitis due to Colophony. In: PepysJ, ed. Clinics in immunologyandallergy. Occupationalrespiratory allergy. London:WB Saunders& Co, 198455. 4. Longbottom JL. Occupationalallergy due to animai allergens. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB Saunders Co, 1984:23. 5. Cuthbert OD, Jeffrey IG, McNeil1 HB, WoodJ. ToppingMD. Barn allergy among Scottish farmers. Clin Allergy 1984; 14:197. 6. Grant IWB, Blyth W, WardropVE, GordonRM. PearonsJCG, Mair A. Prevalenceof farmerslung in Scotland:a pilot survey. Br Med J 1972;1:530. 7. Hendrick DJ, Butcher BT. Connolly MJ. Occupationalasthma due to allergens of organic origin. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB SaundersCo, 1984:37. 8. Pepys J. Types of allergic reaction. Clin Allergy 1973:3:491. 9. JonesRN, Hughes JM, Lehrer SB, Butcher BT, Glindmeyer HW, Diem JE, Hammand YY, Salraggis J, Weill H. Lung function consequencesof exposurein hypersensitivity to green coffee beans. Am Rev Respir Dis 1982;125:199. 10. Burge PS, EdgeG, O’Brien IM, Harris MG, Hawkins R, Pepys J. Occupational asthmain a researchcentre breeding locusts. Clin Allergy 1980;10:355. 11. PepysJ, Hutchcroft BJ. Bronchial provocationtestsinetiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829. 12. McCarthy DS, Pepys 3. Allergic broncho-pulmonary aspergillosis. Clinical immunology: Pt 1: clinical features;Pt 2: skin, nasal and bronchial tests. Clin Allergy 1971;1:261,415. 13. Pepys J, JenkinsPA. Precipitin (F.L.H.) test in farmers lung. Thorax 1965;20:21. 14. Bryant DH, Bums MW, Lazarus L. New type of allergic asthmadue to IgG “reaginic” antibody. Br Med J 1973;4:589. 15. Cockcroft DW, Ruffin RE, Dolovich J. Hargreave FE. Allergen-inducedincreasein non-allergic bronchial reactivity. Clin Allergy 1977;7:503.
1062
Pepys
16. Gwynn CM, Almosawi T, StanworthDR. Clinical associations with serum allergen-specific IgG, antibodies. Clin Allergy 1982;12:459. 17. Gwynn CM, Ingram J, Almosawi T, StanworthDR. Bronchial provocation tests in atopic patients with allergen-specific IgE antibodies. Lancet 1982;1:254. 18. Davies RJ, Pepys J. Egg allergy, influenza vaccine and immunoglobulin E antibody. J ALLERGYCLIN IMMUNOL 1975; 56:417. 19. Hargreave FE, Dolovich J, RobertsonDG, Kerigan AT. The late asthmaticresponses.Can Med Assoc J 1976;110:415. 20. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthmaafter exposureto grain dust. Am Rev Respir Dis 1976; 114:1011. 21. Newman-Taylor AJ, Davies RJ, Hendrick DJ, Pepys J. Recurrent nocturnal asthmaticreactionsto bronchial provocation tests. Clin Allergy 1979;9:213. 22. PepysJ, ParishWE, Cromwell 0, HughesEA. Passivetransfer in man and the monkey of Type I allergy due to heat labile and heat stable antibody to complex salts of platinum. Clin Allergy 1979;9:99. 23. Pepys J. Hypersensitivity diseasesof the lungs due to fungi and organic dusts. Monogr Allergy 1969;4:71. 24. Pepys J, JenkinsRA, FestensteinGN, Gregory PH, Lacey M, Skinner FA. Farmers lung. Thermophilic actinomycetis as a sourceof “farmers lung hay” antigen. Lancet 1%3;2:607. 25. WarrenCPW, Chemiack RM, Tse K. Extrinsic allergic alveolitis from bird exposure. Clin Allergy 1977;7:303. 26. Edwards JH. A quantitative study on the activation of the alternative pathway of complement by mouldy hay dust and thermaphilic actinomycetes.Clin Allergy 1976;6:19. 27. Spector WG, Heesom W. The production of granulomataby antigen-antibody complexes. J Path Bact 1969;98:31. 28. Boros DL, Warren KF. Bentonite granuloma characterisation of a model system for infection and foreign body granulomatous infiltration using soluble mycobacterial, histoplasma and schistosomaantigens. Immunology 1973;24:51I. 29. Lacey J, Pepys J, Cross T. Actinomycete and fungus spores in air as respiratory allergens. In: Shapton DA, Board RG, eds. Safety in microbiology. London: Academic Press, 1972:151. 30. Molina C. Occupationalextrinsic allergic alveolitis. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB SaundersCo, 1984:173.
J. ALLERGY
CLIN. IMMUNOL. NOVEMBER 1986
31. Cuthbert OD, Brostoff J, Wrath DG, Brighton WD. Barn allergy: asthma and rhinitis due to storage mites. Clin Allergy 1979;9:229. 32. Cuthbert OD. The incidence and causative factors of atopic asthma and rhinitis in an Orkney farming community. Clin Allergy 1981;11:217. 33. Chan-Yeung M. Immunologic and non-immunologic mechanisms in asthma due to Westernred cedar (Thuju plicatu). J ALLERGYCLINIMMUNOL1982;70:32. 34. Chan-YeungM, Lam S, Koemer S. Clinical featuresand natural history of occupational asthmadue to Westernred cedar (Thuju plicata). Am J Med 1982;72:411. 35. Evans E, Nicholls PJ. Histamine releaseby Westernred cedar (Thuja plicatu) from lung tissue in-vitro. Br J Ind Med 1974; 31:28. 36. Chan-YeungM, Giclas PC, Heuson PM. Activation of complement by plicatic acid, the chemical compoundresponsible for asthmadue to Westernred cedar.J ALLERGY CLINIMMUNOL 1980;65:333.
37. Newman-Taylor AJ, Longbottom JL, Pepys J. Respiratory allergy to urinary proteins of rats and mice. Lancet 1977;2:847. 38. ChapmanMD, Tovey ER, Wilkins SR, Platts-Mills TAE. The allergensresponsiblefor housedust mite allergy. In: Kerr JW, GanderstonMA, eds. Proceedingsof the EleventhInternational Congressof Allergology andImmunology. London: Macmillan PressLtd, 1983:531. 39. Pickering CAC, Moore WKS, Lacey J, Holford-StevensVC, Pepys J. Investigation of a respiratory diseaseassociatedwith an air-conditioning system. Clin Allergy 1976;6:109. 40. Friend JAR, Gaddie J, Palmer KNV, Pickering CAC, Pepys J. Extrinsic allergic alveolitis and contaminatedcooling water in a factory machine. Lance11977;1:297. 41. EdwardsJH. Microbial and immunological investigations and remedial action after an outbreak of humidifier fever. Br J Ind Med 1980;37:55. 42. Edwards JH, Cockcroft A. Inhalation challenge in humidifier fever. Clin Allergy 198I ; I I :227. 43. Edwards JH, Griffiths AJ, Mullins J. Protozoa as sourcesof antigen in “humidifier fever”. Nature (Land) 1976;264:438. 44. Fink JN, BanaszakEF, Thiede WH, Barbotiak JJ. Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med 1971;74:80.
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
VOLUME NUMBER
Occupational
78 5. PART 2
TABLE I. Occupational
organic
allergic
Animal sources Birds Feathers,excreta Insects Bees Carmine (dye extracted from Coccus cactus) Locusts Mites/weevils Silkworms Mammals Danders, urinary proteins Pancreaticenzyme supplements Seafood Crabs, oysters; Prawns Vegetablesources Bromelain (pineapple enzyme) Castor oil bean Coffee (green coffee dust) Colophony (pine resin) Cotton, flax, hemp dust Devil’s tongue root Grain/flour (barley, corn, oats, rye, wheat) Gums (acacia, arabic, karaya) Mushrooms Papain (proteolytic enzyme) Psyllium Soya bean oil Soya bean flour Tea Tobacco woods African zebra wood Californian redwood Central American walnut lroko Tanganyika aningre Quillaja bark Westernred cedar *Indicatesprobablemechanism. t Indicatespostulatedmechanism.
1059
allergens Possible
Allergen
lung disease
Occupational
environment
Immunologic
Poultry industry; upholstery and bedding workers; pet shop workers
+*
Beekeepers Clothing manufacture
+ ?t
Pesticideresearch Domestics;cleaners, grain handlers Silk producers
+ + ?I
Veterinarians;laboratory workers
+
Distributors of theseenzymesused in the managementof cystic fibrosis
c
mechanism
Pharmacologic
+
Crab processors;culture oyster workers; Prawn processors
+
Pineappleprocessors;meat tenderizers
+
Vegetableoil manufacture;dock workers Plantation workers; coffee processors Tin-lead solderers(used as flux); hot-melt glue workers Textile workers Producersof the Japanesefood, Konnyaku Farmers;grain handlers; bakers
+ + ?
?
9
17
+ +
?
Printing industry
+
Workersprocessingmushroom soup powder Pharmaceuticindustry; meat tenderizer
+
Producersof the laxative Metamucil This is an additive in polyvinylchloride and has been shown to be contributory to “meat wrappers asthma” Food industry Plantation workers; tea packagers Tobacco harvesters;cigarette and tobacco workers
? ?
Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners, Carpenters,joiners,
lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers lumberworkers
Other
+
3
?
+ ?t + + + ? ? ? + +
? Continued
1060 Pepys
J. ALLERGY
CLIN. IMMUNOL. NOVEMBER 1986
TABLE I -Continued Possible Allergen
Microbial sources Enzymes from Bacillus subtilis
Mold contaminants Penicillium casei Tricophyton rubrum
Pharmaceuticals Penicillins
Occupational
environment
Immunologic
Enzyme detergentindustry; brewing, baking, silk and leather industries Many industries, especially farmers, grain workers Cheesewashers Chiropodists
+
Antibiotic manufacture
?t
Histologic featuresarecompatiblewith a type IV reaction, but type IV skin test reactionshave seldombeenelicited to date. The pathology of the diseaseis granulomatouspneumonitis, consisting of patchy bronchiolar and alveolar wall infiltration with epithelioid, lymphoid, and giant cells, the latter with characteristiccytoplasmic clefts. Granulomaformation is a feature of type IV allergy but can also be produced by insoluble antigen-antibody complexesZ7and by particulate antigens.28 The clinical findings consist of dyspnea (which may be very severe),fever, malaise, and myalgia, and frequently a rapid loss of weight. There is a restrictive ventilatory defect and a decreasein gas exchange and lung compliance. Radiographsmay show micronodular to nodular shadowing of the upper lobes and, if progressive, fibrosis and cystic changesappear. The circumstancesof exposure play an important part in its production. Intensive exposure is usually necessaryfor sensitizationof nonatopic individuals. Intermittent exposure of sensitized subjects is followed by acute episodesafter several hours. Regular exposure results in an insidiously developing disease,whereasbronchial challengeunder controlled conditions elicits typical acute episodes. It is not uncommonfor subjectswho have beenexposed,apparently without symptomsand evenfor very long periods, to develop the diseasewhen reexposedafter a short or even lengthy period of nonexposure. ORGANIC ALLERGENS Control of occupational respiratory allergy dependson identification of the sourcesand the nature of the allergens (e.g., physical features such as size and chemical, biochemical, and biologic properties). Vegetable dusts. Aerobiologic studies using Cascadeimpactorsfor microscopicexamination and the Andersensampler (Andersen Samplers, Inc., Atlanta, Ga.) for cultural identification can provide detailed and quantitative analyses of the ambientand inspired air.29Nonviable or nonculturable spores are no less important allergens. The hazards arise mainly from the handling of moldy as opposed to clean grain, straw, hay, etc.‘” For example, actinomycetesand bacteria (lob/m’) in the air surrounding undisturbed moist
mechanism Pharmacologic
Other
? + +
barley number 6.92 but rise to 1800 during loading; total fungi increasefrom 1 to more than 1000.*pThis high spore count sensitizes nonatopic individuals, producing allergic alveolitis. Investigating the presenceof precipitins against the suspectedagent would be especially useful, but this requires clinical or provocation test confirmation. On the other hand, atopic individuals can be sensitized by only small amounts of organic allergens. Many of the organic particles and particularly the spores of thermophilic actinomycetessuch as Micropolyspora faeni (Faenia rectivirg&z) are 2 to 4 pm in diameter, a size conducive for penetration to and retention in the peripheral gas-exhanging parts of the lung. Grain and storage dusts. Bronchial disorders causedby grain dust appear to be related to cigarette smoking, and more problems arise from inhalation of flour.’ Among the flora of vegetabledusts causing respiratory allergy are the storagemites.“. ” Wood dust products. The sawdust of Westernred cedar causesasthmain about 5% of workersJ3and this condition provides an excellent study model. Provocation tests with the active allergen in the wood dust, plicatic acid (molecular weight 400 daltons), elicited immediate, dual, or isolated late reactions in different subjects.“’ Bronchial hyperreactivity to nonspecific agents increased after late asthmatic reactionswere elicited. RAST test results demonstratedthat specific IgE antibodies were presentin 40% of the patients. Bronchial hyperreactivity tendsto disappearon cessationof exposure, indicating that this symptom is related to exposure, sensitization, and disease.‘4In addition to this immunologic evidence,plicatic acid has nonspecific properties in that it is a histamine liberator” and activates the classic complementpathway.‘” Wider implications for the role of the low molecularweight organic acid plicatic acid in Westernred cedar are shown by the allergenicity of abietic acid in pine resin (colophony) in the production of asthma in 20% of workers using this material as a soft solder in the electronics industry” The fumes of the pyrolyzed resin are potently allergenic in those subjects in whom vigorous immediate, nonimmediate,and dual reactionscan beelicited by inhaling as little as one to three breaths of fumes such as that en-
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TABLE II. Causes of extrinsic (allergic) alveolitis Disease
Farmers’ lung Bagassosis Mushroom workers’ lung Ventilation pneumonitis Humidifier fever Maple bark pneumonitis Sequoiosis Wood-pulp pneumonitis Suberosis Malt worker’s lung Cheeseworker’s lung Wheat weevil lung Bird Breeder’s (fanciers) lung Rat handler’s lung Silk culturer’s lung
Source of antigen
Moldy hay, grain, etc. Moldy sugar cane, bagasse Mushroom compost Heating and air conditioning systems Humidification systems Moldy maple bark Moldy redwood sawdust Moldy wood dust Moldy oak bark Moldy barley Molds or mites on cheese Infested wheat Pigeon, budgerigar, etc. excreta Rat urine Silk worms
countered at work. Some affected workers develop asthmatic reactionsin pine forests, presumablyfrom the fragrant resin. It is probable that other types of wood and wood products causesimilar reactions. Animal allergens. It is increasingly recognizedthat there are large amounts of allergens in the excreta of animals. For example, the urine of rats, mice, and other laboratory and farm animals contain potent allergens.‘.” Such knowledge makesit possible to control the main sourceof alleygens for a particular species. Insect allergens. Allergens in the excreta of mite species (e.g., Dermatophagoides sp.yRneed to be studied further in regard to sources of antigen and may lead to more informative test materials. Fungal allergens. A clinical syndromeof humidifier fever with most of the featuresof extrinsic allergic alveolitis can result from the inhalation of aerosolsof contaminatedwater used for humidification purposes.X9-42 The suspectedcause is free-living amoebasthat flourish in contaminatedwater.4’ Humidifier fever and ventilation pneumonitis attributed to thermophilic actinomycete spores44are examples of oftenunrecognized sources of organic antigens in occupational and other environments. CONCLUSION Investigation of occupational respiratory allergy caused by organic and other agentsrequires clinical, ancillary, and laboratory personnel with proper training in the field for effective treatment,prevention, and control. Efforts require supportfrom regulatory authorities who determinethe availability of clinical and laboratory resources. REFERENCES 1. DaviesRJ, Blainey AD, Pepys J. Occupational asthma. In: MiddletonJr E, ReedCE, Ellis EF, eds.Allergy: principles andpractice.St Louis:The CV MosbyCo, 1983:1037. 2. Keskinen H. Epidermiology of occupational lung diseases:
asthmain allergicalveolitis.In: KerrJW,Ganderson MA, eds.
Causal agent
M. faeni, F. rectivirgula Thermoactinomyces sacchari Actinobifida dichotomica M. faeni Acanthamoeba spp. etc Cryptostroma corticale Aureobasidium pullulans Alternaria sp . Penicillium frequentans Aspergillus clavatus, A. fumigatus P. casei, Acarus siro Sitophilus granarius
Serum and excretory proteins Serum and urinary proteins Larval urine
Proceedingsof the Eleventh International Congressof Allergology and Clinical Immunology. London: Macmillan Press Ltd, 1983:403. 3. Burge PS. Occupational asthma, rhinitis and alveolitis due to Colophony. In: PepysJ, ed. Clinics in immunologyandallergy. Occupationalrespiratory allergy. London:WB Saunders& Co, 198455. 4. Longbottom JL. Occupationalallergy due to animai allergens. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB Saunders Co, 1984:23. 5. Cuthbert OD, Jeffrey IG, McNeil1 HB, WoodJ. ToppingMD. Barn allergy among Scottish farmers. Clin Allergy 1984; 14:197. 6. Grant IWB, Blyth W, WardropVE, GordonRM. PearonsJCG, Mair A. Prevalenceof farmerslung in Scotland:a pilot survey. Br Med J 1972;1:530. 7. Hendrick DJ, Butcher BT. Connolly MJ. Occupationalasthma due to allergens of organic origin. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB SaundersCo, 1984:37. 8. Pepys J. Types of allergic reaction. Clin Allergy 1973:3:491. 9. JonesRN, Hughes JM, Lehrer SB, Butcher BT, Glindmeyer HW, Diem JE, Hammand YY, Salraggis J, Weill H. Lung function consequencesof exposurein hypersensitivity to green coffee beans. Am Rev Respir Dis 1982;125:199. 10. Burge PS, EdgeG, O’Brien IM, Harris MG, Hawkins R, Pepys J. Occupational asthmain a researchcentre breeding locusts. Clin Allergy 1980;10:355. 11. PepysJ, Hutchcroft BJ. Bronchial provocationtestsinetiologic diagnosis and analysis of asthma. Am Rev Respir Dis 1975; 112:829. 12. McCarthy DS, Pepys 3. Allergic broncho-pulmonary aspergillosis. Clinical immunology: Pt 1: clinical features;Pt 2: skin, nasal and bronchial tests. Clin Allergy 1971;1:261,415. 13. Pepys J, JenkinsPA. Precipitin (F.L.H.) test in farmers lung. Thorax 1965;20:21. 14. Bryant DH, Bums MW, Lazarus L. New type of allergic asthmadue to IgG “reaginic” antibody. Br Med J 1973;4:589. 15. Cockcroft DW, Ruffin RE, Dolovich J. Hargreave FE. Allergen-inducedincreasein non-allergic bronchial reactivity. Clin Allergy 1977;7:503.
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16. Gwynn CM, Almosawi T, StanworthDR. Clinical associations with serum allergen-specific IgG, antibodies. Clin Allergy 1982;12:459. 17. Gwynn CM, Ingram J, Almosawi T, StanworthDR. Bronchial provocation tests in atopic patients with allergen-specific IgE antibodies. Lancet 1982;1:254. 18. Davies RJ, Pepys J. Egg allergy, influenza vaccine and immunoglobulin E antibody. J ALLERGYCLIN IMMUNOL 1975; 56:417. 19. Hargreave FE, Dolovich J, RobertsonDG, Kerigan AT. The late asthmaticresponses.Can Med Assoc J 1976;110:415. 20. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthmaafter exposureto grain dust. Am Rev Respir Dis 1976; 114:1011. 21. Newman-Taylor AJ, Davies RJ, Hendrick DJ, Pepys J. Recurrent nocturnal asthmaticreactionsto bronchial provocation tests. Clin Allergy 1979;9:213. 22. PepysJ, ParishWE, Cromwell 0, HughesEA. Passivetransfer in man and the monkey of Type I allergy due to heat labile and heat stable antibody to complex salts of platinum. Clin Allergy 1979;9:99. 23. Pepys J. Hypersensitivity diseasesof the lungs due to fungi and organic dusts. Monogr Allergy 1969;4:71. 24. Pepys J, JenkinsRA, FestensteinGN, Gregory PH, Lacey M, Skinner FA. Farmers lung. Thermophilic actinomycetis as a sourceof “farmers lung hay” antigen. Lancet 1%3;2:607. 25. WarrenCPW, Chemiack RM, Tse K. Extrinsic allergic alveolitis from bird exposure. Clin Allergy 1977;7:303. 26. Edwards JH. A quantitative study on the activation of the alternative pathway of complement by mouldy hay dust and thermaphilic actinomycetes.Clin Allergy 1976;6:19. 27. Spector WG, Heesom W. The production of granulomataby antigen-antibody complexes. J Path Bact 1969;98:31. 28. Boros DL, Warren KF. Bentonite granuloma characterisation of a model system for infection and foreign body granulomatous infiltration using soluble mycobacterial, histoplasma and schistosomaantigens. Immunology 1973;24:51I. 29. Lacey J, Pepys J, Cross T. Actinomycete and fungus spores in air as respiratory allergens. In: Shapton DA, Board RG, eds. Safety in microbiology. London: Academic Press, 1972:151. 30. Molina C. Occupationalextrinsic allergic alveolitis. In: Pepys J, ed. Clinics in immunology and allergy. Occupational respiratory allergy. London: WB SaundersCo, 1984:173.
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31. Cuthbert OD, Brostoff J, Wrath DG, Brighton WD. Barn allergy: asthma and rhinitis due to storage mites. Clin Allergy 1979;9:229. 32. Cuthbert OD. The incidence and causative factors of atopic asthma and rhinitis in an Orkney farming community. Clin Allergy 1981;11:217. 33. Chan-Yeung M. Immunologic and non-immunologic mechanisms in asthma due to Westernred cedar (Thuju plicatu). J ALLERGYCLINIMMUNOL1982;70:32. 34. Chan-YeungM, Lam S, Koemer S. Clinical featuresand natural history of occupational asthmadue to Westernred cedar (Thuju plicata). Am J Med 1982;72:411. 35. Evans E, Nicholls PJ. Histamine releaseby Westernred cedar (Thuja plicatu) from lung tissue in-vitro. Br J Ind Med 1974; 31:28. 36. Chan-YeungM, Giclas PC, Heuson PM. Activation of complement by plicatic acid, the chemical compoundresponsible for asthmadue to Westernred cedar.J ALLERGY CLINIMMUNOL 1980;65:333.
37. Newman-Taylor AJ, Longbottom JL, Pepys J. Respiratory allergy to urinary proteins of rats and mice. Lancet 1977;2:847. 38. ChapmanMD, Tovey ER, Wilkins SR, Platts-Mills TAE. The allergensresponsiblefor housedust mite allergy. In: Kerr JW, GanderstonMA, eds. Proceedingsof the EleventhInternational Congressof Allergology andImmunology. London: Macmillan PressLtd, 1983:531. 39. Pickering CAC, Moore WKS, Lacey J, Holford-StevensVC, Pepys J. Investigation of a respiratory diseaseassociatedwith an air-conditioning system. Clin Allergy 1976;6:109. 40. Friend JAR, Gaddie J, Palmer KNV, Pickering CAC, Pepys J. Extrinsic allergic alveolitis and contaminatedcooling water in a factory machine. Lance11977;1:297. 41. EdwardsJH. Microbial and immunological investigations and remedial action after an outbreak of humidifier fever. Br J Ind Med 1980;37:55. 42. Edwards JH, Cockcroft A. Inhalation challenge in humidifier fever. Clin Allergy 198I ; I I :227. 43. Edwards JH, Griffiths AJ, Mullins J. Protozoa as sourcesof antigen in “humidifier fever”. Nature (Land) 1976;264:438. 44. Fink JN, BanaszakEF, Thiede WH, Barbotiak JJ. Interstitial pneumonitis due to hypersensitivity to an organism contaminating a heating system. Ann Intern Med 1971;74:80.