Indoor allergens

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33.

34. 35.

36.

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38.

Smoking and atmospheric pollution

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Warrell DA, eds. Oxford textbook of medicine, ~016. Oxford: Oxford University Press, 1983:93-7. Huber TE, Joseph SW, Knoblock E, Redfeam PL, Karakawa JA. New environmental respiratory disease (Yokohama asthma). AMA Arch Ind Hyg 1954;10:399-408. Dawson KP, Allan .I, Fergusson DM. Asthma, air pollution and climate: a Christchurch study. NZ Med J 1983;96:165-7. Hackney JD, Thiede FC, Linn WS, et al. Experimental studies on human health effects of air pollutants. IV. Short term physiological and clinical effects. Arch Environ Health 1978; 33:176-81. Kerr HD, Kulle TJ, McIlhany ML, Swidersky P. Effects of nitrogen dioxide on pulmonary function in human subjects: an environmental chamber study. Environ Res 1979;19:392-404. Orehek J, Massari JP, Gayrard P, Grimaud C, Charpin J. Effect of short-term, low level nitrogen dioxide exposure on bronchial sensitivity of asthmatic subjects. Clin Invest 1976;57:301-7. Koenig JQ, Pierson WE, Frank R. Acute effects of sulphur dioxide plus sodium chloride aerosol on pulmonary function in asthmatic adolescents. Environ Res 1980;22:145.

39. Koenig JQ, Pierson WE, Horike M, Frank R. Bronchoconstrictor responses to sulphur dioxide plus sodium chloride droplets in allergic, non-asthmatic adolescents. J ALLERGY CLIN IMMUNOL 1982;69:339-44. 40. Golden JR, Nadel JA, Boushey HA. Bronchial hyperirritability in healthy subjects after exposure to ozone. Am Rev Respir Dis 1978;118:287-94. 41. Bates DV, Bell GM, Bumham CD, et al. Short term effects of ozone on the lung. J Appl Physiol 1972;32: 176-81. 42. Young WA, Shaw DB, Bates DV. Effect of low concentrations of ozone on pulmonary function in man. 1 Appl Physiol 1964;19:765-8. 43. Nagy L, Lee TH, Kay AB. Neutrophil chemotactic activity in antigen-induced late asthmatic reactions. N Engl J Med 1982;306:497-501. 44. Walters EH, O’Byme PM, Holtzman MJ, Nadel JA. The relationship between neutrophils and hyperresponsive airways. Thorax 1984;39:23OP.

Indoor allergens Henning Lowenstein, Ph.D., D-SC., Suzanne Grsvesen, Ph.D., Lisbeth Larsen, Ph.D., P. Lind, Ph.D., and Bmte Schwartz, Ph.D. Copenhagen,

Denmark

Housedust appearsto be one of the most important indoor allergens and is an extremely complex biological material. House dust includes human and animal hair and dander, mites, molds, textiles, food leftovers, bacteria, and decomposed material.ld A number of allergenic molecules have now beenisolatedandcorrespondingreagents,monospecific antibodies, and monoclonal antibodieshave beendeveloped for the determination of the distribution of these allergenic materials.5~” Knowledge about the allergenicity of materials derived from mites has been obtained principally by cultivation. Short-term cultivation of Dermatophagoides pteronyssinus in allergen-free containers and subsequentremoval of the animals yielded potent extracts of the remains.’ Excrement particlesobtainedfrom mite intestinesby microsurgerywere found highly allergenic in patients allergic to house dust.‘” Sieving techniques with larger yields of material have allowed moredetailed studieson allergensin culture fractions. The precise origin of these componentsis, however, more difficult to define, as mite-free culture fractions may contain secretions and fragments of disintegrated mite bodies besides the bulk of fecal particles. Independentobservations From the Protein Laboratory. Reprint requests: Henning Lowenstein, Ph.D., D.Sc., The Protein Laboratory, Sigurdsgade 34, DK-2200 Copenhagen N, Denmark.

in three laboratorieshave demonstratedthe presenceof major allergen P, (Dp 42 = Dpt 12) of D. pteronyssinus in the excrement/usedmedium fraction.‘. *. ‘I Small amounts of this allergen arealso found in intact mite bodies, probably as part of undelivered fecal material.2.I’ The powerful allergenicity of D. farinae excrement fraction has also been demonstrated.I*.I3 Among the four hitherto identified major or intermediate allergens, P, has the most clear associationwith fecal particles. The three other important allergens (Dp X, Dp Y, and Dp 23) exhibit different distribution patterns. An index of relative enrichment in excrementvs. mite body fraction would produce the following ranking: P, > Dp X > Dp Y > Dp 23.‘” The indoor ecological factors that determine the growth of housedust mites appearedfrom both cultivation and field studiesperformedon D. pteronyssinus and D. furinae. The population growth is largely dependenton air humidity and is fastest around 80% relative air humidity, whereas the temperature-within the range normally encounteredin human habitations-is of little influence.‘, Is Severalinvestigators have demonstratedthat the bed and mattress is the primary habitat for house dust mites.“.” However, when indoor humidity is high, mites may thrive more or less throughout the house in carp&s, furniture, and clothing. ” 1035

1036

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of

et al.

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dust samples

20

15

10

5

I ClC

n 102-

3.102

3.102

-103

3.103

3.103

104.

3.10”

-104

3.104

-105

>105

ng

Pl/

g dust

FIG. 1. Distribution of mite-allergenic materials in dust samples from 22 Danish homes (nonallergics). The level of mite contamination is given as nanograms P, (and the &responding molecules from D. farinae and D. microceras) and was measured by an ELISA technique.19 The limit of detection corresponded to 20 ng P,/gm dust.

Knowledge concerning the distribution of house dust mites in various regions hasbeenobtainedfrom acarologists who have used microscopic techniques for their investigations. Recently, allergologists have introduced various immunochemical methodsto detect the distribution and level of mite material within houses. Through a series of such investigations in western Europe and the United States, a greatvariation in the level of the various Dermatophagoides spp. appeared,reflecting both local and regional climatic differences. The absolutelevel of “mite infection” in houseshasbeen expressedas microgramP, (or the correspondingmolecules from D. farinae) determined by radioimmunoassaytechnique with polyclonal antibodies.I8The enzyme-linked immunosorbentassay(ELISA) with species-specificantibodies to P, (and equivalents) has also been used to determinethe amount of P, and correspondingD. farinae and D. microceras. ” Finally, counter-current immunoelectrophoresis (CUE) has been used currently for the detection of mites, the results of which have been presented as a titer.” A correlation exists between these methods and the number of mites. From these various investigations it appearsthat the level in the investigated homes of both patients with allergy and normal individuals varies between <20 and 100,000 ng P, (or the corresponding antigens from D. farinae and D. microcera) per gram of dust (Fig. 1). PETS The commonhouseholdpetscatsand dogsarethe animals that most often cause allergic reactions in the western societies. However, other animals, such as guinea pigs, hamsters, mice, and rats usedas pets or laboratory animals, and larger animals, such as cows and horses, cause allergic problems. Becauseof the detailed characterization of the antigensfrom thesesources,knowledge is increasing about the major allergenic molecules. This has madepossibleprecise estimation of these allergenic sourceswithin houses.

CLIN. IMMUNOL. NOVEMBER 1966

The keepingof pets is very commonin Europeand North America. In the United Statesthere are approximately 100 million pets in a population of 250 million people. In Sweden, an epidemiologic study based on all school children (n = 40,000) showedthat out of 38,000 nonasthmaticchildren, 52% had indoor furred pets.” Furthermore, because horseriding and animal care are very common among children, 25% of the children ride or have contact with animals in barns and stables,thus giving rise to a certain amount of this allergenic material within their homes.Among children with asthma who claim no allergy to dander, the actual incidence of pet keeping is higher (55%) than that among healthy children. Significant amountsof dog allergenshave also beenfound in dust samplesfrom homesin which dogshave never been kept. Thus dog allergy may possibly be induced without direct exposure to dogs.2Z Some rodents, especially guinea pigs and hamsters,are used as indoor pets and contribute significantly to the allergenic exposure within homes. Likewise, mice and rats, either kept aspetsor becauseof their great numbersin some regions, and birds may contribute to allergenic exposure.” The major source of allergenic material from cat, dog, horse, and cow is dander.z4Twelve allergenic moleculesof cat origin have been identified. All were presentin dander; albumin and Ag 8 were presentin serum;the major allergen (cat Ag l), albumin, and five others were also present in saliva; and, with three exceptions, these latter compounds were also in urine. 25Only the serum-specificallergenswere shown to be partially identical to antigens of dog origin.24 Most probably, the major allergen, cat Ag 1, originates from saliva and other glandular secretions,26but the ratio cat Ag l/cat albumin is higher in dander than in saliva.‘4 Eleven allergenic molecules were detectedin dog dander material. Several of these antigens (albumin, dog immunoglobulin, and Ag 6) were present in serum, whereas the strongest IgE-binding molecules were not.24As for cat saliva, dog saliva has also been shown to be a potent source of allergens*’ and some allergenic activities have been determined in urine. In cow dander, eleven IgE-binding antigens have been detected.The three most important ones are also presentin saliva and urine.** In the case of horse dander, the three major allergenswere also presentin urine, but not in serum. In the rodents, the major sourceof allergens seemsto be urine.29In guinea pigs, mice, and rats the major urinary allergenic molecules were not detectablein serum.29In addition to the urinary allergens, danderfrom guinea pigs and rats contained other allergenic molecules.29However, as relates to cats, dogs, cows, horses, and rodents, no extra allergenic molecules that were nut in dander have been detectedin saliva, serum, or urine. The presence of pet-derived allergenic material is of course independent of environmental factors such as humidity, temperature, altitude, or the quality of buildings, except in casesin which the building’s insulation was made partially with hair from various animals, or in which furniture, carpets, and so forth are made of unmanufactured materialsthat releaseallergenic substances.28 The major fac-

VOlUME NUMBER

Indoor

76 5, PART 2

( Number

Colony counts/agar

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allergens

1037

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3634. 32, 30. 28.

26* 24. 22.

20. 18% 16, 14. 12*

0

2 102

a

32 lc?

128 10’

512

Titer (Cc%)

ng Cat Agl 105 /g dust

4 FIG. 2. Distribution of cat allergenic material in dust samples from allergic patients’ homes. In 1018 dust samples analyzed by means of CCIE,a cat allergens were found in 46%. The limit of detection corresponded to 100 ng cat Ag l/gm dust.

tor of importance is the more or less thorough cleaning carried out within housesrelated to the material from pets, either derived directly in the houseor brought into the house from outside contact with pets. The immunochemical methods that have been used to determinethe content of allergensextractedfromhousedust are CCIE and ELISA. In both casesthe extracted material is analyzed by the use of species-specificrabbit antibodies raised against the various allergens (cat, dog, horse, cow, guinea pig, rat).” Results of the CCIE are reported as the highest twofold dilution titer of the dust sample that gives a positive result with an error of one titer step. In ELISA in which immunoabsorbedmonospecific antibodies against major allergens have been used, results can be expressed relative to absolute amounts of the purified major allergen (Fig. 2). By routine analyses,cat allergens were found in 54% of 1018 dust sampleswith a titer variation of 0 to 1024, corresponding to 100 to 10,000 ng cat Ag I per gram dust.” Routine analysesof 1077 dust samplesrevealed dog allergens in 63%. Because of the lack of completely purified major allergenic molecules from dog dander,results cannot be given in absolute amounts. These results illustrate that the amount of allergenic material may vary at least IOOOfold (Fig. 2). Similar data have been obtained for other animal danders, and in al) casesin which major allergens have been isolated it is possible to expressthe level of the major alIergen within the dust. However, at present we do not know the ratio betweenthe amountof specific allergenic material in dust and the correspondingamountin the indoor air. Furthermore, we do not know the limit or acceptable

50 -

2 -

25 lo %

JFMAMJJASOND FIG. 3. Ten years of investigation of the airborne mold flora studied by 20-minute exposure of open culture plates in Danish private homes (5325 rooms). The cumulated frequencies of the colony counts have been calculated and the 25%, 50%, and 75% are percentile depicted. The seasonal variation of the mold colony is reproducible. The “normal colony count” was determined based on the 50% percentile, to estimate the fungal contamination, regardless of season, that should serve as a guidetine for the clinician in renovation and other spore-reducing procedures for the patients.“”

level for sensitive patients within houses. However, such data may be derived and could be useful as an upper limit for public buildings. Such studies have been performedfor rodents, especially in animal research laboratories.29. 3” In thosecases,rat allergens per squaremeter were determined (ranging from 0.1 to 105 p,g). After an allergen elimination programthat included the introduction of new cleaning procedures, a significant fall was observed (range 0.1 to 60 pg). It is worth noting that the staff also felt that their indoor environment had improved. MOLDS In the literature, prevalencesof type 1 allergy to molds range from 2% to 30% of an allergic population.3’ The discrepanciesmay be explained partly by the variable quality of the extractsusedearlier, and partly by ignoranceof molds as a theoretic factor in respiratory allergies. The prevalence of type 3 allergy evoked by microorganismsis essentially unknown. Qpe I allergy to mold allergens is not a special featureof allergy, but affectspatients with atopic disposition like the other common allergens do. Molds may be divided into unavoidable (outdoor) and

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et al.

avoidable (indoor) sources. The aim of detection of both growths is twofold: (1) to take different precautions, and (2) to establish a fungal allergen avoidance. It is essential to stress that molds, like the real plants, make specific demands on. the environment for optimal growth. Climatic factors such as temperature and humidity, as well as the vegetation, influence the composition of the mold flora. The molds that cause type 1 allergy may be present in great amounts in the air both outdoors and indoors.32.33These are Cladosporium, Alternaria, Penicillium, and Aspergillus. Mucor, Aureobasidium, and Botrytis are also considered important allergenic microfungi.‘4. 35The indoor environment naturally changes much more than the outdoor climate. As a result, special ecological niches can be created, with the occurrence of molds other than the ones dominating outdoors, resulting in specific sensitization of

the patients. Very little is known about the distribution of allergenic molecules within molds-especially the allergenically most which involves Alternaria, important fungi Imperfecti, Cladosporium, and Aspergillus. From air sampling of mold parts, it is known that the spores comprise >90% of the particles of the relevant size, and it has been shown recently in a study of Alternaria that the spores contain several distinct allergens and antigens as compared with the mycelium.36. 37It was also shown that the content of the major allergen Alt-1”. 38could be higher in the mycelium than in the spores. Studies performed in patients indicated sporespecific reactions, as did a RAST inhibition experiment.” It was concluded that mycelium may contain many of the same allergenic materials as the spores, but that some sporespecific allergen also existed. In contrast, in a study on Aspergillus the highest allergenic activities by various immunochemical techniques were found for the mycelium fraction.)’ At present no knowledge about the actual position of the major allergenic molecules within the molds is available. In Denmark, indoor mold surveys based on microscopic techniques have been an important supplement to the clinical

investigations.N43Demonstration and identification of indoor molds may serve various purposes. In general they give an idea of the specific exposition to the different mold genera. Seasonal variation with peaks in late summer and autumn (with the exception of Penicillium, which is an allyear mold) was demonstrated (Fig. 3). Fungal growth encountered indoors is often a result of constructive faults in the house, such as poor insulation or poor ventilation. But a certain relationship between the outdoor vegetation of plants (the growth season) can be demonstrated.‘* The level of allergenic molecules in mold within houses has not yet been detected by immunochemical methods, but from the range of mold spores found per cubic meter (1 to lOOO), the figure can be roughly estimated. CONCLUSION Humans are exposed to many antigenic components that give rise to allergic reactions. Outdoor allergens are mainly

J. ALLERGY

CLIN. IMMUNOL. NOVEMBER 1986

determined by climatic and local factors, and in many parts of the world daily forecasting of results from pollen and spore counts as well as review of the season now occur. Such data are tremendously useful for the prediction of allergic reactions. The indoor allergens, on the other hand, are mainly influenced by the indoor climate, by the inhabitants themselves, and by the physical activity of inhabitants within. Through manipulation of these factors, the exposition of some of the indoor allergens can be prevented. These data may in the future be used for defining a limit of acceptable content of indoor allergens-data that can be used to prevent patients from developing allergic diseases to indoor allergens. REFERENCES 1. C&en SD, WeekeB, LBwensteinH. Analysis of antigensin a commercial housedust extract by means of quantitative immunoelectrophoresis.Allergy 1979;34:155-66. 2. Marsh DC. Allergens and genetics of allergy. In: Sela, ed. The antigens, vol 3. New York: Academic Press, 1975:271359. 3. Lewenstein H, GravesenS, Schwartz B. Airborne allergens-

identification, problems and the influence of temperature,humidity and ventilation. In: Fenger E, Valbjem F, eds. Proceedingsof the First International WHO Indoor Climate Symposium. Copenhagen:StatensByggeforskningsinstitut, 1979. 4. Koivikko A, Lllwenstein H, eds. Sourcesof allergens. Allergy 1985;4O(supp13):1-71. 5. Ford AW, Rawle FC, Lind P, Spieksma FI’hM, Lewenstein H, Platts-Mills TAE. Standardization of Dermatophagoides pteronyssinus: assessmentof potency and allergen content in ten coded extracts. Int Arch Allergy Clin Immunol 1985; .76:58-67. 6. Chapman MD, Plans-Mills TAE. Purification and characterization of the major allergen from Dermatophagoides ptero-

nyssinus-antigen P,. J Immunol 1980;125:587-92. 7. Lind P. Purification and partial characterizationof two, major allergens from the housedust mite, Dermarophagoides pteronyssinus. J ALLERGY CLIN IMMUNOL 1985;76:753-61. 8. Stewart GA. Isolation and characterizationof the allergen Dpt 12 from Dermatophagoides pteronyssinus by chromatofocus-

ing. Int Arch Allergy Appl Immunol 1982;69:224-30. 9. VoorhorstR, SpieksmaFThM, VarekampH. Housedust atopy and the house dust mite Dermatophagoides pteronyssinus

(Trouessart1897). Leiden: Stafleu’s Scientific Publishing Co, 1967. 10. Halmai ZS, Alexander FAR. Studieson the housedustallergen. Allergy Immunol 1971;17:69-71. 11. Tovey ER, Chapman MD, Platts-Mills TAE. Mite ftieces are a major source of house dust allergens. Nature 1981;289: 592-3.

12. Miyamoto T, OshimaS, Ishizaki T, Sate S. Allergenic identity between the common floor mite (Dermatophagoides farinae Hughes, 1961) and house dust as a causative antigen in bronchial asthma. J ALLERGYCLIN IMMUNOL 1%8;42: 14-28. 13. Mitchell WF, Wharton GW, Larson DG. House dust, mites and insects. Ann Allergy 1969;27:93-9. 14. Lind P, Weeke B, L@wensteinH. A referenceallergen preparationof the housedust mite D. pteronyssinus,producedfrom whole mite culture-a part of the DAS 76 study. Comparison with allergen preparations from other raw materials. Allergy 1984;39:259-75.

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Indoor allergens

78 5. PART 2

1.5. Korsgaard J. House dust mites and absolute indoor humidity. Allergy 1983;38:85-92. 16. Maunsell K, Wraith DG, Cunnington AM. Mites and house dust allergy in bronchial asthma. Lancet 1968;1:1267-70. 17. Rao VRM, Dean BV, SeatonA, Williams DA. A comparison of mite populations in mattressdust from hospital and from private housesin Cardiff, Wales. Clin Allergy 1975;5:209-15. 18. Tovey ER, Chapman MD, Wells CW, Platts-Mills TAE. The distribution of dust mite allergen in the housesof patients with asthma. Am Rev Respir Dis 1981;124:630-5. 19. Lind P, Distinct epitopes on correspondingmajor allergens of D. preronyssinus (Dp-42 = P,), D. furinae (Df-6) and D. microcerus(Dm-6). ELISA for detection of each speciesin dust samples. Allergy 1984;2:39. 20. Lind P, KorsgaardJ, LowensteinH. Detection andquantitation of Dermatophagoides antigensin housedust by immunochemical techniques. Allergy 1979;34:319-26. 21. Kjellmann B, PettersonR. The problem of furred pets in childhood atopic disease.Allergy 1983;38:65-73. 22. Vanto T, Koivikko A. Dog hyposensitivity in asthmatic children. Acta Paediatr Stand 1983;72:571-5. 23. Rudolph R. Frequency of animal sensitization. In: Kerr JW, ed. Proceedingsof the XI International Congressof Allergology and Clinical Immunology. London: Macmillan PressLtd, 1983:437-44. 24. Lowenstein H. Domestic animal allergens. In: Kerr JW, ed. Proceedingsof the XI International Congressof Allergology and Clinical Immunology. London: Macmillan Press Ltd, 1983:545-8. 25. Lowenstein H, Lind P, Weeke B. Identification and clinical significance of allergenic molecules of cat origin. A part of the DAS 76 study. Allergy 1985;40:430-41. 26. Bartholome K, Kissler W, Baer H, WahnU. The origin of cat allergen 1. J ALLERGYCLIN IMMUNOL1984;73(suppl):160. 27. Viander M, Valovirta E, VantoT, Koivikko A. Cross-reactivity of cat and dog allergen extracts. RAST inhibition studieswith special referenceto the allergenic activity in saliva and urine. Int Arch Allergy Appl Immunol 1983;71:252-60. 28. Prahl P. Allergens in cow hair and dander. Allergy 1981; 36:561-71. 29. Longbottom JL. Characterizationof allergens from the urines of experimental animals. In: Kerr JW, ed. Proceedingsof the XI International Congress of Allergology and Clinical Immunol%y. London: Macmillan PressLtd, 1983:525-9. 30. Schwartz B, Lind P. Immunochemical methods for investigations of allergic patients’ environment. Resultsof elimina-

tion treatmentof the allergen source.J ALLERGY CLINIMMUNOI. 1984;73(suppl):156. 31. Gravesen S. Fungi as a cause of allergic disease. Allergy 1979;34:135-54. 32. Larsen LS. A three year survey of microfungi in the air of Copenhagen1977-79.Allergy 1981;36:15-22. 33. Gravesen S. Cutaneousreactions to moulds. Correlation between test and local indoor content of airborne spores. In: Proceedingsof the X International Congressof Allergology, Jerusalem, 1979. 34. Wilken-JensenK, GravesenS, eds. Atlas of moulds in Europe causing respiratory allergy. Copenhagen: ASK Publishing, 1984. 35. Al-Doory Y, Domson JF, eds. Mould allergy. Philadelphia: Lea & Febinger, 1984. 36. Hoffman DR, Kozak PP, Gillman SA, Cummius LH, Gallup J. Isolation of spore specific allergens from Altemaria. Ann Allergy 1981;46:310-6. 37. Aukmst L, Borch SM, EinarssonR. Mold allergy-spores and mycelium as allergen sources.In: Koivikko A, Lowenstein H, eds. Sourcesof allergens. Allergy 1985;4O(suppl3):43-8. 38. Nyholm L, Lowenstein H, Yunginger JW. Immunochemical partial identity between two independently identified and isolated major allergens from Alternaria alternaru (Alt-I and Ag 1). J ALLERGYCLIN IMMUNOL1983;71:461-7. 39. Kauffman HF, van der Heide S, BeaumontF, de Monchy JGR, de Vries K. The allergenic and antigenic properties of spore extracts of Aspergillus fumigatus: a comparativestudy of spore extracts with mycelium and culture filtrate extracts. J ALLERGY CLIN IMMUNOL1984;73:567-73. 40. GravesenS. Identification and quantitation of indoor airborne microfungi during 12 months from 44 Danish homes. Acta Allergol 1972;27:337-54. 41. Gravesen S. Identification and prevalence of culturable mesophilic microfungi in house dust from 100 Danish homes. Allergy 1978;33:268-72. 42. GravesenS, Gyntelberg F, Larsen L, Skov P. Demonstration of microorganismsand dusts in schools and offices. Allergy 1986;41:27. 43. Gravesen S, Larsen L, Skov P. Aerobiology of schools and public institutions-part of a study. Ecology Dis 1983;2: 41 l-3. 44. GravesenS, SondergaardI, Larsen L. Determinationof “normal-colony count” of indoor airborne microfungi. Allergy 1982;37:l-8.

Food antigens and D. A. Moneret-Vautrin;

M.D. Nancy, France

From the Service of Medecine “D,” Immuno-Allergologie, C.H.U. de Nancy-Brabois. Reprint requests:Dr. D. A. Moneret-Vautrin, Service de Medecine “D,” Immuno-Allergologie, C.H.U. de Nancy-Brabois, 54511 Vandoeuvre-les-NancyCEDEX, France.

Clinical disorders attributed to food hypersensitivity inelude urticaria, Quincke’s edema,eczema,asthma,rhinitis,

gastrointestinal disorders, and anaphylactic reactions. The true frequency of food allergy as a prominent cause in allergic diseasemay be difficult to deterpine because of the 1039