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ALLERGIC HYPERSENSITIVITY TO FUNGIBy J. PEPYS, M.B., M.R.C.P., M.R.C.P.E.

Senior Lecturer in Allergy, Institute of Diseases of the Chest, Brompton Hospital, London

Allergic reactions to the ubiquitous pathogenicand non-pathogenic fungi are models for the studyof hypersensitivity. Emphasis will be placedwherever possible in this paper on findings inman, in whom fungal hypersensitivity is widelyprevalent. These findings throw light upon fungalantigens in relation to clinical manifestations andupon the nature and mechanism of allergic re-actions. It is hoped that this outline will serve asa guide to some of the many problems requiringfurther study.A description of certain of the features of the

three clearly defined types of allergic hyper-sensitivity will be given as a source of referencefor the subsequent discussion.

Delayed, Tuberculin Type of HypersensitivityThis is characteristic of the allergy of infection.

The reaction to skin tests develops slowly and ismaximal at 48 to 72 hours. The antibody respon-sible for the reaction appears to be linked to cellsof the reticulo-endothelial system and is trans-ported by circulating lymphoid cells to the siteof the test reaction. Passive transfer of thedelayed type of hypersensitivity can be effectedby the injection of these cells, but not the serum,of a sensitive donor into a non-sensitive recipient.

Immediate, Anaphylactic Type, Hyper-sensitivity

This is characteristic of the clinical allergicdisorders such as asthma, hay fever, conjunc-tivitis and urticaria. The reaction to skin tests isof the urticarial weal and flare type, developingwithin a few minutes, becoming maximal within20 to 30 minutes and resolving within II to 2hours. The non-precipitating antibody presentin the serum is capable of sensitizing the skinand smooth muscle and is known as reaginic anti-body. Passive transfer of the hypersensitivity iseffected by the injection of serum from a sensitivedonor into a non-sensitive recipient.

Arthus Type HypersensitivityArthus reactions are customarily studied in

experimental animals. Arthus reactions in manhave been suspected because of the similarity ofthe histological changes in Arthus reactions inanimals to those found in vascular reactions inman which are regarded as being possibly ofallergic origin. The Arthus skin test reactiondevelops after several hours, that is, later than theimmediate type weal reaction, and is maximalwithin 24 hours, that is, earlier than the delayedtype reaction. Arthus hypersensitivity is de-pendent upon precipitating antibody and can betransferred passively by the injection of serumcontaining precipitins into a non-sensitive re-cipient.The induction of hypersensitivity is influenced

by antigenic configurations which can be modifiedso as to favour one or other form of hypersensi-tivity (Benacerraf and Gell, I959; Gell and Bena-cerraf, 1959). The various types of hyper-sensitivity may co-exist and the reaction elicitedon testing depends upon the antigenic componentemployed. In addition, it seems that immediateor Arthus reactions or both may interfere withthe development of delayed reactions. There area number of examples where it would be mostinstructive to make a clear distinction of thevarious types of hypersensitivity which may bepresent at the same time.

Fungal HypersensitivityFungal hypersensitivity may be classified under

two main headings: (i) delayed type hyper-sensitivity associated with pathogenic fungi, and(2) immediate type hypersensitivity associatedwith non-pathogenic fungi. Whilst these groupsare well defined other forms of hypersensitivitymay co-exist.

Hypersensitivity to Pathogenic FungiInfections with these fungi provide classical

examples of the allergy of infection. For example,Bloch (I928) described the accelerated response,rapid course and early resolution which appearedon re-infection with a fungus of subjects who hadpreviously been infected. This phenomenon is

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analogous to that described by Koch in tuber-culous re-infection. The appearance of delayedtype hypersensitivity is closely associated withthis accelerated response to infection.

Delayed Type HypersensitivityThe passive transfer of delayed hypersensitivity

in man to tuberculin and other delayed typeantigens by the injection of circulating white bloodcells from sensitive subjects has been reported byLawrence (1956). Similar passive transfer ofdelayed hypersensitivity in animals had beenreported earlier by Chase (I945) and has beenrepeated by many other workers. More recentlyRappoport and others (I959) have reported thepassive transfer in man (by the same methods) ofdelayed type hypersensitivity to a fungal antigen,coccidioidin, thus illustrating a common mechan-ism in delayed type hypersensitivity to a varietyof antigens.

Delayed type hypersensitivity is present in thesystemic mycotic infections, and in infectionsconfined to the skin. Skin tests with the appro-priate antigens give delayed reactions in histo-plasmosis, blastomycosis, sporotrichosis, coccidio-idomycosis, moniliasis (candidiasis), and ringworminfections.

In some instances cross-sensitivity has beenfound, for example in histoplasmosis and blasto-mycosis, and in coccidioidomycosis and blasto-mycosis. Although this cross-sensitivity may notbe of a high order, it may be important. Apertinent example is provided by Peck (1950),who found that delayed skin test reactions totrichophytin were elicited in 6o per cent. ofsubjects who gave similar reactions to penicillinand in 33.3 per cent. of those who did not react topenicillin. Delayed skin test reactions to bothpenicillin and trichophytin were elicited in 9.7 percent. of treated subjects, and to penicillin alone in3.2 per cent. This cross-sensitivity is relevant-tothe allergic reactions which may appear within24 hours after the administration of penicillin forthe first time. Caution is necessary at the presenttime, however, before attributing this to tineainfection, since penicillin may be ingested un-wittingly in foodstuffs.

' Id' EruptionsThese are naturally occurring manifestations in

fungal infections, and are regarded as expressionsof delayed type reactions in distant tissues to thefungi or their allergenic products. The ' id'eruptions of tinea infections, and possibly ofmoniliasis, are attributed to haematogenous dis-tribution of antigen to the skin, and includevesicular, morbilliform, lichenoid, urticarial andother manifestations. Injection of antigens such

as trichophytin in skin tests may also excite ' id'eruptions (Sulzberger, I940).Erythema nodosum may occur in fungal infec-

tions, for example in 5 per cent. of patients withcoccidioidomycosis (Kligman and DeLamater,1950), and these subjects may show a high degreeof sensitivity to coccidioidin (Wilson, 1957).There is some evidence to suggest that erythemanodosum may be an Arthus type reaction, butdecisive evidence in favour of delayed or Arthushypersensitivity is lacking.Immediate Type Hypersensitivity

Immediate weal reactions in skin testing havebeen reported in some of the systemic mycoses,for example in coccidioidomycosis and blasto-mycosis. In coccidioidomycosis, Hirsch andBenson (1927) and Smith and others (1948)obtained immediate reactions on skin testing.The latter workers elicited immediate reactionsto coccidioidin in persons who failed to givedelayed reactions, and generalized urticaria ap-peared in two subjects within 8 and i8 hoursrespectively after skin testing. A similar case isreported by Krudy and Hoff (1959), their patientalso failing to give a delayed reaction. Someconfusion exists in these reports since Smith andothers (I948) found, as would be expected, that acontrol test injection with sterile water also pro-duced wealing. The use of prick tests with suit-able antigens and of appropriate non-irritantvehicles for the test materials would overcomeany doubts as to the reactions. Prick tests with acarbol saline extract of Candida albicans cells gaveimmediate weal reactions in about one-quarter ofasthmatic patients tested by the author. It isnot unlikely that similar reactions may occur inthe other mycoses, requiring improved antigensor more careful methods of testing for theirdemonstration.

Immediate weal reactions to trichophytin inthe superficial fungus infections of the skin arenot uncommon. Marcussen (I937) has describedthe successful passive transfer of this hypersensi-tivity in man by the injection of serum, indicatingthat reaginic antibody is involved. Sulzberger(1932) has also reported that the injection oftrichophytin into sensitive subjects may provokeallergic reactions such as asthma and rhinitis,these manifestations also being associated withthe presence of reaginic antibody. Anaphylacticand smooth-muscle sensitization to trichophytinin infected animals was reported by Jadassohnand others (I932, 1937).

In a study of trichophytin skin test reactions inpatients infected with Trichophyton rubrum andTrichophyton mentagrophytes, Lewis and Hopper(1948) found that in patients infected with

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T. rubrum 53 per cent. gave immediate reactionsonly, io per cent. gave delayed reactions only,and 32 per cent. gave both immediate and delayedreactions, the remaining 5 per cent. being negativeon testing. In patients infected with T. mentagro-phytes the results were quite different, only 1.5per cent. giving immediate reactions only, 72.9per cent. giving delayed reactions only, 1.5 percent. giving both types of reaction, and io.6 percent. no reactions at all. It would seem, therefore,that the appearance of an immediate skin testreaction has militated against the appearance of adelayed reaction. The patterns of reactivity inthe two infections probably arise from differencesin the antigenic configurations in the two fungi,leading to the production of predominant imme-diate type hypersensitivity in the T. rubrum infec-tion and to predominant delayed type hyper-sensitivity in the T. mentagrophytes infection.

Arthus Type SensitivitySince fungal precipitins have been reported in

the serum of man the possibility that Arthus typehypersensitivity is participating in the pathologicalmanifestations should be considered. The presenceof these antibodies provides the immunologicalbasis for this type of reaction.

Precipitins have been reported in systemicmycotic infections, such as blastomycosis, cocci-dioidomycosis and histoplasmosis. Analysis ofthe tissue reactions of these infections, and inparticular of allergic manifestations such as ery-thema nodosum, for evidence of Arthus typehypersensitivity is indicated. Hirsch and Benson(I927) reported that the immediate weal reactionto a coccidioidin skin test was followed by a latereaction, coming on 6-I2 hours later and maximalat 24-36 hours, this reaction being suggestive ofan Arthus reaction.

Precipitins have also been reported againstantigens from fungi responsible for superficialskin infections. Pepys, Riddell and Clayton (I959)have demonstrated precipitins in a high propor-tion of human sera against T. rubrum and T. men-tagrophytes. Agar-gel tests were performed by theOuchterlony method (1953), employing antigensderived from the cell-sap of the fungal mats andfrom the culture medium filtrates. Commonantigens were demonstrated in the two Tricho-phyton species, which appear also to possessantigens in common with other fungi such asAspergillus fumigatus, Cladosporium herbarum andPenicillium notatum. The presence of these pre-cipitins makes it necessary to re-examine thedelayed skin test reaction to trichophytin for thepossible participation of Arthus hypersensitivityin its production.

Hypersensitivity to Non-pathogenic FungiFungal spores have become increasingly recog-

nized as inhalant allergens, responsible for asthma,rhinitis and conjunctivitis and perhaps eczema andurticaria. Blackley, in I873, inhaled Penicilliumspores which provoked a reaction he did not careto repeat, and Van Leeuwen and others (1925)described fungal spores as a cause of asthma, withemphasis on the Aspergillus species. Many otherworkers have contributed to this subject, and inmore recent times Feinberg (I946) played animportant part in giving fungal spores theirappropriate place as ubiquitous, common andpotent allergens. A comprehensive discussion onoutdoor and indoor fungi is provided by Maunsell(I954).Immediate Type Hypersensitivity

Aerobiological studies have helped to define aseasonal incidence for respiratory allergic dis-orders to several important fungi. In Britainthe summer grass pollen season is followed closelyby increasing amounts of the spores of Clado-sporium and Alternaria in the air, which are attheir peak in August and September when theyare responsible for troublesome autumnal asthma.Penicillium spores tend to be present throughoutthe year, and the Aspergillus spores are mostevident in the winter months. Among other fungicommonly included in investigations are thosecausing Dry Rot, various Yeasts and Tricothecium.Most workers in various countries seem to empha-size the above fungi in their reports. Consideringthe vast numbers of fungal species, it would besurprising if the few examples given here aremore than a small proportion of the potentialfungal inhalant allergens.

Skin tests by the prick method with suitableextracts of the commoner fungal allergens insensitive subjects give immediate weal reactions,which are of considerable help in elucidating thesesomewhat obscure causes of allergic symptoms.

Arthus Type HypersensitivityThe Aspergillus genus have been mentioned

above as an important and early recognized sourceof inhalant allergens. The potential pathogenAspergillus fumigatus has also been identified as acause of broncho-pulmonary aspergillosis, inwhich pulmonary eosinophilia is a feature (Hinsonand others, I952).

In recent investigations (Pepys and others, I959)it was found that A. fumigatus is present in thesputum of asthmatics more frequently than inother patients. Also present in many asthmaticswith the hypersensitive type of pulmonary asper-gillosis were febrile episodes, associated with pul-monary infiltrations and with blood and sputum

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eosinophilia, these patients constituting onevariety of pulmonary eosinophilia (Crofton andothers, I952).

Skin tests with aspergillus extracts in thesepatients excited immediate weal reactions and ina number of patients a further reaction appearedseveral hours after the weal reaction had dis-appeared. This later reaction was maximal at24 hours. The immediate weal reactions to skintests and the asthmatic reaction to inhalation testsindicate that reaginic antibody characteristic ofimmediate type hypersensitivity was present. Thelater reaction, however, was suggestive of anArthus reaction, coming on after the immediatereaction, and being maximal before the delayedreaction. Histological examination of these reac-tions showed an intense eosinophile cell infiltrationand differed from the characteristic perivascularlymphoid cell granuloma of delayed type hyper-sensitive reactions. Evidence to support the viewthat Arthus type hypersensitivity was present wasprovided by the demonstration of Aspergillusprecipitins in the serum ofmany asthmatic patientswith A. fumigatus in their sputum. These pre-cipitins were demonstrated by the agar-gel dif-fusion test (Ouchterlony, I953), the antigensbeing derived from the cell-sap expressed fromfungal mats and from the culture medium filtrate.The presence of common allergens in at least

six members of the Aspergillus genus was shownby the immediate weal reactions elicited in mostsensitive subjects with extracts of all of thefollowing, A. fumigatus, A. flavus, A. glaucus,A. nidulans, A. niger, and A. terreus. Commonantigens in these fungi (except for A. glaucuswhich was not tested) were demonstrated byprecipitation reactions in the agar-gel tests withthe human sera. Antigens in common with theAspergillus extracts were also found in the agar-geltests with extracts of Cladosporium herbarum andPenicillium notatum.

There is evidence, therefore, that both non-precipitating reaginic antibody and precipitatingantibody may be present in patients with thehypersensitive type of pulmonary aspergillosis,and that they may be responsible for differentmanifestations. Injection treatment with Asper-gillus extracts led in some patients to the dis-appearance of precipitins from the serum, butinhalation tests with Aspergillus extracts in thesesubjects continued to provoke asthmatic reactions,suggesting that the precipitins were not respon-sible for the asthma. Precipitins have also beenfound in non-asthmatic patients with pulmonaryAspergillus mycetomata.

Delayed Type HypersensitivityDelayed reactions to skin tests with fungal

allergens are not uncommon, but they have notbeen investigated sufficiently to indicate whetherthey are of Arthus or the delayed type. Thepresence of delayed hypersensitivity cannot beexcluded, since immediate weal reactions mayinterfere with the appearance of delayed skin testreactions.

General ConsiderationsThe ubiquity of pathogenic and non-pathogenic

fungi and of human hypersensitivity to themoffers many opportunities for study. The fungiare versatile in the types of hypersensitivity theyproduce, since the demonstration of human pre-cipitins which may mediate Arthus type reactionsto fungal antigens suggests that this type ofhypersensitivity in man may be as readily studiedas the immediate and delayed types. The highincidence of the various types of antibody in manand the frequency with which exposure to thecorresponding fungal antigens occurs poses theinteresting question as to whether these may leadto reactions in parts of the body other than thosein which the fungi produce their commonlyrecognized disorders. A recent example of thiswith other allergens is given in the report byHardwicke and others (1959) of a case of nephrosiswith eosinophil cell infiltration in the kidney,attributed to pollen hypersensitivity.

Analysis of the antigenic patterns of fungi andtheir further chemical characterization is essentialfor the provision of the standardized test materialsnecessary for uniform investigations. For example,the crudeness of the commonly used antigensfrom Trichophyton and Candida species is a barrierto quantitative measurements of hypersensitivity.In this respect, too, the demonstration of humanprecipitins to the fungi should be of considerablehelp.

Localization of ' id ' EruptionsThere are indications from experimental fungal

infections of the factors which may influencewhere and how antigen and antibody may meetin the body, react and set in motion local disturb-ances. These factors are clearly of wider sig-nificance than for fungal hypersensitivity only.The factors which are known to influence thelocalization of ' id ' eruptions have some bearingon this problem. Minimal trauma in animalswith viable fungi in their circulation leads tolocalized areas of infection, or in the case of non-viable antigens to the localization of eruptions(Sulzberger, I940). In man the injection oftrichiphytin has been reported to precipitate 'id"eruptions sometimes generalized, though notenough is known to indicate whether these appearat the sites of previous lesions or at the sites of

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trauma. The factors producing local susceptibilityof this type may include trauma produced by avariety of agents. To this may be added immuno-logical trauma, such as previous allergic reactionsand perhaps also immediate type reactions, whichby increasing capillary permeability may permitcirculating antigen to meet antibodies in thetissues. Where the antibodies concerned areprecipitins more persistent reactions are likely tobe excited. In this context it can be postulatedthat an immediate reaction to one antigen mayalso permit another antigen to escape from thecirculation and to react with antibodies in thetissues. If this hypothesis were sustained, fungiand fungal precipitins might well be prominentcauses of such reactions.Examples of experimental localization of allergic

reactions are contained in the report by Seegaland Seegal (I933), that the injection of glycerineinto the anterior chamber of the eye of a sensitizedanimal led to a reaction in that eye, following onthe systemic injection of the specific antigen at alater date. When Mott and Kesten (I930) in-jected whole cells of Candida albicans into theanterior chamber of the eye of animals, followedat a later date by the intravenous injection of apolysaccharide from this fungus, inflammationdeveloped in the previously inoculated eye. It isprobable that in these experiments a high localconcentration of antibody was produced by thenon-specific and specific stimuli, the glycerineand Candida cells respectively. This, togetherwith persistent capillary damage which couldencourage local concentration of the antigen aswefl, may have determined the site of the reactionin the treated eye.

Effect of Immediate Reactions on Appear-ance of Delayed Reactions to Skin Tests

Whereas it has been suggested above thatincreased capillary permeability may permit anti-gen or antibody, or both, to enter the tissues andexcite reactions, the position is altered in skintesting in which increased capillary permeabilityand exudation of serum may inhibit the appear-ances of reactions at test sites, by diluting andspreading the antigen and by enhancing itsabsorption.The possibility that immediate and perhaps

Arthus reactions may interfere with the subse-quent appearance of a delayed reaction is supportedby the report that the production of wealingreactions by a variety of agents of tuberculin testsites leads to the inhibition of the reaction (Pepys,1955). Allergic weals are equally effective inenhancing absorption of substances from the skin(Abramson and Engel, 1938). The possibilitythat an immediate or Arthus reaction to an antigen

or a member of an antigenic complex may preventthe appearance of a delayed reaction and therebymask the presence of delayed type hypersensitivitymust be considered before postulating that othertypes of antibody are blocking the reaction orthat the antigen is altered in some way, thus pre-venting the delayed reaction. It should be notedthat T. rubrum infection, in which immediatereactions predominate, is more recalcitrant andresistant to treatment than T. mentagrophytesinfection, in which delayed reactions predominate.Similarly, animal ringworm infections give riseto low degrees of delayed hypersensitivity inanimals and are refractory in such animals,whereas in man they excite a high degree ofdelayed hypersensitivity and are more success-fully eradicated. In coccidioidomycosis, too,there are reports (Wilson, 1957) that the presenceof delayed hypersensitivity is a good, and itsabsence is a bad, prognostic sign.These findings suggest that the demonstration

of the various types of hypersensitivity may be ofimportance in assessing host resistance. In casesin which one or other of the hypersensitivityreactions appears absent, other methods of testingand improved antigens may be informative.

This brief analysis bears out the views ofSulzberger (I940) that familiarity with the allergyof fungal infections is desirable for the under-standing of allergy to infection in general. Tothis may equally well be added that the under-standing of the allergy to fungi is desirable forthe understanding of allergic reactions in general.

BIBLIOGRAPHYABRAMSON, H. A., and ENGEL, M. J. (1938), J. invest. Derm.,

I, 65.BENACERRAF, B., and GELL, P. G. H. (I959), Immunology, 2, 53.BLACKLEY, C. H. (I873), 'Catarrhus Aestivus (Hayfever), its

Causes, Treatment, and Effective Prevention,' ExperimentalResearches, London.

BLOCH, B. (1928), Handb. d. Haut. u. Geschechtskr., II, 300.CHASE, M. W. (I945), Proc. Soc. exp. Biol. (N.Y.), 59, 134.CROFTON, J. W., LIVINGSTONE, J. L., OSWALD, N. C.,

and ROBERTS, A. T. N. (ig52), Thorax, 7, '.FEINBERG, S. M. (x946), 'Allergy in Practice,' 2nd ed., The Year

Book Publishers Inc., Chicago.GELL, P. G. H., and BENACERRAF, B. (I959), Immunology, 2,64.HARDWICKE, J., SOOTHILL, J. F., SQUIRE, J. R., and

HOLTI, G. (I959), Lancet, i, 5oo.HINSON, K. F. W., MOON, A. J., and PLUMMER, N. S. (i952),

Thorax, 7, 317.HIRSCH, E. F., and BENSON, H. (1927), J. infect. Dis., 40, 629.JADASSOHN, W., SCHAAF, F., and SULZBERGER, M. B.

(1932), Klin. Wschr., II, 857.JADASSOHN, W., SCHAAF, F., and WOHLER, G. (1937),

7. Immunol., 32, 203.KLIGMAN, A. M., and DeLAMATER, E. D. (I950), Ann. Rev.

Microbiol., 283.KRUDY, A. G., and HOFF, R. (I959), Amer. Rev. Tuberc., 79, 78.LAVVRENCE, H. S. (1956), Amer. J. Med., 20, 428.LEWIS, G. M., and HOPPER, M. F. (I948), 'An Introduction to

Medical Mycology,' 3rd ed., The Year Book Publishers Inc.,Chicago.

MARCUSSEN, P. V. (i937), Arch. Derm. Syph. (Chicago), 36, 494.MAUNSELL, K. (1954), 'Progress in Allergy,' S. Karger, Basel,

P. 457.Bibliography continued on page 469

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August I959 MAUNSELL: Drugs in Treatment of the Allergic Nose 469

nasal trouble left no doubt about the diagnosis ofrhinitis medicamentosa due to adrenergic drugsand in main to naphazoline.

Unfortunately, it is still possible for the patientsto obtain these drugs over the counter. Educationof the patient is therefore needed, and theirco-operation obtained to restrict the use to theworst episodes.

Steroid HormonesThe second large group of anti-allergic drugs

which can exert their action at the site of theirdeposition on the mucous membrane are steroidhormones. Of the known active adrenocorticalcompounds, hydrocortisone and prednisolone(deltahydrocortisone) can act locally, whereascortisone and prednisone cannot. Hydrocortisoneis soluble in water, only I: 4,ooo, and hydro-cortisone acetate is insoluble in water. Bothdrugs can be given as nasal snuff.Herxheimer and McAllen (I956) saw good

results in hay fever, using I5 mg. hydrocortisonelocally daily. Good results in nasal allergy withprednisolone locally were reported by Andersonand Ogden (1956). The writer took part in twosmall controlled trials where patients with hayfever were treated by inhalation of either pred-nisolone snuff (i mg. twice daily) or by an inertsnuff containing lactose (Godfrey, Maunsell,and Pearson, 1957). The results in 1956suggested that the daily inhalation of 2 mg.prednisolone snuff is of considerable value in thecontrol of symptoms due to hay fever. The1956 season was, however, unusually mild, and afurther study during the pollen season of I957,when pollen counts were much higher, showedthat prednisolone snuff alone in dosages of2-4 mg. did not sufficiently control severe cases.It is, however, considered as a most valuable helpin treatment of hay fever and can be given inconjunction with antihistamines and hyposensi-tization. No side effects were observed; in par-ticular the absence of the rebound phenomenonwas noted. Prednisolone as prednisolone sulphate

(Predsol) can be used in watery solution. Thedrops are instilled three to four times daily andthis treatment is of valuable help in controllingseasonal and perennial' rhinitis. Polypi sometimesshrink considerably with hydrocortisone snuff aswell as with prednisolone. An increase of infectedepisodes has not been noted.An important use of prednisolone and hydro-

cortisone was mentioned previously, i.e. thecounteraction of the rebound effect.

Since we have to learn more about the applica-tions and results of the local steroid therapy itseems unfortunate that the pharmaceutical in-dustry set out to combine vasoconstrictors andsteroid hormones. For example, Cortibiotic nasaldrops contain prednisolone, soframycin and thevasoconstricting phenylephrine; Hydrospray con-tains hydrocortisone, neomycin and the vasocon-stricting propadrin; Efcortelan nasal spray con-tains hydrocortisone, thiomersal and naphazolinenitrate, and in Delta-Fenox prednisolone iscombined with two vasoconstrictors, phenylephrineand naphazoline. Other similar preparations arealso on the market.

Since a certain amount of the locally appliedhormones will be swallowed after travelling upthe nasal passages via the naso-pharynx, one hasto watch carefully for toxic general effects. Inour cases neither gastro-intestinal trouble norsigns of Cushing's syndrome have been noted.Yet one should be careful and refrain from givinglocal steroids to patients with gastric ulcers, con-gestive heart failure, diabetes and tuberculosis.One should not be too enthusiastic about theimprovement of the rhinitis and polypi but realizeand let the patients realize that these drugs donot cure the disease but only suppress the clinicalmanifestations.

BIBLIOGRAPHYANDERSON, J. R., and OGDEN, H. D. (I956), Ann. AUergy,

'4, 44.GODFREY, M. P., MAUNSELL, K., and PEARSON, R. S.

Bruce (I957), Lancet, i, 767.HERXHEIMER, H., and McALLEN, M. (I956), Ibid., i, 537.LUCAS, H. A. (Iosi). 7. Laryng.. 66. 480.

Bibliography continued-from Pa-ae 440-7. Pebvs. M.B.. M.R.C.P.. M.R.C.P.E.MOTT, E., and KESTEN, H. D. (I930), Proc. Soc. exp. Biol.

(N.Y.), 28, 320.OUCHTERLONY, 0. (I s3), Acta. path. microbiol. scand., 32, 23!.PECK, S. M. (Ig5o), Ann. N.Y. Acad. Sci., 50, 1362.PEPYS, J. (I95 ;), Amer. Rev. Tuberc., 73, 4Q.PEPYS, J., RIDDELL, R. W., and CLAYTON, Y. M., in press.PEPYS, J., RIDDELL, R. W., CITRON, K. M., CLAYTON,

Y. M., and SHORT, E. I., Amer. Rev. Tuberc., forthcomingissue.

RAPPOPORT, F. T., LAWRENCE, H. S., PAPPAGIANIF, D.,and SMITH, G. (I959), in press.

SEEGAL, B. C., and SEEGAL, D. J. (I933), . Immunol., 25, 221.

SMITH, C. E., WHITING, E. G., BAKER, E. C., ROSENBER-GER, H. G., BEARD, R. R., and SMITH, M. T. (1948),Amer. Rev. Tuberc., 57, 330.

SULZBERGER, M. B., and WISE, F. (I932), J. Amer. med. Ass.,99, '759.

SULZBERGER, M. B. (1940), 'Dermatological Allergy,' C. C.Thomas, Springfield, Illinois.

Van LEEUWEN, W. S., BIEN, Z., KREMER, W., andVAREKAMP, H. (1925), Z. Immun Forsch., 44, I.

WILSON, J. W. (I957), 'Clinical and Immunological Aspects ofFungous Diseases,' C. C. Thomas, Springfield, Illinois.

Bibliography continued from page 466-R. S. Bruce Pearson. D.M.. F.R.C.P.QUANLES VAN UFFORD, W. J. (I952), Int. Arch. Alergy

(N. Y.), 3, 229.ROSA, L., BERGAMI, G., and CENACCHI, G. C. (1957),

Acta. allerg. (Kbh.), iI, 8i.

SAVIDGE, R. S., and BROCKBANK, W. (I954), Lancet, il, 889.VEST, H. F. (I957), Ann. rheum. Dis., x6, 322.WEST, H. F. (i958), Ibid., 17, 273.WILLIAMS, R. S. (x9gs), Lancet, i, 698.

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