Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from 436

ALLERGIC HYPERSENSITIVITY TO FUNGI By 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 pathogenic experimental animals. Arthus reactions in man and non-pathogenic fungi are models for the study have been suspected because of the similarity of of hypersensitivity. Emphasis will be placed the histological changes in Arthus reactions in wherever possible in this paper on findings in animals to those found in vascular reactions in man, in whom fungal hypersensitivity is widely man which are regarded as being possibly of prevalent. These findings throw light upon fungal allergic origin. The Arthus skin test reaction antigens in relation to clinical manifestations and develops after several hours, that is, later than the upon the nature and mechanism of allergic re- immediate type weal reaction, and is maximal actions. It is hoped that this outline will serve as within 24 hours, that is, earlier than the delayed a guide to some of the many problems requiring type reaction. Arthus hypersensitivity is de- further study. pendent upon precipitating antibody and can beProtected by copyright. A description of certain of the features of the transferred passively by the injection of serum three clearly defined types of allergic hyper- containing precipitins into a non-sensitive re- sensitivity will be given as a source of reference cipient. for the subsequent discussion. The induction of hypersensitivity is influenced by antigenic configurations which can be modified Delayed, Tuberculin Type of Hypersensitivity so as to favour one or other form of hypersensi- This is characteristic of the allergy of infection. tivity (Benacerraf and Gell, I959; Gell and Bena- The reaction to skin tests develops slowly and is cerraf, 1959). The various types of hyper- maximal at 48 to 72 hours. The antibody respon- sensitivity may co-exist and the reaction elicited sible for the reaction appears to be linked to cells on testing depends upon the antigenic component of the reticulo-endothelial system and is trans- employed. In addition, it seems that immediate ported by circulating lymphoid cells to the site or Arthus reactions or both may interfere with of the test reaction. Passive transfer of the the development of delayed reactions. There are http://pmj.bmj.com/ delayed type of hypersensitivity can be effected a number of examples where it would be most by the injection of these cells, but not the serum, instructive to make a clear distinction of the of a sensitive donor into a non-sensitive recipient. various types of hypersensitivity which may be present at the same time. Immediate, Anaphylactic Type, Hyper- sensitivity Fungal Hypersensitivity This is characteristic of the clinical allergic Fungal hypersensitivity may be classified under disorders such as asthma, hay fever, conjunc- two main headings: (i) delayed type hyper- on September 25, 2021 by guest. tivitis and urticaria. The reaction to skin tests is sensitivity associated with pathogenic fungi, and of the urticarial weal and flare type, developing (2) immediate type hypersensitivity associated within a few minutes, becoming maximal within with non-pathogenic fungi. Whilst these groups 20 to 30 minutes and resolving within II to 2 are well defined other forms of hypersensitivity hours. The non-precipitating antibody present may co-exist. in the serum is capable of sensitizing the skin and smooth muscle and is known as reaginic anti- Hypersensitivity to Pathogenic Fungi body. Passive transfer of the hypersensitivity is Infections with these fungi provide classical effected by the injection of serum from a sensitive examples of the allergy of infection. For example, donor into a non-sensitive recipient. Bloch (I928) described the accelerated response, rapid course and early resolution which appeared Arthus Type Hypersensitivity on re-infection with a fungus of subjects who had Arthus reactions are customarily studied in previously been infected. This phenomenon is Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from August 1959 PEPYS: Allergic Hypersensitivity to Fungi 437 analogous to that described by Koch in tuber- as trichophytin in skin tests may also excite ' id' culous re-infection. The appearance of delayed eruptions (Sulzberger, I940). type hypersensitivity is closely associated with Erythema nodosum may occur in fungal infec- this accelerated response to infection. tions, for example in 5 per cent. of patients with coccidioidomycosis (Kligman and DeLamater, Delayed Type Hypersensitivity 1950), and these subjects may show a high degree The passive transfer of delayed hypersensitivity of sensitivity to coccidioidin (Wilson, 1957). in man to tuberculin and other delayed type There is some evidence to suggest that erythema antigens by the injection of circulating white blood nodosum may be an Arthus type reaction, but cells from sensitive subjects has been reported by decisive evidence in favour of delayed or Arthus Lawrence (1956). Similar passive transfer of hypersensitivity is lacking. delayed hypersensitivity in animals had been reported earlier by Chase (I945) and has been Immediate Type Hypersensitivity repeated by many other workers. More recently Immediate weal reactions in skin testing have Rappoport and others (I959) have reported the been reported in some of the systemic mycoses, passive transfer in man (by the same methods) of for example in coccidioidomycosis and blasto- delayed type hypersensitivity to a fungal antigen, mycosis. In coccidioidomycosis, Hirsch and coccidioidin, thus illustrating a common mechan- Benson (1927) and Smith and others (1948) ism in delayed type hypersensitivity to a variety obtained immediate reactions on skin testing. of antigens. The latter workers elicited immediate reactions Delayed type hypersensitivity is present in the to coccidioidin in persons who failed to give systemic mycotic infections, and in infections delayed reactions, and generalized urticaria ap- confined to the skin. Skin tests with the appro- peared in two subjects within 8 and i8 hours Protected by copyright. priate antigens give delayed reactions in histo- respectively after skin testing. A similar case is plasmosis, blastomycosis, sporotrichosis, coccidio- reported by Krudy and Hoff (1959), their patient idomycosis, moniliasis (candidiasis), and ringworm also failing to give a delayed reaction. Some infections. confusion exists in these reports since Smith and In some instances cross-sensitivity has been others (I948) found, as would be expected, that a found, for example in histoplasmosis and blasto- control test injection with sterile water also pro- mycosis, and in coccidioidomycosis and blasto- duced wealing. The use of prick tests with suit- mycosis. Although this cross-sensitivity may not able antigens and of appropriate non-irritant be of a high order, it may be important. A vehicles for the test materials would overcome pertinent example is provided by Peck (1950), any doubts as to the reactions. Prick tests with a who found that delayed skin test reactions to carbol saline extract of Candida albicans cells gave trichophytin were elicited in 6o per cent. of immediate weal reactions in about one-quarter of subjects who gave similar reactions to penicillin asthmatic patients tested by the author. It is http://pmj.bmj.com/ and in 33.3 per cent. of those who did not react to not unlikely that similar reactions may occur in penicillin. Delayed skin test reactions to both the other mycoses, requiring improved antigens penicillin and trichophytin were elicited in 9.7 per or more careful methods of testing for their cent. of treated subjects, and to penicillin alone in demonstration. 3.2 per cent. This cross-sensitivity is relevant-to Immediate weal reactions to trichophytin in the allergic reactions which may appear within the superficial fungus infections of the skin are 24 hours after the administration of penicillin for not uncommon. Marcussen (I937) has described the first time. Caution is necessary at the present the successful passive transfer of this hypersensi- on September 25, 2021 by guest. time, however, before attributing this to tinea tivity in man by the injection of serum, indicating infection, since penicillin may be ingested un- that reaginic antibody is involved. Sulzberger wittingly in foodstuffs. (1932) has also reported that the injection of trichophytin into sensitive subjects may provoke ' Id' Eruptions allergic reactions such as asthma and rhinitis, These are naturally occurring manifestations in these manifestations also being associated with fungal infections, and are regarded as expressions the presence of reaginic antibody. Anaphylactic of delayed type reactions in distant tissues to the and smooth-muscle sensitization to trichophytin fungi or their allergenic products. The ' id' in infected animals was reported by Jadassohn eruptions of tinea infections, and possibly of and others (I932, 1937). moniliasis, are attributed to haematogenous dis- In a study of trichophytin skin test reactions in tribution of antigen to the skin, and include patients infected with Trichophyton rubrum and vesicular, morbilliform, lichenoid, urticarial and Trichophyton mentagrophytes, Lewis and Hopper other manifestations. Injection of antigens such (1948) found that in patients infected with Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from 438 POSTGRADUATE MEDICAL JOURNAL August I95'9 T. rubrum 53 per cent. gave immediate reactions Hypersensitivity to Non-pathogenic Fungi only, io per cent. gave delayed reactions only, Fungal spores have become increasingly recog- and 32 per cent. gave both immediate and delayed nized as inhalant allergens, responsible for asthma, reactions, the remaining 5 per cent. being negative rhinitis and conjunctivitis and perhaps eczema and on testing. In patients infected with T. mentagro- urticaria. Blackley, in I873, inhaled Penicillium phytes the results were quite different, only 1.5 spores which provoked a reaction he did not care per cent. giving immediate reactions only, 72.9 to repeat, and Van Leeuwen and others (1925) per cent. giving delayed reactions only, 1.5 per described fungal spores as a cause of asthma, with cent. giving both types of reaction, and io.6 per emphasis on the Aspergillus species. Many other cent. no reactions at all. It would seem, therefore, workers have contributed to this subject, and in that the appearance of an immediate skin test more recent times Feinberg (I946) played an reaction has militated against the appearance of a important part in giving fungal spores their delayed reaction. The patterns of reactivity in appropriate place as ubiquitous, common and the two infections probably arise from differences potent allergens. A comprehensive discussion on in the antigenic configurations in the two fungi, outdoor and indoor fungi is provided by Maunsell leading to the production of predominant imme- (I954). diate type hypersensitivity in the T. rubrum infec- tion and to predominant delayed type hyper- Immediate Type Hypersensitivity sensitivity in the T. mentagrophytes infection. Aerobiological studies have helped to define a seasonal incidence for respiratory allergic dis- Arthus Type Sensitivity orders to several important fungi. In Britain Since fungal precipitins have been reported in the summer grass pollen season is followed closely by increasing amounts of the spores of Clado-Protected by copyright. the serum of man the possibility that Arthus type sporium and Alternaria in the air, which are at hypersensitivity is participating in the pathological their peak in August and September when they manifestations should be considered. The presence are responsible for troublesome autumnal asthma. of these antibodies provides the immunological Penicillium spores tend to be present throughout basis for this type of reaction. the year, and the Aspergillus spores are most Precipitins have been reported in systemic evident in the winter months. Among other fungi mycotic infections, such as blastomycosis, cocci- commonly included in investigations are those dioidomycosis and histoplasmosis. Analysis of causing Dry Rot, various Yeasts and Tricothecium. the tissue reactions of these infections, and in Most workers in various countries seem to empha- particular of allergic manifestations such as ery- size the above fungi in their reports. Considering thema nodosum, for evidence of Arthus type the vast numbers of fungal species, it would be hypersensitivity is indicated. Hirsch and Benson surprising if the few examples given here are (I927) reported that the immediate weal reaction more than a small proportion of the potential to a coccidioidin skin test was followed by a late fungal inhalant allergens. http://pmj.bmj.com/ reaction, coming on 6-I2 hours later and maximal Skin tests by the prick method with suitable at 24-36 hours, this reaction being suggestive of extracts of the commoner fungal allergens in an Arthus reaction. sensitive subjects give immediate weal reactions, Precipitins have also been reported against which are of considerable help in elucidating these antigens from fungi responsible for superficial somewhat obscure causes of allergic symptoms. skin infections. Pepys, Riddell and Clayton (I959) have demonstrated precipitins in a high Arthus Type Hypersensitivity

propor- on September 25, 2021 by guest. tion of human sera against T. rubrum and T. men- The Aspergillus genus have been mentioned tagrophytes. Agar-gel tests were performed by the above as an important and early recognized source Ouchterlony method (1953), employing antigens of inhalant allergens. The potential pathogen derived from the cell-sap of the fungal mats and Aspergillus fumigatus has also been identified as a from the culture medium filtrates. Common cause of broncho-pulmonary aspergillosis, in antigens were demonstrated in the two Tricho- which pulmonary eosinophilia is a feature (Hinson phyton species, which appear also to possess and others, I952). antigens in common with other fungi such as In recent investigations (Pepys and others, I959) Aspergillus fumigatus, Cladosporium herbarum and it was found that A. fumigatus is present in the Penicillium notatum. The presence of these pre- sputum of asthmatics more frequently than in cipitins makes it necessary to re-examine the other patients. Also present in many asthmatics delayed skin test reaction to trichophytin for the with the hypersensitive type of pulmonary asper- possible participation of Arthus hypersensitivity gillosis were febrile episodes, associated with pul- in its production. monary infiltrations and with blood and sputum Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from August I959 PEPYS: Allergic Hypersensitivity to Fungi 439 eosinophilia, these patients constituting one allergens are not uncommon, but they have not variety of pulmonary eosinophilia (Crofton and been investigated sufficiently to indicate whether others, I952). they are of Arthus or the delayed type. The Skin tests with aspergillus extracts in these presence of delayed hypersensitivity cannot be patients excited immediate weal reactions and in excluded, since immediate weal reactions may a number of patients a further reaction appeared interfere with the appearance of delayed skin test several hours after the weal reaction had dis- reactions. appeared. This later reaction was maximal at 24 hours. The immediate weal reactions to skin General Considerations tests and the asthmatic reaction to inhalation tests The ubiquity of pathogenic and non-pathogenic indicate that reaginic antibody characteristic of fungi and of human hypersensitivity to them immediate type hypersensitivity was present. The offers many opportunities for study. The fungi later reaction, however, was suggestive of an are versatile in the types of hypersensitivity they Arthus reaction, coming on after the immediate produce, since the demonstration of human pre- reaction, and being maximal before the delayed cipitins which may mediate Arthus type reactions reaction. Histological examination of these reac- to fungal antigens suggests that this type of tions showed an intense eosinophile cell infiltration hypersensitivity in man may be as readily studied and differed from the characteristic perivascular as the immediate and delayed types. The high lymphoid cell granuloma of delayed type hyper- incidence of the various types of antibody in man sensitive reactions. Evidence to support the view and the frequency with which exposure to the that Arthus type hypersensitivity was present was corresponding fungal antigens occurs poses the provided by the demonstration of Aspergillus interesting question as to whether these may lead precipitins in the serum of many asthmatic patients to reactions in parts of the other body than those Protected by copyright. with A. fumigatus in their sputum. These pre- in which the fungi produce their commonly cipitins were demonstrated by the agar-gel dif- recognized disorders. A recent example of this fusion test (Ouchterlony, I953), the antigens with other allergens is given in the report by being derived from the cell-sap expressed from Hardwicke and others (1959) of a case of nephrosis fungal mats and from the culture medium filtrate. with eosinophil cell infiltration in the kidney, The presence of common allergens in at least attributed to pollen hypersensitivity. six members of the Aspergillus genus was shown Analysis of the antigenic patterns of fungi and by the immediate weal reactions elicited in most their further chemical characterization is essential sensitive subjects with extracts of all of the for the provision of the standardized test materials following, A. fumigatus, A. flavus, A. glaucus, necessary for uniform investigations. For example, A. nidulans, A. niger, and A. terreus. Common the crudeness of the commonly used antigens antigens in these fungi (except for A. glaucus from Trichophyton and Candida species is a barrier which was not tested) were demonstrated by to quantitative measurements of hypersensitivity.

precipitation reactions in the agar-gel tests with In this respect, too, the demonstration of human http://pmj.bmj.com/ the human sera. Antigens in common with the precipitins to the fungi should be of considerable Aspergillus extracts were also found in the agar-gel help. tests with extracts of Cladosporium herbarum and Penicillium notatum. Localization of ' id ' Eruptions There is evidence, therefore, that both non- There are indications from experimental fungal precipitating reaginic antibody and precipitating infections of the factors which may influence antibody may be present in patients with the where and how antigen and antibody may meet hypersensitive type of pulmonary aspergillosis, in the body, react and set in motion local disturb- on September 25, 2021 by guest. and that they may be responsible for different ances. These factors are clearly of wider sig- manifestations. Injection treatment with Asper- nificance than for fungal hypersensitivity only. gillus extracts led in some patients to the dis- The factors which are known to influence the appearance of precipitins from the serum, but localization of ' id ' eruptions have some bearing inhalation tests with Aspergillus extracts in these on this problem. Minimal trauma in animals subjects continued to provoke asthmatic reactions, with viable fungi in their circulation leads to suggesting that the precipitins were not respon- localized areas of infection, or in the case of non- sible for the asthma. Precipitins have also been viable antigens to the localization of eruptions found in non-asthmatic patients with pulmonary (Sulzberger, I940). In man the injection of Aspergillus mycetomata. trichiphytin has been reported to precipitate 'id" eruptions sometimes generalized, though not Delayed Type Hypersensitivity enough is known to indicate whether these appear Delayed reactions to skin tests with fungal at the sites of previous lesions or at the sites of Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from POSTGRADUATE MEDICAL JOURNAL August I5 trauma. The factors producing local susceptibility or a member of an antigenic complex may prevent of this type may include trauma produced by a the appearance of a delayed reaction and thereby variety of agents. To this may be added immuno- mask the presence of delayed type hypersensitivity logical trauma, such as previous allergic reactions must be considered before postulating that other and perhaps also immediate type reactions, which types of antibody are blocking the reaction or by increasing capillary permeability may permit that the antigen is altered in some way, thus pre- circulating antigen to meet antibodies in the venting the delayed reaction. It should be noted tissues. Where the antibodies concerned are that T. rubrum infection, in which immediate precipitins more persistent reactions are likely to reactions predominate, is more recalcitrant and be excited. In this context it can be postulated resistant to treatment than T. mentagrophytes that an immediate reaction to one antigen may infection, in which delayed reactions predominate. also permit another antigen to escape from the Similarly, animal ringworm infections give rise circulation and to react with antibodies in the to low degrees of delayed hypersensitivity in tissues. If this hypothesis were sustained, fungi animals and are refractory in such animals, and fungal precipitins might well be prominent whereas in man they excite a high degree of causes of such reactions. delayed hypersensitivity and are more success- Examples of experimental localization of allergic fully eradicated. In coccidioidomycosis, too, reactions are contained in the report by Seegal there are reports (Wilson, 1957) that the presence and Seegal (I933), that the injection of glycerine of delayed hypersensitivity is a good, and its into the anterior chamber of the eye of a sensitized absence is a bad, prognostic sign. animal led to a reaction in that eye, following on These findings suggest that the demonstration the systemic injection of the specific antigen at a of the various types of hypersensitivity may be of Mott and later date. When Kesten (I930) in- importance in assessing host resistance. In casesProtected by copyright. jected whole cells of Candida albicans into the in which one or other of the hypersensitivity anterior chamber of the eye of animals, followed reactions appears absent, other methods of testing at a later date by the intravenous injection of a and improved antigens may be informative. polysaccharide from this fungus, inflammation This brief analysis bears out the views of developed in the previously inoculated eye. It is Sulzberger (I940) that familiarity with the allergy probable that in these experiments a high local of fungal infections is desirable for the under- concentration of antibody was produced by the standing of allergy to infection in general. To non-specific and specific stimuli, the glycerine this may equally well be added that the under- and Candida cells respectively. This, together standing of the allergy to fungi is desirable for with persistent capillary damage which could the understanding of allergic reactions in general. encourage local concentration of the antigen as wefl, may have determined the site of the reaction BIBLIOGRAPHY in the treated eye. ABRAMSON, H. A., and ENGEL, M. J. (1938), J. invest. Derm., I, 65. BENACERRAF, B., and GELL, P. G. H. (I959), Immunology, 2, 53. http://pmj.bmj.com/ Effect of Immediate Reactions on Appear- BLACKLEY, C. H. (I873), 'Catarrhus Aestivus (Hayfever), its Causes, Treatment, and Effective Prevention,' Experimental ance of Delayed Reactions to Skin Tests Researches, London. Whereas it has been suggested above that BLOCH, B. (1928), Handb. d. Haut. u. Geschechtskr., II, 300. CHASE, M. W. (I945), Proc. Soc. exp. Biol. (N.Y.), 59, 134. increased capillary permeability may permit anti- CROFTON, J. W., LIVINGSTONE, J. L., OSWALD, N. C., gen or antibody, or both, to enter the tissues and and ROBERTS, A. T. N. (ig52), Thorax, 7, '. FEINBERG, S. M. (x946), 'Allergy in Practice,' 2nd ed., The Year excite reactions, the position is altered in skin Book Publishers Inc., Chicago. testing in which increased capillary permeability GELL, P. G. H., and BENACERRAF, B. (I959), Immunology, 2,64. and exudation of serum may inhibit the HARDWICKE, J., SOOTHILL, J. F., SQUIRE, J. R., and on September 25, 2021 by guest. appear- HOLTI, G. (I959), Lancet, i, 5oo. ances of reactions at test sites, by diluting and HINSON, K. F. W., MOON, A. J., and PLUMMER, N. S. (i952), spreading the antigen and by enhancing its Thorax, 7, 317. HIRSCH, E. F., and BENSON, H. (1927), J. infect. Dis., 40, 629. absorption. JADASSOHN, W., SCHAAF, F., and SULZBERGER, M. B. The possibility that immediate and perhaps (1932), Klin. Wschr., II, 857. JADASSOHN, W., SCHAAF, F., and WOHLER, G. (1937), Arthus reactions may interfere with the subse- 7. Immunol., 32, 203. quent appearance of a delayed reaction is supported KLIGMAN, A. M., and DeLAMATER, E. D. (I950), Ann. Rev. the Microbiol., 283. by report that the production of wealing KRUDY, A. G., and HOFF, R. (I959), Amer. Rev. Tuberc., 79, 78. reactions by a variety of agents of tuberculin test LAVVRENCE, H. S. (1956), Amer. J. Med., 20, 428. sites leads to the inhibition of the reaction LEWIS, G. M., and HOPPER, M. F. (I948), 'An Introduction to (Pepys, Medical Mycology,' 3rd ed., The Year Book Publishers Inc., 1955). Allergic weals are equally effective in Chicago. enhancing absorption of substances from the skin MARCUSSEN, P. V. (i937), Arch. Derm. Syph. (Chicago), 36, 494. MAUNSELL, K. (1954), 'Progress in Allergy,' S. Karger, Basel, (Abramson and Engel, 1938). The possibility P. 457. that an immediate or Arthus reaction to an antigen Bibliography continued on page 469 Postgrad Med J: first published as 10.1136/pgmj.35.406.436 on 1 August 1959. Downloaded from August I959 MAUNSELL: Drugs in Treatment of the Allergic Nose 469 nasal trouble left no doubt about the diagnosis of (Predsol) can be used in watery solution. The rhinitis medicamentosa due to adrenergic drugs drops are instilled three to four times daily and and in main to naphazoline. this treatment is of valuable help in controlling Unfortunately, it is still possible for the patients seasonal and perennial' rhinitis. Polypi sometimes to obtain these drugs over the counter. Education shrink considerably with hydrocortisone snuff as of the patient is therefore needed, and their well as with prednisolone. An increase of infected co-operation obtained to restrict the use to the episodes has not been noted. worst episodes. An important use of prednisolone and hydro- cortisone was mentioned previously, i.e. the Steroid Hormones counteraction of the rebound effect. The second large group of anti-allergic drugs Since we have to learn more about the applica- which can exert their action at the site of their tions and results of the local steroid therapy it deposition on the mucous membrane are steroid seems unfortunate that the pharmaceutical in- hormones. Of the known active adrenocortical dustry set out to combine vasoconstrictors and compounds, hydrocortisone and prednisolone steroid hormones. For example, Cortibiotic nasal (deltahydrocortisone) can act locally, whereas drops contain prednisolone, soframycin and the cortisone and prednisone cannot. Hydrocortisone vasoconstricting phenylephrine; Hydrospray con- is soluble in water, only I: 4,ooo, and hydro- tains hydrocortisone, neomycin and the vasocon- cortisone acetate is insoluble in water. Both stricting propadrin; Efcortelan nasal spray con- drugs can be given as nasal snuff. tains hydrocortisone, thiomersal and naphazoline Herxheimer and McAllen (I956) saw good nitrate, and in Delta-Fenox prednisolone is results in hay fever, using I5 mg. hydrocortisone combined with two vasoconstrictors, phenylephrine locally daily. Good results in nasal allergy with and naphazoline. Other similar preparations are Protected by copyright. prednisolone locally were reported by Anderson also on the market. and Ogden (1956). The writer took part in two Since a certain amount of the locally applied small controlled trials where patients with hay hormones will be swallowed after travelling up fever were treated by inhalation of either pred- the nasal passages via the naso-pharynx, one has nisolone snuff (i mg. twice daily) or by an inert to watch carefully for toxic general effects. In snuff containing lactose (Godfrey, Maunsell, our cases neither gastro-intestinal trouble nor and Pearson, 1957). The results in 1956 signs of Cushing's syndrome have been noted. suggested that the daily inhalation of 2 mg. Yet one should be careful and refrain from giving prednisolone snuff is of considerable value in the local steroids to patients with gastric ulcers, con- control of symptoms due to hay fever. The gestive heart failure, diabetes and tuberculosis. 1956 season was, however, unusually mild, and a One should not be too enthusiastic about the further study during the pollen season of I957, improvement of the rhinitis and polypi but realize when pollen counts were much higher, showed and let the patients realize that these drugs do http://pmj.bmj.com/ that prednisolone snuff alone in dosages of not cure the disease but only suppress the clinical 2-4 mg. did not sufficiently control severe cases. manifestations. It is, however, considered as a most valuable help in treatment of hay fever and can be given in BIBLIOGRAPHY conjunction with antihistamines and hyposensi- ANDERSON, J. R., and OGDEN, H. D. (I956), Ann. AUergy, '4, 44. tization. No side effects were observed; in par- GODFREY, M. P., MAUNSELL, K., and PEARSON, R. S. ticular the absence of the rebound phenomenon Bruce (I957), Lancet, i, 767.

HERXHEIMER, H., and McALLEN, M. (I956), Ibid., i, 537. on September 25, 2021 by guest. was noted. Prednisolone as prednisolone sulphate 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. SMITH, C. E., WHITING, E. G., BAKER, E. C., ROSENBER- (N.Y.), 28, 320. GER, H. G., BEARD, R. R., and SMITH, M. T. (1948), OUCHTERLONY, 0. (I s3), Acta. path. microbiol. scand., 32, 23!. Amer. Rev. Tuberc., 57, 330. PECK, S. M. (Ig5o), Ann. N.Y. Acad. Sci., 50, 1362. PEPYS, J. (I95 ;), Amer. Rev. Tuberc., 73, 4Q. SULZBERGER, M. B., and WISE, F. (I932), J. Amer. med. Ass., PEPYS, J., RIDDELL, R. W., and CLAYTON, Y. M., in press. 99, '759. PEPYS, J., RIDDELL, R. W., CITRON, K. M., CLAYTON, SULZBERGER, M. B. (1940), 'Dermatological Allergy,' C. C. Y. M., and SHORT, E. I., Amer. Rev. Tuberc., forthcoming Thomas, Springfield, Illinois. issue. Van LEEUWEN, W. S., BIEN, Z., KREMER, W., and RAPPOPORT, F. T., LAWRENCE, H. S., PAPPAGIANIF, D., VAREKAMP, H. (1925), Z. Immun Forsch., 44, I. and SMITH, G. (I959), in press. WILSON, J. W. (I957), 'Clinical and Immunological Aspects of SEEGAL, B. C., and SEEGAL, D. J. (I933), . Immunol., 25, 221. Fungous 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 SAVIDGE, R. S., and BROCKBANK, W. (I954), Lancet, il, 889. (N. Y.), 3, 229. VEST, H. F. (I957), Ann. rheum. Dis., x6, 322. ROSA, L., BERGAMI, G., and CENACCHI, G. C. (1957), WEST, H. F. (i958), Ibid., 17, 273. Acta. allerg. (Kbh.), iI, 8i. WILLIAMS, R. S. (x9gs), Lancet, i, 698.