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·MEDICAL MYCOLOGY
An Introduction to its Problems
BY
GC AINSWORTH, BSc, PhD, F.LS
Department of Botany
Umpersity Colirye of the South Best of England
Exeter Devon
LONDON
SIR ISAAC PITMAN & SONS, LTD

·First published 1952
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·PREFACE BOTH medical men and mycologuts incline to the view that medical mycology is a confused and somewhat esoteric subject. Medical mycologists are not of this opinion They would maintain that the apparent confusion must in large measure be attributed to the neglect into which this branch of mediane and mycology has fallen and the failure to appreciate the results of modern research. Daring the two past decades much has been done to dispel obscunties enveloping both clinical and mycological aspects of fungus infections in man and if, at the same time, unsuspected deficiencies in knowledge have been disclosed, stimulating prospects for future work have been revealed Much of the recent work is still scattered through many penodicals and no synthesis has yet been made This little book, which is neither a systematic account of pathogenic fungi nor an aid to the diagnosis of mycoses, does pot adequately fill the gap It is, however, an attempt to provide students of mycology, medicine, and microbiology with an introduction to medical mycology by using the principal mycoses affecting man to illustrate some general problems of this borderline subject I can claim only "amateur" status as a medical mycologist and thus book owes much to the published work of others I am particularly grateful to Dr J T Duncan, formerly Reader in Medical Mycology in the University of London, for arousing my interest in fungi of medical importance and to all those professional inedical mycologists who by conversation and correspondence have done so much to deepen this interest My very best thanks are given to the authors and pub. lishers who have allowed me to reproduce their work, to friends who generously supplied me with photographs or matenal from which illustrations have been prepared, to my colleagues for their criticism of the manuscript, and to my wife for help with the chapter on poisonous fungi and for making drawings GCA EXETEL oth October 1951

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·CONTENTS am PAGE V 1 II 27 38 Preface 1 INTRODUCTORY II MYCOSES OF THE SKIN Ringworm fung and the taxonomic problem III MYCOSES OF THE RESPIRATORY TRACT Mycelial yeasts and the problem of pathogenic sta vs IV MADURA Foot AND CHROMOBLASTOMYCOSIS The problem of multple causation V SYSTEMIC MYCOSES The problems of dimorphism and the source of infection VI SEROLOCY OF PATHOGENIC FUNGI A problem of diagnosis VII FUNGUS SPORES AS ALLERGENS A problem of sensitization VIII POISONOUS FUNGI A foxological problem Explanat on of The Plates 48 62 74 84 93 B blography 95 Index 103

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·PLATES (between pp 94 and 95) 1. Black Piedra (Predrana kortin) IL Trichophylos senlagropkytes III Tinca Imbrica (Trichophytort CONCERTTUUM) IV. Tisca Captas (Alacsospors CSSES) V Atuerosporum cau VL + Black grau "Alzdura fast" 2 Vladwella mycetoms grain th ISSUE 3 dainomyces grain in lung tissue VIL Chromoblacromycosts 3 Plualophora cells ta tissue 1 Sporotrichosis VUE 1 Arborne spores 2 Colonies from arborbc spores 3 Cryptocortus neoformans in brain 4 Paracoccidiondes brasiliensis Mulople buddang Coradiardes munitus spherule TADLES TACE 6 Nucetbonal Requirements of Tungs of Differng Pathogoaty 11 Differdal Characters of Superficial and Deepescared Fug 7 22 40 # Generic Classifications of the Dermatophyres V Differentiation of Candid Spouses V Refresciatyc Organisms Caumg "Maduzz Foor" VI Relation of age. Sex, and Occupation to Inadence of Systezza Alycoses Vil Cross-teacdons of Fungal Anugerus Viif. Serwianicy of Asthmasc Subjects to Dext and Aloudy. 62 83

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·CHAPTER ! INTRODUCTORY The beginnings of medical mycology case be traced to Western Europe just over a century ago It w25 IN 1835 that the Italian, Agostino Bass (1773-1856), first offered experimental proof that onc lving organism could cause disease in another by has demonstration that the muscardinc discase of salkworms x 25 Clused by the fungis now known as Ekaupena bassiana Within the next ten yeart the funny associated with favus and thrush in man were described Incerest in fing as pathogens of man was thus aroused bust before the controversy was finally scited as to whether such fungs were the result rather than the cause of disease, the bacteriological discoveries of Pasteur, Koch, and Cohn brougke about a change of emphasis The subsequent recos nnon of the undoubted importance of pratozoa and viruses as patho gens of man completed the almost total ochpse of the consideration of fung in etiology, an eclipse from which medical mycology is only Dow emerging No medical mycologist would claim thar fungi rank in smportance with bacteria and viruses as a causse of disease in mus Fungus discases may, honchet, bc of greater importana than hitherto suppoxd, for dhe effects of those already know are not impressive Emmons (1948) recently drew attention to the fact that of cc 1,385,187 dezels recorded in Vital Sisuse of the Umcd Slates for 1943, 359 were attrabuced to fung! Although this is less than o os per cent of the total at ancarly twice as many as all the deaths during the same period from paratyphoid fever, undulant fevet, smalipox, rabies, leprosy, plague, cholera, yellow fever, and relapsing fever it is greates than chat from 1} the typhus-like diseases and more than half the number from syphord fever, tetanias, or poliomyelizas The 1945 retums show a similac partern (Salve, 1950w) It should be noted, however, as Emmons points out, that effccuve prophylacoc and control measures prevenc dcaths from many better known diseases while no control measures are known for sucral fungur diseases which are usually focal On the other hand, lack of knowledge might invoke arnbuting some deaths due to fungi to other auses and a pumber the most wide spread fungus discases are not fata! 2 ·MEDICAL MYCOLOGY Rchable statistics are not available for other countries. A prehminary survey made during the war showed fungus diseases to be of comoa Occurrence in Batam (Duncan, 1945) where, according to a recent compilazon, more than saxty species of fungi have been damed as pathogenic for man and animals (Ainsworth, 1950, 1951) It was us the United States at the turn of the century that the first mycological plant pathologists were appointed by a Department of Agriculture and it was there about twenty years ago that the first trained mycologist was appointed by a Public Health Service. Most couotnies have folored the example of the United States in the field of plant pathology Very few harc yet appointed their first medical mycologist. This state of affairs is to be deplored because the significance to public health of the recogruzed fungus diseases is often scall obscure and the possible implicacon of fungi ments consideration in any disease of uncertain cause Disease Nomenclature Fungus diseases of man and animals, unlike the more numcrous bacterial discases of Iran and fungus diseases of plants, are distinguished by a speaal name in all languages, such a fungus infection is known as a mycosts Mycoses are commonly differcatated by the use of a prefix wbuch is cicher derived from the part of the body affected or from the name, usually the generic name, of the packages involved For example, a mycosis of the skin is termed a dermatomyrosis, one of the bronclu a bronchomycosts, and one of the pals an onychomycosis, while the discases resulting from an actinomycete and from Coccidioides immitis are designated actinomycosts and coccidioidomycosts, respecavely An alteraure method for coming disease names is by adding the suffix wosts to the genenc name of a pathogen as in aspergillosis (from Asper pillus), murosporosis (Aficrosporum, etc Oxbers are distinguished on a geographical basis, og North American blastomycosis wluch must zot be confused with South American blastomycosis or wth European blastomycosis (torulosus) Howevet derived, a number of disease names have an international currency wbuch is liable to mislead an unwary clinician into the behef that the meanings also have an internado al tuformury Unfortunately, this us not always so Alany diseasc names are applied to condidous nduced by more than one pathogen and if used wishout any indication of the particular fungus involved, are a frutful source of misunderstanding ·INTRODUCTORY بما Pathogenic Fungi The fungi which cause mycoses are many and diverse. To describe these fungi in detail us outside the scope of this review. So too, is a detailed account of fungi in general for which the reader is referred to any of the standard mycological textbooks (eg Bessey, 1980) To appreciate the significance of what follows it is necessary only to of vegetative filaments is known as mycelium and the individual filaments 13 hyphae The characteristic unit of reproduction is the spore and the four main Classes of Fungi are distinguished by the method of spore formation in three Classes spore formation may be preceded by nuclear fusion in the Basıdıomycetes thus sexual fusion takes place in a special unicellular structu the basidster, on which scxual spores (basidiospores), usually four in number, are bome exogenously (see Fig 7. p 91), whilst in the Ascomycetes, typically eight ascospores are formed endogenously in a somewhat similar organ known as the ascus (Plate 1(7-21) and Fig 2) Sexual reproduction in the thurd and most primitive Class, the Phycomycetes, results in thick-walled resting sporcs In addition to scrual, or perfect spores, members of these Classes may give rise to asexual or imperfect spores Sometimes there is a regular alternation of perfect and imperfect states, sometimes one spore form predominates Many fungi arc only known to produce rol sh.T. ---- > unrecognized, some are the imperfect states of known perfect fung? and arc classified in the Fungi Imperfect for the sake of convenience, and others, the great majority, are fungi which are believed to be unable to reproduce sexually In addition to the fungi proper, mycologists, and particularly medical mycologists, frequently deal with certain actinomycetes, organisms which show characters in cominon with bacteria, such as the tubercle bacillus, on the one hand and with Fungi Imperfect on LL. Tt 1. anaerobic Actinomyces and the aerobic Nocardia, brcak up into short rod-or coccus-like clements which function as spores (arthrospores) ·MEDICAL, MYCOLOGY Fungs are characteristically either parasites of plants or saprophytes of plant products Plant-parasitic fungs are well represented in al} Classes of the fungi and several important Orders and Families are composed exclusively of such forms Some major groups such as the Rusts (Uredinales) are obligate parasites of plants, other Orders of plant pathogens, such as the Smuts (Ustilaginales), can be grown in araficial culture, when the growth may be very different from the mycelial parasitic phase, whilst for many fungi the transition from the parasitic to the saprophytic mode of life, or vice versa, can be very casily cffected Fungi pathogerus for man and animals show an meresang contrast They are unrepresented in the Basidiomycetes, a Class which docs. however, include fungi poisonous for man The pathogenic status of the few undoubted Phycomycetes found associated with diseased conditions is often very doubtful, as for example, is that of Absidia corymbifera, 2 Mlucor-like mould somcames isolated from the car af man Ascomycetes, also, are rarely pathogenic, and the few that are do not usually produce ascospores in the parasitic state An interesting exception is Piedraia hortai which causes a disease of the hair in the tropics known as Black Piedra. This weakly pathogenic fungus develops as small black unsightly nodules on the hur shaft and causes no serious discomfort but it is remarkable in producing asc and ascospores withun the concretions while still attached to the living hair (Plate I) It 13 possibly related to the Asterncae, a group of cropical ascomycetes which grow parasitically in sather a similar way on the surface of leaves. Most of the important fungus pathogens of man are imperfect forms and although some can be classified without difficulty, the relationslups of others are very obscure Another contrast with plant-pathogenic fungs is the ranty, or per haps absence, of obligate parasitism A few actinomycetes and Rhinosporidium seebers, the cause of polyp-like growths in the nose and other organs, have not been cultured but most of the other known fung; pathogenic for man and asumals grow well on arpficial media It was Nickerson (1947) who first drew attention to the striking contrast between the nutritional requrements of pathogeruc fungi and pathogetuc bacteria. Among bacteria increasing pathogeructy » correlated with decreasing synthetic ability and in a genus containing both saprophytic and pathogenic forms the latter invariably have the more exartug nutional requirements Plant pathogenuc fungi wbuch in vitro ·INTRODUCTORY are obligate parasites also exbubet marked nutrigonal specializado Fung parhogenic for man, on the other hand, show a negative correlsoon between pathogenicity and spealized nutrition Thus ut illustrated in Table I where the nitrogen and growth factos requirements of sercral pathogenic frings are summarized Dryrosporing osale, the bottle biobius" of Unna is clearly the most specialized of the series for in additon to the need for organic nitrogen i requises tuamin (vitamin B1) and is the only known micro-organism for the Normal growth of which a trace of fasty ad us essendal Thus minute yeast is usually found associated with dandruff scales It has been claimed to be a conrnbutory cause of seborrhoesc dermatius and other defcets of the skin but its role in these disorders is very obscure and 1 usual stacus is probably that of a hughly specialized saprophyte. Ar the other cxtreme is Blastomyces demaindos, a virulent pathogen, which can make satisfactory growth is a simple glucose-pruneral sales medus The ringworm fungi and the mycelial yeasts show nutritional and pathogenic characteristics which are intermediate between these extremes Geographical Distribution A few mycoses lusve a world-wide discibucion Acinomycosis (Actinomyces israelt) has beess diagnosed "wherever there is a microscope and a laboratory" (Core, 1938, p 27) by the Gram posiaus, acid fast granules composed of deliace brachung hypłac, ofics with charac ECTISCC penipheral "clubs," found w pus from tissues and an assure sections (Plate VI ()) (in passing it may be noted that the filure to supplement mucroscopal observations with criacal cultural studies has resulted in uncertainty regarding the species of Actinomyces involved A single species was thought to cause actinomycosis of tuin and cradle According to the recent work of Erikson (1940) and Thompson (1950), these ase almost certainly Momlsasss caused Candido) en is various manifesta cons u also ubiquiows Both these diseases are what is termed endogenous That is, the causal organisms may be solated from apparently normal individuals and are found very rarely, if ever, Unissociated with man or animals. In contrast to thus are the exogenous decis un sluch infection is incurred from 28 outude source For some discases, such as sporotrichosis (Spototrichum xhenckt), the pathogen » a recogfuzed saprophyts, for others, such as South American blasromycosis (Pracocadioides braselsenses) which » believed to be of exogenous ongin, no external source of infection has Petice of ·8 MEDICAI, MYCOLOGY mycoses the differental characters of these two groups as summanzed by Hentia are set out in Table I TABLE II DIFFERENTIAL CHARACTERS OF SUPERFICIAL AND DEEP-SEATED FUNGUS DISEASES Superficial Mycoses Deep-seated Mycoses }(dermatomycoses moniliases) (blastomycoss torulosis, etc.) Nortaal babi of growth Parasite Saprophytic of the pathoga Lecans Mid, nuperficial, retneted Severe deep spreading Age incidence Usualy young, children Usually older people and young aduurs Occupational madence No particular occupaons Occupations exposuig the tissues to soil or vegetable zaster by wounds or in asution Geographical distribu- World-wide sot restricted Restricted or if world-wide much mort prevalent in rer tion tain areas Course Self limited, rarely fatal Prostcare oftta bel (From Heard (1940) Table I p 115) Two points may be emphasized The first us that the fungr respotsible for superficial mycoses are normally parasites of man and animals and are nell adapted for this mode of Life The diseases they cause are typscally endogenous Many of the fung responsible for the systemic mycoses, on the other hand, are believed to love normally 15 saprophytes and in general they are less wel adapted for parasıtasını The second, and perha more intesting point, is that the course of superficial mycoses follows a similar pattern to that of most bacterial and virus diseases. The incubation penod 15 relanvely short, the onser of the disease sudden, and the symptoms, which are severe at first decrease in severity with ume and so spontaneous healing results Deep-teated mycoses, in contrast, show smaanties to aberrant bacterial discases such as tuberculosis and leprosy caused by species of Mycobacterium The incubation penod us protracted, the onset of symptoms Basidious, and the subsequent course one of mascasing severity which not infrequently terminates an death.

·9 INTRODUCTORY Doth types of fungus diseases, hon ever, show a common feature in chac chey induce an allergic state in the infected subject (see Chapter VI) According to Von Perquct, a parasite is not injurious directly but only after the cells of the host have become sensazed to is products Altemauvely, according to Pleiffer, she invading organism contuns within its protoplasm endotoxins which act on the host tissues after death and disintegraton of the cells of the parasite These VICWI aC not, as Henna points out, mutually excasive Aspergillus fumigatus luch immediately produces acute disease when joculated into experin mental arumuts concausis an endotoxin, and so too, probably, docs Candida albicans which produces a similar result. Endotoxins also occur on non-pathogeruc fungi such as Rhizopus stolonifer but the occurrence of diese toxins us Dor usual among pathagetuc fungs, massive doses of which cause no Coxse reaction Experimental evidence obcaused by Henna with a fumigatus suggests that sensitization may play a parte mfection by this fungus for dere are two modal umes for death of experimental anumals, at one ro two days with large doses, and with soaller doses at about the tenth day, when the lesions change from abcesses to tubercles (sce p 46) It may be that it is about the tenth day that an afected animal becomes hypersensitized to the products of the fungus it u ac thus time that the skin teses become postuse In dermatomycoses, after a lesion has developed sufficiently the skin becomes hypersensitive so that an almost identical leston can be produced by moculation with nutrageti-concasuing polysacchinde extracted from the fungus On the other hand, a hyperscrisieve animal nuy be immune to Toinoculation or the new lesion develops much more rapidly Hearia suggests that these apparently contradictory effects of the allergic start the injurious and the procective may be due to the scac of the allergic reaction inucalation with tuberculin will protect a gunca-pig agarst re-inoculation with the tubercle baallus but a large injection of tuberculin may lead to an extension of pulmonary tuberculosis in mar in one cax út organism and products of the teampon arc cast off to the exterior in cu ocher diey are liberated into the assues in thus manner an allergic reaction in the skin muy be protectvc, un the long or kidney it may result in tension of the decax Only pathogezic fungi appear able to induce byperseritetty This type of senssity s not the usual anaphylcuc senatzsity which prevails in diseases such as asthma and hay-fever Iske sensanity to tuberculin, It is not accompanied by the development of bumeral anabodies ·12 MEDICAL MYCOLOGY to replace Tokelau itch, because the infected skin scales appeared to be imbricated, 1e like overlapping tiles It was nearly twenty years later that the French worker Blanchard named the fungus Trichophyton concentram after the concentric patterns which it caused on infected skin (Plate II) The recognition of Tokelau itch as a mycosis was the result of discoveries made in Europe some thirty-five years before by a number of workers but particularly by David Gruby (181098) who may justly be claimed as the founder of medical mycology Gruby was a Hungarian Jew who studied medicine in Vienna and in 1840, rather than submit the certificate of baptism necessary for a professonal chair, L 1 LJ LA 14 was not, however, fully appreciated antall the last decade of the century when Raymond Sabouraud (1864-1938] began his classical studies on the ringworm fungi by pure culture methods, studies which by their magnitude and authonty gave Sabouraud an unique position in twentieth century medical mycology PTY ne that is to say ores of a 18 no reaction unol the skin is scratched when a mycotic lesion develops at the point of injury The action of some dermatophytes is confined to the skin, as for example, is that of Trichophyton concentricum Epidermophyton floccosum (a cause of ringworm of the groin and feet) is also unable to attack hair, although it occasionally invades the nails, but most species are able to parasztize both skin and hair The current nomenclature of the ringworm diseases has a topical basis Ringworm of the head is designated tinea capitis, ringworm of the feet as tinea pedes, that of the body as tinea corporis and so on Although these names are valuable to the clinician they lack prension because more than one fungus is able to cause disease at any one site It is not always clear whether similar clinical conditions caused by different pathogens should be given the same therapeutic treatment There is general agreement, for example, that tinea capitis in children due to Microsporum audouini, a fungus found naturally only on man, is more difficult to cure than the very similar condition caused by M canis from cats and dogs These two types of microsporosis are distinguished with certainty only by culturing the pathogen, but sometimes ·. MYCOSES OF THE SKIN 13 an experienced climaan is able to distinguish the latter by its more inflammatory reaction which may on occasion be so severe as to induce the type of lesion known as a kenon Body fingworm in man resulting from the cattle ningworm fungt may also be pustular and such a reaction is a general characteristic of animal ringworm fungi in man. Dermatophytes found naturally only in man tend to cause less eflammation than those from animals Epidemiology A detailed consideration of the epidemiology of ringworm would here be out of place It is only necessary to illustrate the importance 1 1 another in France, species of Tnchophyton predominate, in castern Europe, Asia Minor, and North Africa other species of the same genus replace those commonly found in western Europe, whilst in the Braaish Isles the fungi most frequently involved are two species of Microsporum, M audouini and I canis (see Walker, 1950) Head ringworm, being popularly associated with uncleanliness, is still considered by muddle and upper class mothers to be a somewhat disreputable disease The animal type of Microsporum may, however, be introduced into families in all strata of society by infected pets Large outbreaks caused by this species sometimes orginate by many children having access to one source of infection such as the school cat, although most infections are of one chuld by another Alcants is generally amenable to topical treatment, or is eliminated spontancously as a result of the inflammatory reaction induced, and thus shows a marked contrast to the very intractable Af audouni which responsible for the major epidemics among children of school age A1 audouini, which was first described by Gruby in 1843, appears to have onginated in western Europe Its inadence falls off in eastern Europe and the only records from topical countries are infections in children of European residents It has, presumably as a consequence of emigration, become firmly established in the temperate parts of North America and in Australasia where, as in Britain, epidemics are dot infrequent The signs of the disease arc hairs broken off a few millimetres aborc the scalp to leave stumps surrounded by a loose sheath of spores by ·16 MEDICAL MYCOLOGY baths) are hugh and the hot and humid condition of the feet during working hours favours the growth of the fungus The Ringworm Fungi Ringworm fungi when parasitizing skin rarely show any diagnostic characters Possibly owing to the low nutribve value of keratinized tissue, the growth in skin is chiefly mycelal and the septate, branched hyphac of one species as seen in a scale cleared for microscopic examination by mounting 2 a 20 per cent solution of custic potash (KOH) are very similar to those of another (Plate III (-)) The morphology and arrangement of the spores (arthrospores) resulting from the fragmentation of hyphac are also non-specific in skin although the size and desposition of arthrospores developed on an infected hair may give valuable clues to the identity of the pathogen (Fig 1, h-), Plate (1)). It is only by growth in pure culture on artificial media that the full potentialities of a dermatophyte are revealed and no dermatophyte can be identified with certainty until its cultural characters, both macroscopic and microscopic, have been determined The nutnove requrements of the ringworm fungi arc not unduly cxactung (see p 6) Provided nitrogen is available in an organic form, such as that offered by the amino-aad mixture of a peptone, most dermatophytes will make profuse growth on a great variety of media and in order that the results obtained by one, worker might be correlated with those of another many attempts have been made to standardize diagnostic culture media The most widely used medium 15 scall the peptone-sugar medium known as “Sabouraud's Agar" which was developed by Sabouraud in the eighteen nineties Unfortunately, Sabouraud used a particular French peptone, Granulée de Chassaing, whuch has not been generally available since the First World War, in combination with a specal brand of impure maltose (Brute de Chanut) or glucose (Massée de Chanut) Later workers have shown that pure glucose or maltose may be substituted for that recommended by Sabouraud and that good results are obtained with other types of peptone, but a really satisfactory standard medium which could be prepared in any mycological laboratory has yet to be devised The importance of the composition of the medium is in part due to the emphasis that Sabouraud, and others who undertook the first purc culture-studies of the ringworm fung, placed on macroscopic cultural characters such as whether the colony is cortony (floccose, lanose), ·MYCOSES OF THE SKIN 17 powdery, or smooth (glabrous) and the pattern of the folds or conarrillo, f ---- + 1 + 1 + 1 ------- TL 1 -I . . - - Tergnes 1910 (sce Plate II) Since the publication of that mycologia) classic, medical men with little knowledge of mycology have tended to make their identifications by matching cultures against Sabouraud's figures without any attempt to ascertain the characters of the spores and other microscopical features which arc, as Sabouraud knew, of great taxonomic importance Dermatophytes produce three types of asexual spores in culture 3 conditons not yet fully understood They are often most readily produced in a primary culcure (the culture derived from an inoculum of infected material) and sometimes, as in Aficrosporum audount and Trichophylon violaceum, it is the lack of the appropriate growth sub scances which prevents their development (Hazen 1947 Georg 1948) Among other microscopic structures mention may be made of hyphae composed of cells cach dilated at one end, the so-called 'racquette hyphae,' spiral hyphae (see Fig 1) and nodular organs' which are possibly vestigial ascogonia The dermatophytes arc characteristically unstable in culture After * shorter or longer interval the culture becomes overgrown by : cotton wool like mycelium which finally replaces the normal growth (Plate II) This phenomenon is known as pleomorphism and pleomorphic cultures develop no microcondia and few if any microconudia or other diagnostic structures Pleomorphic cultures are soll patho L L Empincal work on the desclopment of media for the prevention of pleomorphic change, has shown that sugar-containing media encourage pleomorphism which is at least delayed by culture on natural media, such as wheat or barley grains, containing complex carbohydrates and on Sabourauds Conservation Agar, a 3 per cent peptone medium containing no sugar W ·20 MEDICAL MYCOLOGY characteristic of clinical favus Microsporum was differentiated by the mosaic-like sheath of small spores around the hair shaft from Trsa chophyton in which the spores were arranged in linear secies The genus Trichophyton was sub-divided into two seres according to whether the fungus developed on the surface of the hair (Ectothrix) or within the hair (Endothrıx) (Fig 1, 1, 1) Twenty years later Sabouraud revised this classification and, while still maintaining the importance of clinical criteria, replaced Trichophyton by Endothrix, Microdes, and Megaspore (Sabouraud, 1929), three genera which have been little used, for most of Sabouraud's followers prefer his earlier groupings and names Grigorakı may be cited as an author who took up an extreme mycological standpoint and devised an elaborate classification, based on the macroscopic and mucroscopic cultural characters and necessatating the creation of six new genera (Grigorakı, 1925, Gwart and Gngorakı, 1928) Vullemin (1931) distributed a number of the ringworm fungi among "non-medical genera of the Fungi Imperfect and CW Dodge (1938) employed eight genera and numerous sub-genera in the primarily mycological classificadon which he devised There is a general feeling among mycologists that genera of fungi are best delimited on morphological grounds and the most useful modern advance in the classification of the dermatophytes was the demonstration by Emmons, a mycologist by training, that three of Sabouraud's genera could be satisfactorily defined in mycological terms (Emmons, 1934) In Emmons' scheme the most important diagnostic criterion is the character of the macroconudium in the genus Microsporum the macroconidium is more or less spindle-shaped multiseptate, and thick-walled, club-shaped, multiseptate, and thinwalled in the genus Trichophyton, and pear-shaped, with no, or only a few, septa in Epidermophyton, while the absence of microconídia in Epidermophyton and other characters which served to differentiate the three genera were shown to be correlated with macrocondual characters (see Fig 1) The species which Sabouraud included in the genus Achorion were found to be naturally accommodated in Microsporum and Trichophyton as delimuted by Emmons and Epidermophyton was reduced to a monotypic genus for E floccosum (syn E inguinale) The generic proposals of Emmons have been widely accepted in North America and elsewhere Medical mycologists of the French school, however, frequently follow the classification employed by the late Professor Langeron, two of whose generic uses call for comment. Langeron and Milochevitch (1930) interpreted the condial masses ·21 MYCOSES OF THE SKIN associated with branched antler-like hyphae exubited by certain species of Trichophyton as perithecu and considered that it would make for a more "natural" classification if these species were classified, not as Fungi Imperfect but as Ascomycetes, that is to say, as Perfect Fung The relationship of the dermatophytes to ascomycetes such as those of the family Gymnoascaceae had long been considered a not unreasonable speculation and it was to the genus Ctenomyces of that famuly that Langeron and Milochevitch transferred these speacs. Langeron's other innovation was to widen the genus Microsporum, 25 a new genus Sabouraudites, so as to include certain species of Trichophyton (Ora and Langeron, 1923) Dermatophytes have been classified in more than thirty genera un addition to those already menuioned Most of these genera were specially proposed for ringworm fungi, but most of them have never been generally used, even by the authors. The relatonshup of the half dozen genenc names used by Sabouraud, Emmons, and Langeron are summarized in Table III Sabouraud disanguished speaes mainly by the character of the growth an culture and by microscopical characters, and most modern mycologists would accept the validity of these criteria even though few would agree that all the species proposed by Sabouraud can be maintained This change of viewpoint is in large measure due to the many investigations on the range of variation cthubited by fungi and by micro-organisms in general The studies by Emmons on spontaneous vanation in Aficrosporum sypseum and Trichophyton mentegrophytes indicated the very wide differences between variants produced from . differences in respect of vitamun requirements between strains within the species T discordes and T ochraciunt Emmons and Hollander concluded that "speacs lines have been drawn too narrowly among dermatophytes and that some so-called umut. ff the "splitung" of species as advocated by Sabouraud makes prease identification of the fungus difcicult if not impossible, extreme ·24 MEDICAL MYCOLOGY paper on ringworm and finds that the only clues to its contents may be the illustrations and the specific names of the funge in the familar Laun Hence the need that the names selected should be internationally acceptable Unfortunately, medical mycologists have showti a regrettable ignorance of the rules of nomenclacure, or they have wilfully infringed the rules in a misguided effort to avoid changes in names which, though famsbar, frequently lacked precisioss or were merely parochial The two man objects of the International Rules are to ensure that cach fungus has but one name in any group in whuch it may be classified and to ensure precision in the application of names The first objective is attained by the farrubar "law of priority." The Cat and dog ringworm fungus, to take a well-known cxample, was named Microsporum canis by Bodm in France, in 1942, M felmeum by Mowbom in New Yosk, also in 1902, and M lanosurn by Sabouraud in 1907 Mewborn refers to Bodin's book and so Bodun's name takes priority, M cans as, therefore, the vald name for this fungus when classified in the genus Microsporum Cats may be more frequently infected than dogs but the rules do not take into account the appropriateness of names M felineum could only be correctly used by an author who believed that different species infect cats and dogs, respecuvely Similarly, there is general agreement that Sabouraud in 1910 gave the name Epidermophyton inguinale to a fungus descnbed many years carlier by Harz as Acrothecium floccostum so that the vald name for the fungus studied by Sabouraud, if Sabouraud's taxonomy as accepted 15 E floccosum (Harz) Langer and Milochev, in spite of the fact that Langerox and Milochevitch did not transfer Hacz's species to Epidermophylon until 1930. The selection of a valid name involves the application of a set of arbitrary rules Most ringworm fungs have more than one valid name and the choice between these involves personal judgment Achorion schoenlem and Trichophyton schoenlems are both valid names for the favus fungus The first is used by workers who accept a genus based on clinical characters, the second by those who think such practice undesirable Agasi, Trichophyton mentagrophytes and Ctenomyces menfagrophytes are both valid and the second name is used by those an whose judgment the absence of ascospores does not prevent the classification of thus species as a perfect fungus. Precision in the use of rames is ensured by the type method Every taxonomic group is based on a type, a family on a type genus, a genus a ·25 MYCOSES OF TIIE SKN on a type species, and a species on a type speamen whuch may be an actual speamen or may be a published description, often with illustrations The application of a name must always include the original sense as indicated by the type It may include much more as, for example, when T schoenlesna is used to cover all the favform speaes of Trichophyton Such usage is valid until the scope includes an older taxon, the name of which then takes pronty Ou and Langeron's generic name Sabouraudites is invalid for this reason. It includes the older genus Aficrosporum of which it is an obligate synonym sunce Aficrosporum and Sabouraudites are based on the same type species The 1 good reason for its rejection Astable taxonomy is a prerequisite for a stable nomenclature and for the dermatophytes as for many other groups of fungi a generally agreed classification is sull far off An attempt to freeze nomenclature on the basis of any current taxonomic system is clearly premature and such action would be intolerable to systematists who must retun their right to devise new and perhaps more natural classifications as knowledge of fungi and their inter-relationships advances and thus to cuange names Workers in branches of applied mycology such as plant pathology and medical mycology, make frequent use of relatively few names and it is changes in these names which raise tempers and when very frequent, make for confusion The latest views of even the most eminent systematist are not necessarily final and it is often advisable to treat them with a certain sceptiasm Modifications in classification involving name changes do not invalidate earlier names which do not infringe the Rules of Nomenclature and, as already pointed out, a species may have several interacionally valid names. It may therefore, assust uniformity of usage of acceptance of a proposal to change the name of an important pathogen is deferred until it is known whether the new classification is acceptable to other systematists interested in the particulat group of fungi involved Even if there is agreement among systematists, a sound knowledge of the Rules of Nomenclature and action by an International Botanical Congress may reader changes in the names of important fungi unnecessary for the past fifteen years 1 ·28 MEDICAL MYCOLOGY can the presence of mycelium be demonstrated but the arrangement of the whorls of budding cells (blastospores) can also be conveniently studied An alternative method, which depends on the culture medium preserving the mycelial structure of the submerged growth is to take a four- to seven-day-old slope culture, wash off the surface growth remove the whole slope from the tube, and then mount thin transverse sections in lactophenol (cf Fig 2, li8, h) It is frequently difficult to induce ascospore formation in a sporogenous yeast and a number of different techniques is available Almeida and Da Silva Lacaz (1940) advocate incubation for 24-48 hours in sterile s per cent potato starch solution for this purpose and their technique has the additional advantage of revealing mycelial growth at the same time Morphology is of limited value in distinguishing species of yeasts In the LUS Candida the production of thick-walled spherical chlamydospores in com (maize) meal agar differentiates C albicans (although the absence of these structures does not exclude this species) and the flat or wrinkled, dry growth of C kruser on Sabouraud's or on beer wort agar is characteristic Usually, species are more certainly differentiated by carbohydrate fermentation tests similar to those employed for differentiating bacterial species but with the various sugars at a concentration of 2 per cent The four sugars—glucose, sucrose, maltose, and lactose-are now generally considered sufficient for the recognition of the commoner pathogenic and non-pathogenic species of Candida Castellant (1937) by using thirteen carbohydrates and other special tests, recognized more than thirty species but most of these are no longer accepted The diagnostic characters of three common species of Candida are summarized in Table IV Yeasts of Medical Importance and their Nomenclature With a few exceptions, the yeasts of medical importance are fungu imperfecti The cause of torulosis (see P 48) is an asporogenous, non-mycelial yeast sometimes classified in the genus Torulopsts but which, if the arguments recently advanced by Skinner (1950) are accepted, is best designated Cryptococcus neoformans Petyrosporum ovale (see ps), belongs to the same group The most common and ubiquitous pathogenic yeasts, however, are characterized by mycelium (or more accurately, pseudomycelium, for the hyphae may be interpreted as elongated budding cells) and belong to the genus Candida

·YEASTS
ASCOMYCETES
FUNGI IMPERFECTI
Order: Endomycetales Order : Moniliales
Family Saccharomycetaceae Family Pseudosaccharomycetaceae
(Sporogenous Yeasis)
(Asporogenous Yeasts)
a
80
Cryptococcus
b
Saccharomyces
с
d
Endomycopsis
Candida
Hc. 2, SpotOGCYOUS AND ASTOROGENOUS YUTS
Sathornyes vegetare alls, four skospores o an IT
Eskwa yopishi bypla with buding cells, dixu (after Guillermond)
YYT
-

·28 MEDICAL MYCOLOGY can the presence of mycelium be demonstrated but the arrangement of the whorls of budding cells (blastospores) can also be conveniently studied An alternative method, which depends on the culture medium preserving the mycelial structure of the submerged growth, is to take a four- to seven-day-old slope culturc, wash off the surface growth, remove the whole slope from the tube, and then mount thin transverse sections in lactophenol (cf Fig 2, f, g, h) It is frequently difficult to induce ascospore formation in a sporogenous yeast and a number of different techniques is available Almeida and Da Silva Lacaz (1940) advocate incubation for 24-48 hours in sterile 5 per cent potato starch solution for this purpose and the technique has the additional advantage of revealing mycelal 1 of yeasts spherical chlamydospores in corn (maize) meal agar differentiates Calbicans (although the absence of these structures does not exclude thus species) and the flat or wrinkled, dry growth of C kruses on Sabouraud's or on beer wort agar is characteristic Usually, species are more certainly differentiated by carbohydrate fermentation tests similar to those employed for differentiating bacterial species but with the various sugars at a concentration of 2 per cent The four sugars-glucose, sucrose, maltose, and lactose--are now generally considered sufficient for the recognition of the commoner pathogenic and non-pathogenic species of Candida Castellana (1937) by using thirteen carbohydrates and other special tests, recognized more than thirty species but most of these are no longer accepted The dragnostic characters of three common species of Candida are summarized in Table IV Yeasts of Medical Importance and their Nomenclature With a few exceptions, the yeasts of medical importance are funga imperfecti The cause of torulosis (see p 48) is an asporogenous, non-mycelial yeast sometimes classified in the genus Torulopsis but wluch, if the arguments recently advanced by Skinner (1950) are accepted, is best designated Cryptococcus neoformans Pityrosporum ovale (see ps), belongs to the same group The most common and ubiquitous pathogenic yeasts, however, are characterized by mycelium (or more accurately, pseudomycelium, for the hyphae may be interpreted as elongated budding cells) and belong to the genus Candida

·YEASTS
ASCOMYCETES
FUNGI IMPERFECTI
Order Endamycetales Order Montales
Family Saccharomycetaceae Famuty Pseudosaccharomycetaceae
(Sporogenous Yeasts)
(Asporogenous Yeasts)
C
e
8
Cryptococcus
b
Saccharomyces
C
d
h
Endomycopsis
Candida
Fic 2 SPOZOGENOUS AND ASPOROGENOUS YEASTS
Saccharomyces a vegetatke cells fout ascosports on an 2x2
Endowmpas Bypne prch budding celle dascus (after Cubermood)
Cryptus, regetagne Cells
Cmd de dagnaramatic action of a colody on solid peditum kawag
furface mass of year he details and tabroerged cluster
of budding cells connected by pscudom celom (y detail), chlasy
dospores of C abia (Al exceptſ *650 approx)

·TABLE IV DIFFERENTIATION OF CANDIDA SPECIES Cand da albicans C trop cals *C krusti Growth on Sabourauds Agar Growth on Blood Agat Growth on Commeal Agar Creamy Creamy Flat and dry Medium-sized dull grey Mycelial fange to colony Colores regular in KLC and colony shape Myceliumt Mycelium Mycelium wih blastospores like crossed stacks Chlamydosporest No chlamydaspores No chlamydospores Carbohydrate reactions Glucose Maltose Sucrose Lactose Afa) and Gas) AG AG AG AG AG (Adapted from Martin, Jones Yao and Lee (1937) P 117) Thus species possibly an imperfect state of Pha (Saccharomycetaceae) and would be better classified in the genus Afycoderma (Mackintion and Artagaveyta Allende 1943) † See Fig 2, hi ·31 MYCOSES OF THE RESPIRATORY TRACT The taxonomy and nomenclature of pathogenic yeasts, and of the genus Candida un paracular, is complex, Diddens and Lodder (1942) atc 87 synonyms for C. albicans. The problem has been much clarified during recent years and it need only be mentioned that, kafortunately, there are serious technical objections to the generic Kate Candida wbuch may have to be replaced by an older and less ambiguous name It was customary for medical writers to classify these yeast-like fungi as Monilia (hence the disease name mans genus properly used for the funei wh 1 2 as since 7020 . b ul 10 cuecision of an Internanonal BC -- # wus were found to be possible and desirable. The Problems of Pathogenic Status The best known, and medically the most important, of the mycelial yeasts > Candida albicans This fungus was recognized by Gruby 151 1842 as the cause of thrush, a disease of the buccal cavity characcerized by a whore fungal growth over the mucous membrane lining la addition, it is responsible for paronychia (an infamunatory infection of the nail bed), cutaneous infections (sometimes generalized but more usually confined to the interdigital spaces and to the axillae), vaginas, pathological conditions of the digestive tract, and disease of the lungs All these conditions are expressions of the disease complex known as morlasis in which other species of Candida may also be involved According to Mackinnon (1940). C albicans appears to be the only cause of thrush and interdigital erosion wlule C tropicalis often tem places Colbicans as the cause of monulasis of the lungs and paronychsa. Several other pathogenic species are recognized by the same author who regards C krusei and C. chalmersh as two common saprophytes wluch are frequently found contaminasng asolates of pathogeruc species Vagifles caused by albicans is most prevalent among pregnant women, especially during the churce months precedug labour, probably due to an increase of glycogen in the vaginal mucosa, there beng spontaneous cure after delivery Babies may contract thrush ac birth from such infected mothers with the result that the discase occasionally becomes epidemuc in a maternity ward The demon- Strabon of the fungus nature of the patches of skrush and the death of affected chưdren leares Attic doubt of the mycotic ongin of the disease and the visulence of the parhogen Smlarly, the mucroscopic and ·MEDICAL MYCOLOGY cultural demonstration of a species of Candida from a typical case of Paronychia leaves little doubt that the fungus is present as a primary pathogen Under other circumstances, however, the status of the fungus may be far from clear and for other conditions the role of the fungus is often, if not usually, uncertain During the nineteen-twenties it was thought that Monilia pstlosts (now regarded as idential with C albicans) played an imporcant part in the coology of tropical spruc since this fungus was repeatedly demonstrated in the stools of many affected persons Later work led to the conclusions that sprue is due to a nutritional deficiency and that the infection by species of Candida was only a secondary effect. It also became apparent that Calbicans occurs in the freces of about is per cent of normal individuals, whether from cities or country districts, and thus the demonstration of Candida in the faeces is no conclusive evidence of intestinal disease Similarly, the demonstration of Candids in sputum is very unreliable evidence on which to base a diagnosis of moniliasts of the respiratory tract Budding cells are frequently seen in stained sputum smcars These cells may have originated from the mouth Species of Candids were demonstrated by Epstein in 1924 (see Skinnes, 1947) in the mouths of 54 per cent of infants 2-6 weeks old, in 46 s per cent of those up to one year of age, and in 38 s per cent of the 1-6 year group, whilst Todd (1937) found c albicans in 14 per cent of 1,000 normal individuals (70 per cent mouth and throat, 3 1 per cent mouth only, 3 9 per cent throat only), the incidence in females (18 2 per cent) being hugher than in males (9 3 per cent) The incidence of yeasts may exceed even this level, particularly in persons with parual or complete dentures for whom Koughton (1939) found the incidence of all yeasts to be 61 per Cent in contrast to 32 per cent in a longer senes of mouths without dentures (It is interesting to note that the inadence of C albicans in the last two series was approximately constant at 24 per cent and 22 per 11 - mare h which they can be demonstrated and their number must then be taken into account The number may mislead, for Candida species are able to muluply with great rapidity in sputum at laboratory temperature and so if the sample cannot be cultured immediately it is essential that it should be stored in the refrigerator Even if budding cells are demonstrated in a succession of sputum samples and evidence for an oral ·MYCOSES OF THE RESPIRATORY TRACT 33 ongm can be discounted a dezgnosis of monukasis of the respiratory tract is not wified because I now wel establisised that Candida species are frequently present as secondary invaders, particularly in sufferers from tuberculosis in a seres of nine surveys involving the examination of acarly four thousand samples of sputum from cases in which tuberculosis was known or suspected, the percentage of speczmens in wluch Condida was demonstrated ranged from 85-75. 9-36 per cent yielding C aletceres (Skinnes, 1947, Table 1) If tuberculosis or other mfccuon cannot be demonstrated and if X-ray examination rescats a pulmonary detect, then the repeated isolaxon of Candida gives greatct justificaton for a dragnost of monedasis, thus opnion say be supported by serological cvidence (see g 70) but it is recovery after che applicaton of therapeuuc measures against moniliases which affords final proof char the dugnosis was correct Two types of lung involvement by species of Candida have been distinguished. In the one, bronchopulmonary monilasis of "bronchomonchases," which was first recogsuced by Castellans about loos, infection is confined to the bronchi, in the other, for which the term "pulmonary moniliasis” is reserved by Canant a al (1945), che Parenchyma of the img is involved The first is the commoner and qulder of the two Thic chacf symptom is a fough and, in 1906, Cascellana diagnosed "tea tasfers' cough" in Ceylor as a form of bronchomopliasis, the infecbon beung introduced in the tea dust which entered che nasal cavicies when the quality of dry tez was tested by its smell X-ray examination usually shows little more chan a son. specific type of peribronchial thickening in contrast to the heavier X-ray shadows of pulmonary momlasis woch resemble thase of broncho-pneumonia Conasis et al, loc au) These two categories of moniliases of the lungs are not, however, universally accepted Shrewsbury (1936) in the bgke of an extensive examinagon of the occuTENCE of Candida ta tuberculous sputin and moral, nasal, and throat swabs from healthy babies and adults, while recognizing that secondary thrush of the broncha does occut, camac to the conclusion this A mocal review of the literature of bronchomoniasis does not tereal any convincing reasons for the recogon of the Bume sa medical nosology petrary, independent disease should exhebat some detinenve clinical and pathological characters, bronchomorubasis exhibis more that cannot Era berefenku wote cater angezed disease Even if this conclusion s rather citieme, s sall Swinds supporters.

·36 MEDICAL MYCOLOGY who was found after death to have been suffering from a pancreatic cancer The recent recognition of the occurrence of monukasis as a secondary effect following the therapeutic use of antibiotics has focused attention on the possible effect of competition between the bacterial flora and Candida in limuting the growth of the latter Harris (1950) drew attenbon to the possibility that aldıcans normally present in the bowel may overgrow and perhaps increase in virulence following the destruction of the intestinal bacterial flora by the action of aurcomyan or chloramphenicol (Chloromycetin*) and then invade tissues, the resistance of which may have been lowered by the effects of riboflavin or vitamin B complex deficiency More recently, Woods, Manning, and Patterson (1981) have given particulars of twenty-five cases of clinical monikasis following the therapeutic use of peruallun, aureomyan, or chloramphenicol In evventy patients the oropharynx was involved 24-72 hours after successful treatment of a sore throat with an antibrotic. Three of the other cases were intestinal and the remaining two were of bronchomoniltasis. In vitro studies by these authors showed na fart on the nutriment in the substrate which allowed the monskass to develop They also tentatively concluded that treatment with vitamin B seemed to have some therapeutic value There is little evidence of any consistent differences in pathogenuary between "saprophytic" and "parasiac" isolates of C albicans and Rothman altes an interesting observation that C albicans from a patient with monilial granuloma in which the oral mucosa, scalp, face, and finger nails were involved, caused only the usual and easily cured superficial intertriginous moniliasis in an individual of 'normal susceptibility It should now be clear that the nght interpretation of fungi found in sputum or associated with pulmonary disorders is a matter for experienced judgment Neither the mycologist nor the clinician alone is usually in a posioon to come to a correct decision. A mycologist who has isolated a potentially pathogenic fungus is as wrong to assume that f was present as a primary pathogen without full knowledge of the case as is the clinician to attnbute disease to any fungus which may be reported as having been isolated from pathological material without • Regutered trade mark of Messrs. Parke, Davis & Co ·" MYCOSES OF THE RESPIRATORY TRACT 37 considering the normal disibution of the organism in question On the other hand, in the opinion of David T Smith (1946, p 3), “mycone infections occur with sufficient frequency to jusufy their beng considered as the differential diagnosis of every difficulę and complicated pulmonary and systematı infection References Mycologists are referred to the mongraphs by Diddens and Lodder (1912) and Mackinnon (1940) for details of Candida and other yeasts or yeast-like fungi of medical intportance and to the paper by Corant (1950) for the technique of sputum examination Useful clinical accounrs of pulmonary mycoses are given by D T Smith (1947), Canant et al (1945), and Almeida and Silva Lacaz (1942) The valuable review of the genus Candida by Slunner (1947) should be consulted ·46 MEDICAL MYCOLOGY here, as infection of the foot is the primary interest, the condicion designated by the original name The granules in Madura foot caused by actinomycetes are usuall small and may be white or yellow (Nocardia madurae) or red (Strepto myces somaliensis S pelletier) They are entirely composed of fin radiating hyphac and the peripheral hyphal endings may be club-like The actinomycetes usually associated with Madura foot are aerobi species That is, they probably normal members of the flora of the soil and decay mg vegetable matter Occasionally an anaerobic actino mycete is involved In current usage, actinomycosis in its variou. manifestations is the discase caused by anaerobic species which are only found in association with living organums Some authors would PIC TABLE V REPRESENTATIVE ORGANISMS CAUSING "MADURA FOOT Organisms Geographical Distributor Colour of Gran ACTINOMYCETES Actinomycoses (Chalmers and Archibald) Mycetomas (Punay) Actinomycetaceae (anaerobic) Act nomyces A ustaeli Braxıl and elsewhere yellowish Nocardiaceac (aerobic) YELLOW GRAN MYOTOMAS Nocard 4 N asteroides (Eppinger) Blanchard Europe Brazil, Argentina yellow Philippines Nbah ensu da Sun Broni yellow N convoluta Chalmen and Christo- Sudan (Khartoum) orange pherson N madurae (Vincent) Blanchard Africa (Abyssinia Algeria wbute Egyp: Senegal Soma Iland) America (Cuba Argentina) Asu (India) Europe (Cyprus Greece) N mex cant (Boyd and Cutchford) Oua USA Los Angeles) white-yellowish N ponces Verdun yellow N Transvalensis Pyper and Pullinger S. Afaca whitish Streptomycetaceae (aerobic) RED GRAIN MYCKTOMAS Shepromtyres S africanas (Payper and Pullinges) Waks S Africa ted and Henrici S pelletteri (Layeran) Waka and Hen Egypt Senegal India ted Brzl S somal ensis (Brutrpe) Walls and Somaliland, Sudan C. reddish-yellow Henna Africa na ·*MADURA FOOT" AND CHROMOBLASTOMYCOSIS TABLE V-conto) Organism Geographerd Dustbution Colour of Great FUNGI IMPERFECT Madalromycoses (Cualness and Atchubeld), Trac Mycetoazas (Puzoy) Montales BLACK GRAN MYCKTOMAS Clercepers Clapien Catenet Atgerus black C. khartomeu Chalmers and Autos Sudan black buld Gwilony Chalmers und Archibald France ("Inden folder" blact Audrelles At antenna Game! U.SA. Mboro Brumpt Cermaay black 1 pasca Makaron, Ferrada-Uczuz, Paraguay, Argentina black and Montemayor Mikedal Game USA black I lockowana Hanned and Zucts USA black 1 mytetom Brumpt Arabua, Senegal, Brazil black Ar esaldo Horta Braza BACK Mramtroi de Suva Bcaal black M tabarkar Danc and Brun Tunu black At soeun (.colle and Proy) Proy Tutus black Penatis Pwyertogene Mantels and Negra Italy black Phalmphora P jeanselme (Langeran) Ermons Martiaugue USA (hand) back black Wyota GRAIN MYCETOMUS Aspergillst 4. bouffards Brumpt bufe 4. n dulany (Exd20) Water USA white A man var mcalle Pinoy Tunas white Cephalosports C. Saintforme Camion Puerto Rico whate C recifer Leio and Lobo Braz yellow-white Anduella 7 Drumpa da Suvi Braz! white I mentont Brompt Native of Irdu and a whute Chunaqan I reynien Brumpt France, Greece Monosporium Maplopermunt Stocardo Italy Ageru, Brazil, white {ira perfect state of Alleschens borda USA, Shear) (Dela from Gammel (1927), Mackinnon Ferrada, and Moatekoa yor (1947) ) ·44 MEDICAL MYCOLOGY to treatment Ocher disease complexes differ from monilial paronychia in that the response to treatment is conditioned by the pathogen involved. Tinea capitis in chuldren caused by Microsporum camis, for example, has a more favourable prognosis than the simulat condoon caused by M audouina (see p 13) and tinca pedis caused by Trichophyton rubrum is usually more untractable than that caused by T mierdigital As far as is known, both Madura foot and chromoblastomycosis resemble pagonychia in that infections by different fungi give rise to a well-defined cliucal picture and call for like treatment The most interesting cuological difference becucen these two conditions as that whilst chromoblastomycosis is caused by a small group of related fungi, several taxonomacally unrelated groups of related fung? (see Table 1 are responsible for Madura foot Most pathogenic fungi are mycelal i culture in the parasitic stata three rather different types of growth may be destinguished The parasite may produce mycchum freely as when the outer layers of the skin become nddled with the mycelum of a dermatophysc Simularly, the pseudomycekum of Candida may at ames grow freely into the assues of the latestinal wall or of the tonsils, when, as for some dermatophytes, this invasive mycelsum causes liccle local reaction by the tissues Usually the parassac growth is more restricted when the pathogen appears as non-mycelial units of small groups of cells or the mycclal growth may develop as granules within myceto mas as m Madura foot It may be noted that the two examples of parasitic myccual growth ated are both of endogenous pathogens, that is of fungi normally found associated only with animals and well adapted for parasitic existencc The more restricted type of growth us typical of exogenous parhogens for which parasitum, even us fungi oly known assoczated with discase, as possibly only madenca! The unicelular parasiuc habit as often characterized by yeast-like budding cells These are dealt with a more detail in the next chaptes (see P 53) Here the mycetoma will be briefly considered Sunce Carter's time, the mycotic granules of Madura foot have been often compared with the scleroua nhich are a common feature of many different fung! Thus analogy cannot be maintained, for although the resemblance of a granule from a black grain mycetoma to a scleropum may be striking the similarity is only superficial A sclerotism is a hard compacted miss oE plectenchymatous tissue, usually dark in colour, and from a millimetre or so to more than 25 cm in diameter (see Fig 7) Internally there u usually a differentiation into a central region, ·"MADURA FOOT" AND CHROMOBLASTOMYCOSIS 45 la which it may or may not be possible to distinguish the constituent byphal elements, and a cortex of usadiametric cells of which the 3 produced at the expense of the reserve thatenals accumulated within the scierobum A granule from Madura foot contains so speasl reserve materials, it does not give tise to fruiting structures, and it is not a development from a colony It is in fact a whole colony and a closer analogy would be to spherical mould colonies which develop submerged in a solid medium or in shaken lqud cultures Most, but not all, fungi when grown in a suitably aerated, liquidqulcure medium, wluch is kept in constant monon on a shaking trachue, develop as more or less sphencal colonies The size of the colony, its colour, and its general morphology are often characteristic for che species (see Burkholder and Sianott, 1945) and when the internal structure is clucidated by mucroscopical examination, the raduung arrangement and someames definite concentric zoning of the hyphal consatuents recall a Madara fooc granule Most moulds are pot sensiave to gravity and the disc-like surface growth w a stationary culture is determined by the unilateral effects of the nutrsaonal gradients and the acration The development of a granule of a pathogenic fungus in assue mught be merely the result of growth in a Wuform three-dimeksional cavironmcat Such a hypothesis could explain the development of a granule in a pocket of pus but it would hardly suflice when the immediate environment is living tissues and the club-like endings to the peripheral hyphae of an actinomycouc granule probably indicate a boss-parasite interaction la thus connexion ft 3 interesting to note that in an expenmental shaken alruse, whilst the mechanical effect of one colony rubbing against another is possibly a factor in determuwig the morphology, the ups of the peripheral hyphac are undifferentiated, and on a colony coming to test they grow out cadually Attention bas already been ssawn to the simulaty becween an actinomycotc granule from Madura foot and one from a lesion of actinomycosis (Acinomyces israel) (Plate VI (2, 3)) The fungus granule of Madura foot also has its counterpart in Aspergillus fumigatus sfecuon of the lung in which the parasite may develop as a compact growth of radiating hyphae with deeply stating tips Both Henna ·parasite with MEDICAL MYCOLOGY (1940) and Almeida (1946) have drawn attention to stances of the development of “asterosd" or "actinomycetoid" forms of a number of other pathogens includug Sporotrichum schencki, Cocodiodes immitis, and Paracocadioides brasiliensis in which the normal cell becomes surrounded by a microscopic fringe of radiating processes The most probable explanapon of these abnormal outgrowths ts cheat they are 2 defence reaction of the fungus to the host and Henna (1940) discussed the possible beanngs on this phenomenon of the two phases of the infection of experimental animals by A fumigatus The first result of infection is the development of well-defined abscesses, especially w the kidney, after a week to ten days the lessons become cascous, macrophages accumulate and may fuse to fortis giant cells, and so the leston becomes converted into a tubercle In the abcess the mycelum 18 abundant and basophilic Afier cascagon the mycelum becomes pale and acidophilic, much of ic desintegrates but some grows out again as the pocular actinomycetord form At seven to ten days the skin becomes hypersensitive to the pathogen and Heancı incerpress dlac actinomycecord form as the result of 22 maceraction of the sensitized tissue Carnon and Silva (un Nıckerson, 1947) figure short germ tubes from the cells of Phalophosa speaes in tissue but the reason for the lack of mycekal development in chromoblastomycosis is unknown. (It might be interesting to compare the growth of the causal agents of Madura foot and chromoblastomycosis in skaken culture) The reason for the success of these species as pathogens us also obscure Sapsophytc growth in soul or on plant debris from which the fungi could be introduced into a traumanc lesion on the foot would appear to be a prerequisite but why some and not other fungs are constiadly associated with these condigons us stall unknown The physiological studies of fungt from Madura foot have so fac provided no clue Some species of Madurella causing black grain mycetomas have an opumum temperature for growth in the neighbourhood of 37°C buss for M grised the optimum is 30°C and for other fungi is as low as 25°C. It may be that the ability to make growth under unfavourablc condidons is of greater importance than is the ability to make opamum growth under condidons prevailing in the living host References The literature of Madara foot is extensive and confused and the disease badly needs monographuc treatment. The papers by Gamme!

·47 "MADURA FOOT" AND CHROMOBLASTOMYCOSIS (1927). Chalmers and Archibald (1916), and Musgrave and Clegg (1907) all have long bibliographies, whulst the important paper by Brumpt (1900) must still be consulted. Mackinnon, Ferrada, and Montemayor (1949) have recently dealt with the black maduromycoses of South America The papers by Carnon (particularly Carrion and Silva in Nickerson, 1947 and Carnon, 1950) should be consulted for details of chromoblastomycosis ·CHAPTER V SYSTEMIC MYCOSES The Problems of Dimorphism and the Source of infections Trze topics dealt with in this chapter are illustrated by a conssderation of six important systemuc mycoses and, as a background for more detailed discussion, the general characteristics of these diseases are first summarized Coccidioidomycosis (Coccidiordes smorskis). which has a focus sa the warm and regions of the United States, was first described in Argentina in 1892 by Posadas and Werucke who atenbused the discase to a protozoan Four years later Rıxford and Gulchrist described two cases in Southern Califors and proposed the name Coccidioides sommets for the pathogen wluch was cultured and proved to be a fungus by their fellow countrymen Ophuls and Moffit in 1900 The carly cases, in which mortality was high, shoved great chirucal diversity, the lungs, bones, skin and subcutaneous tissues, and the central nervous system bang variously involved in 1937, however, evidence was obtamed that a mild respiratory disease prevalent in the same arca and known as "Valley fever" (after the San Joaquin Valley, California), "desere rheumaaisel," or "the bumps" was the primary form of coccidiosdal granuloma, as cocardioidomycosis was then called. Subsequent invesagaaon showed that only about 02 per cent of cases of the primary form in white males (and 3 5 per cent un negroes) develog into dessemunated infections (See Emmons, 1942, Emmons a Nickerson, 1947) Torulosis (Cryptococeni neoformans) is characteristically a disease of the central nervous system although the lungs, and less frequcady the skun (see Cawley, Grekm, and Curtis, 1950), may also be uvolved Most frequently the disease takes the form of a meningitis or menog Encephalitis, when it can casily be confused with tubercular and other forms of subacute chronic meningitis There are published records of about 150 cases from all parts of the world and the frequency with whuch the diagnosis has been made after death suggests that the disease has a higher madence than thesc records indicate 'If any weatinenc favourably influences the course of torulosis it ss unknown" according 13 ·SYSTEMIC MYCOSES 49 to Cox and Tolhurst (1946) whose monograph and the review by Lodder and De Minjer (in Nickerson 1947) may be consulted for further details Sporotrichosis (Sporotrichum schencki) which has recently been reviewed by Norden (1951) is widely distributed Unlike the two I - ง forearm (Plate VII (3)) and this is followed by a succession of gummata cach similar to the primary lesion at intervals along a thickened lymphatic vessel Sporotrichosis is rarely fatal and responds well to jodide therapy North American Blastomycosis (Blastomyces dermatitidis) This disease as its name implies is endemic to North America where it is most prevalent in the castern half of the United States Two clinical patterns are exhibited systemic and cutaneous and the granulomatous lesions of the latter tately give rise to the disseminated form in which infection of the bones particularly the vertebrae and ribs is coramon Systemic blascomycosis is usually fatal whilst untreated cutaneous lesions may persist for many years Pamary pulmonary infections are common and are lable to be mistaken for tuberculosis Histoplasmosus (Histoplasma capsulatum) Like Coccd ordes imm tis H stoplasma capsulatum was first thought to be a protozoan by Darling who described three fatal cases in Panama in 1905-06 The next record was from Minnesota twenty years later since when many more cases have been encountered in the United States where hustoplasmosis is probably endemuc and occasionally in the British Isles and other parts of the world The fungus invades the reticulo-endothelial system and gives risc to fever emaciation anemia and leucopenia which arc often accompanied by splenomegaly and ulceration The prognosis is grave. Death frequently results from within a few weeks to under a year although the discase may take a prolonged chronic course and spontaneous recovery has been recorded It should, however be nenuoned that recent surveys have revealed many persons in certain parts of the Unuted States who while showing healed pulmonary lesions give no traction to the tuberculin test but are hustoplasmın sensitive (see P 72) Thus suggests that bustoplasmosis exists 22 an unrecognized perhaps sabchael forat sa these areas South American Blastomycosis (Pasacord ordes brasiliensss) 15 limuted to South America and is particularly prevalent in the state of ·$2 MEDICAL MYCOLOGY 3-4ji in diameter on hyphae near septa and slightly larger, (4-su) spherical to pyrform on laterally developed conidiophores Old cultures show numerous chlamydospores 7-12u in diameter Experimental infection of animals effected by inoculation with the mycelial growth results in a return to the yeast phase A primary culture at first tends to be yeast-like and the yeast phase may be induced at will in vitro by growing the fungus on blood agar or nutrient glucose-agar at 37°C By this means, thick-walled budding cells indistinguishable from those of the parasitic phase result Similarly, by modifying the environment Lutz and Splendore in 1908 induced the yeast phase of S schencks in vitro by growth or iftspissated human serum Since then other media such as Francis' glucose cystine agar or brain-heart infusion agar have been shown to be equally suitable provided the incubation temperature is raised to 37°C The yeast form is also pathogenic for suscepuble animals and is usually the most convenient inoculum for experimental purposes 1 11 ܘܕܐܬܐ܂ A чии дасши у. indistinguishable from B dermatitidis when diagnosis is dependent on cultural studies but if multiple buds are observed a diagnosis can be made, for these structures are unknown elsewhere in vivo In section, the spherical parent cell first shows munute doe-like projections from the periphery These increase in size and are finally pinched off so as to le free in the tissue surrounding the mother cell which frequently collapses In culture at laboratory temperature on Sabouraud's agar growth is slow and a rather glabrous colony showing tufts of white aerial mycelium results Dowding has drawn attention to the tendency for the mycelium to grow as three-dimensional network and she designates the small terminal or intercalary conidia (1-4f1 diameter) microconudia At 37°C on nutrient glucose agar the growth form is that of a multiple budding yeast In some strains the budding cells tend to remain massed together (as in P cerebriforme) while in others they break apart to give cha free treast form of a series of sections be cut through a multiple c ·SYSTEMIC MYCOSES $3 which sometimes exhubit budding. In culture on Sabouraud's agar at 1 L. On blood agar at 37°C the moist and yeast-like growth is composed of small budding cells like those seen in animal tissue Rccently, Dowding observed that in the experimental mycelium-ycast transformation the tuberculations of the large chick-walled spores increase in size and are budded off in a similar manner to the multiple buds of P. brasiliensts She therefore interprets the tuberculated spore of Histoplasma and the multiple budding cell of Paracocadioides as being homologous, and regards them both as macrocondia and the buds as secondary condia, the smaller conudia produced in culture being microconidia Brandt (1950) states that when spores of Histoplasma are injected into an experimental animal, endogenously formed yeast cells are liberated into the tissues, that is, the spore functions as a sporangium Such a development has not been observed by Dowdmg who has stated (1951, in liet) that in her hands Feulgen stann reveals nuclei in the sporcs but not in the spore tuberculations and that this, together with the bizarre shapes the tuberculations sometimes take, suggests that they may be mucilaginous exudations She still, however, believes that given the right conditions, the tuberculations become yeast cells The relationships of the growth forms of these fungi are illustrated in Fig 3 The interpretation of dimorphism is a matter for speculation The yeast-like, or non-mycelial, form is characteristic of the parasitic phase and the suggestion has been made by Duncan (1948) that this habit may be a special adaptapon for parasiasm if so, the case with which the transformation from a saprophyac to a parasaç mode of life is effected 14.14 1 . man than is supposed or there may be an animal reservoir, which for coccidioidomycosis and bustoplasmosis is not unbkely (see below) Also, it may be noted, Hestoplasma farcimtinos, which causes epizoonc lymphangitus in horses, is a dimorphic fungus and that dimorphism is common among entomogenous fuogi of the Entomophthorales Alternatively, dimorphust may be an mherent character of certain ·SAPROPHYTIC 25°C PHASE 37°C PARASITIC PHASE b Coccidioides immitis d Cryptococcus neoformans 00 f 9 Sporotrichum schencki th Blastomyces dermatitidis O Histoplasma capsulatum 1 Logo O Paracoccidioides brasiliensis P FIG 3 DIMORPHISM ·$3 SYSTEMIC MYCOSES fungi, a hypothesis in line with the generally accepted view that filamentous forms have been densed from unicellular ancestors and one which can be supported by experimental endence A typial mycelial fungus such as the common saprophyte Mfucor racemosus of grown submerged in sugar solution forms chains of budding cells and Ike brewer's yeast, gives rise to alcohol Plant pathogenic fungi such brooms in a number of higher plants Additional cvidence is forthcoming from the recent investigations by Nickerson on the mechanism of the inycclial-yeast conversion That author believes the formation of filamentous elements from a yeast cell to be due to the selective inhibition of growth (which he defines as an irreversible increase in volume), and experimental evidence indicates that for Candida compounds such as cysteine and glutathione, which contain sulphydral (-SH) groups promote cell division and hence suppress mycelum formation, whilst cobaltous sons by the inhibition of cell division have the reverse effect (Nickerson 1948) In Blascomyces dermatitidis and Paracoccidioides brasiliensis the interconversions appear to be dependent on temperature of incubation only (Nickerson and Edwards, 1949) while Salvin (1947b) found that in Sporotrichum schenckt the maximum quantity of budding cells (and occasional mulople budding) and the minimum of mycelium required a temperature of 37°C, o 15-0 2 per centagar, pH 8 2, and an increase of carbon dioxide tension to between 60 and 80 per cent. Such evidence as this appears to favour the view that dimorphism is a widely-distributed phenomenon among fungi and that it is not peculiar to fungi causing systemic mycoses in man. As for granule formation in myccroma wbuch was discussed in the KEY TO FIG 3 t cells of para as phase Blastomyces dermatitids Myselaal (h) and yeast (1) phases in culture yeast cck of parastic phase note double concoured wall. Histoplasma capsulatum k, macro- and micro-coada 1 tuberculacons of macrocomdium giving rise to budding cells (after Dowding 1941 le budding (Budding 1-1 304) ·56 MEDICAL MYCOLOGY preceding chapter, widely differing fungi are potentially dimorphic (It would be interesting to ascertain whether the saprophytic species of Sporotrichum, for example, possess this ability) and those able to function as pathogens are those which in addition are able to tolerate the conditions prevailing in the animal body Source of Infection As previously noted (p s), mycoses may have an endogenous or an cxogenous origin. In exogenous diseases the infection may be derved from another man, from an animal, or from some other source. All the systemic mycoses under consideration are believed to be exogenous and there is no evidence that they are normally contracted from human sources In Table VI the incidence of these diseases as summarized according to age, sex, and occupation This tabulation suggests that men are more often attacked than women, perhaps because men are more frequently exposed to the hazard of infection Another suggestive relanonslup is the frequency of sporotrichosis among those engaged in agriculture and horticulture and as in this disease the primary lesion is usually on the hand or forearm and can be traced to injury by a thorn or other plant material, strong clues to the normal habitat of the pathogen are provided A very interesting contribution to the epidemiology of sporotrichosis was made by Mackinnon (1949) who was able to ascertain the date of infection in 32 of a series of 46 cases of sporotrichosis which he studied in Uruguay between 1939 and 1948 Twenty-six patients were found 1 antar and non .1. pathogen on its natural habitat was promoted and the chance of intection increased An examination of the weather records of penods when epidemic infections occurred suggested that a relative humidity - nf 16 n° with no Mackinnon claims to have forecast the small epidemic outbreak of tive cases which occurred in April, 1947 Another species of Sporotrichum, S pode, causes bud rot in carnations and silver top disease in June grass, and Benham and Keston (1932) showed that S schencki, also is pathogenic for plants These workers ·TABLB VI RELATION OF AGE, SEX, AND OCCUPATION TO INCIDENCE OF SYSTEMIC MYCOSES Age Duterte Sex Rabo (M = male, Ffemale) Occupations with tugheat ungdence Range Highest trader.ce 038-70 25-35 Primary Progressive M-F M>F Labourers (most frequent in pigmented racea) 10-70 40-60 Cocadioidomycou (Could oldes imons) Torulosis (Cryptococcus neoformans) Sporotsboss (Sporotrichum schencki) IM IN Average age 29 MF (46M 1F in Uruguay. Mackinnon, 1949) Farmert, horticulturalisco, labourers 0-9-80 30-40 OM I Poorer classes North American Dlaktomnycosu (Blastomyces dermant dus) Histoplasmosis (Histoplasma capsulatum) South American Blastotnycosis (Paracoceldoldes brasilientras) 025-70 Children under 13. 38 per cerit Children 2M IF Adults 3M af J-80 21-30 11 SM F Mapual Lbourers (Data for South American Blastomycons from Almeida (1939) for other diseases from Conast et al (1945) ·$8 MEDICAL MYCOLOGY successfully infected carnation buds, a living rose bud, and detached thorns and berries of the barberry with S schencks Positive results were also obtained in carnation with other species of Sporotrichum from man, with S pode, and with an isolate of S purinosum from soil The pathogenicity of S schenckt for rats was shown to be unaffected by passage through carnation and whilst rats were successfully infected with S purinostim, S pose proved to be non-pathogenic for these animals An outbreak of sporotnchosts in the gold mines of the Transvaal during 1941-43 provides one of the most spectacular outbreaks of mycotic disease ever recorded in a little more than two years there were 2,825 cases of sporotarchoss among muners ac thc Ventersport and the Consolidated Main Reef munes (see Sporotnchosis. , 1947) Sixty per cent of the lessons occurred on the hands and armns The source of infection was traced to a saprophytic growth of the fungus on wooden minc props and the epidemic was checked by spraying the props with r YA 4. and extremely wet It may also be noted that the maximum incidence at the Ventersport mine was during January and March, the months of 11 & e chlamydospores and the port of entry is usually the lungs In endemic arcas its incidence is most noticeable among migrant or newlyresident adults and among children of school age, and there is a marked association of cases of the discase and previous exposure to dust storms and agricultural dust The seasonal incidence of coccidioidomycosis is the reverse of that of sporotnchosis It is highest in California during the dry months of June to September and falls when the autumn rains begin The incidence among troops stationed in the San Joaquin Valley was reduced by one third to a half by grassing arrfields and by spraying athletic grounds with mineral 011 (Smith, Beard, Rosenberger, and Whitng, 1946) These facts would appear to implicate the soul and Cocadioides immstes has been isolated from soul in California and Arizona on several occasions in one small outbreak involving seven of fourteen university students who made a field trip to the San Joaquin valley proof that the infection orginated from soil was almost ·SYSTEMIC MYCOSES 59 condusive All the seven students who contracted the disease, and two others who had apparently been immunized by a previous infection, were subjected to a very heavy dust exposure when digging out a rattlesnake which had entered a ground squirrel's hole and subsequendy Cimmins was isolated from soil collected at the site of the inadent (Davis, Smith and Smuth, 1942) The ccological relationship of the fungus to the soil is, however, far from clear The nutritional requirements of C immitis are not exactang (see p 6) and if it was a common saprophyte on plant debris its very restricted geographical distribution would be difficult to explain A possible explanation of the localization of the disease would be an association with an animal host of limited distribution Infected sheep cattle, and dogs have been reported in cndemic areas but the sporadıc inadence suggests that these animals, like man, are only accidentally infected and do not constitute a reserfound that 80 per cent of the pocket mice (Perognathus spp) had a pulmonary mycosis duc to one or both of two fung, Cimmitis and the related Haplosporangium parvum In 124 specimens of Perognathus, Cimmitis was found in 19 and H parvum in 95 The kangaroo rat (Dipodomys merriame) and the Harns ground squirrel (Crtellus hamısı) were also frequently found to be infected On the other hand the whute-footed mouse (Peromyseus eremicus) which is more abundant than the pocket mouse, and the grasshopper mouse (Onychomys spp) were rarely infected although living in burrows adjacent to pocket mice and in spite of the fact that Peromyseits is very susceptible to a fatal infection under experimental conditions The evidence indicated that the infection of these rodents is a chronic disease which has probably little effect on the population and Emmons comes to the tentative conclusion that the presence of immitis in soil is due to contamination from infected rodents and that it is the distribution of appropriate species which limits the distribution of cocadioidomycosis TT 1 the same fungus in the beaver (Castor canadensis) (Erickson 1949) The natural habitats of the pathogens causing the other four diseases are unknown and the data on the inadence of these mycoses gives little help Cryptococcus neoformans was onginally isolated by Sanfelice ·MEDICAL MYCOLOGY in 1895 from the surface and juice of a pcach and found to be pathogenic guiica-Pigs Kleist 182 1901 isolated the fungus from milk but there us no evidence of an contracang infection from such sources Naturally-ın{ected animals have been found, but here again there is no cvidence that these infections are of any significance in the epidemiology of human torulosis Yeasts very similar to C sscoformans are commonly found associated with man and some, such as Tonite lopss glabrata, have beeus isolated only from human sources bac Denham (1935) in an extensive series of anumal noculation experiments found the pathogeriaty of all but C neoformans to be very doubtful {t would appear that the non-mycelial yeasts from the point of view of pathogeracity, are a parallel scries to the mycelal yeasts in whuck the factors which determine whether a normally saprophytic fungus becomes pathogenic arc unknown South American blastomycosis (Paracondodes hrasılsenses) shows astain resemblances to cocadioidomycosis in symptomology (the mo discases have been at times confused), in being geographically localized, and in having a bigh incidence among manual labourers but no animal infections have been recorded and the source of infection is unknown North American blastomycosis (Blascomyces dermatindis) es exceptonal in that there are a few ustances of spread by contagion from one individual to another, but this » very rare Naturallyinfected dogs have been noted but these infections were probably only madental in the only British example of this disease, in a man who was a wood-chopres by occupadon she primary lesion was of the 1:43] Sold and systemic infection secondary (Dowling and Ellsworthy, 1925) This suggested that the section might have been derived from wooden packing cases of imported American motor-cars since Stober (1924) in the United States, in addigon to obtaining a profuse growth of B dermanınds on bread, desobed and figured from the wooden walls of the house of one patient, a fungus which showed piscroscopical and cultural resemblances to the blastomycosis pathogen The evidence for an animal reservoir for histoplasmosis as slightly stronger for there are a number of records of this disease in dogs in a recent rest in the United States of 1,314 dogs wich histoplasmun seven 8214 2 positive skio 1028on and in four of these dogs histoplasmosis was confirmed by cultural and microscopic methods (Cole, Prior and Saslaw, 1950) Emmons, Bell and Olsen (1947) made a survey of the rodent population in a rural district of Virginia where four human 200 three canume cases had been reported and if the results were not so ·61 SYSTEMIC MYCOSES spectacular as those of the rodent survey in connexion with cocadioidomycosts they were at least suggestiye, for Histoplasma capsilatum was isolated from one mouse (Afits musculus) and ten rats (Rattus norvegicus) in a collection of 1,620 animals Raftery (1951) records finding organisms morphologically identified as Histoplasma capsulatum in more than 10 per cent of 436 appendixes surgically removed from children aged 10 and under dunng a ten year period and in a recent case the isolation of H capsulatum in culture Most of the children were suffenng from an undiagnosed chronic disease and there was an unexplained high incidence of lymphoblastoma associated with the infections The high inadence of the disease Ll..! . T 11 ht L. calcifications in individuals who are tuberculin negative but histoplasmın positive suggests that man is exposed to a more general source of infection This, as for coccidioidomycosis, may be dust since H capsulatum has been isolated from soil samples from Virginia (Emmons, 1949) and Tennessee (Ajello and Zeidberg, 1981) Experimental inoculation of Laboratory animals usually results in transient granulomata Do pulmonary calcifications indicate a parallel in mani It is possible that for torulosis, and perhaps histoplasmosis, as for moniliasis (see P 3) infection is influenced by metabolic and other disturbances in the host. Approximately 10 per cent of torulosis meningitis cases have been associated with Hodgkin's discase and Cawley and Curtis (1948) have recorded four cases of histoplasmosis assoaated with lymphoblastoma (two with Hodgkin's disease, two with lymphatic leukemia) Such associations may be only acadental but of significant they may eventually throw light on the reasons for the inqdental parasitism of an apparently natura saprophyte such as C neoformans ·CHAPTER VI SEROLOGY OF PATHOGENIC FUNGI A Problem of Diagnosis IMMUNITY Or resistance shown by an organism to infection by a pathogess may be either natural, that is, an inherent character of cach normal individual, or equired, by chance or by design Natural immunity to fungal attack is widespread among both plants and animals Acqured immunsty, on the other hand, ss exlubited only by animals and so among mycologisos only medical mycologists are usually familiar with the serological techniques used for the investigation of thus phenomenon The theoretical aspects of scrology are complex and the termunology esoteric but the underlying prinaples necessary for an understanding of the present chapter may be brselly outlined Acqured immuruty is dependent on the presence in the blood serum of substances detrimental to the invading organism. Such substances may result from an acadental infection (ic an attack of the disease) or they may be acqured artificially by the use of vaccines consisting of a süb-lethal dose of the pathogen, the dead pathogen, or products of the pathogen { active immunity") or by the introduction of immune serum passive immunity') Active immuruty may last for life, and when artifical' is normally a prophylactic treatment. Passive Immunity as of shorter duration and is more often of therapeutc value The special substances present an immune scrum are called ants bodies and they result from the parenteral introduction into the animal body of other substances known as antigens An essential character of an antigen is that it reacts in some observable way with the anabody to which it gives rise When an antgen, such as a suspension of fungus spores, as mixed with serum contanng the approprate atzetan bodies (the ontiserum) there may be a glutination of the spores and the dilunons at wluch this rcacoon akes place is used to measure the titre (anobody concentracion) of the antiserum. Ssoularly, mixing a nonpazuculate angen with 13 Rerer may result as the formation of a preapitate Agglutinapon and preapicabos depeod on a simple andges-antbody the interaction In lysis, another common anagen-anabody reaction, ·SEROLOGY OF PATHOGENIC FUNGI 63 dissolution of the cells is dependent also on the presence of a thermolabile, non-specific substance or complex of substances present in the normal blood serum of all higher animals and known as complement. For example, the lysis of red cells of sheep's blood (the antigen) by sheep red-cell-immune serum (which contains the antibody) takes place only in the presence of complement, that is, in the presence of blood serum but not in the presence of serum which has been heated to 56°C for 30 minutes to destroy the complement A general property of antigens after reacting for being "sensitized") with their specific antibodies is an ability to "fix" complement and thus ability as used as the basis of the sensitive complement fixatton test for the detection of antigen-antibody reaction In this test the antigen, antibody (antiserum, after heating to remove complement), and complement (usually gumea-pig blood serum) are mixed and after a suitable interval red blood cells and haemolysin (red-cell-immune serum) added if antigen and anabody have reacted and complement fixation has occurred there is no change, if there has been no antigenantibody reaction, lysis of the red cells results The introduction of an antigen into an animal and the development of antibodies may result in the animal becoming hypersensitive to the antigen If, for example, ten days or so after a guinea-pig has been injected with egg albumin a second, and much smaller, injection of the same protein is made, death may result Usually, allergic reactions are less severe and give rise to conditions such as asthma and hay-fever (see Chapter VII) or to the localized reactions which form the basis of skin testing It must be emphasized that specific dermal sensitivity (such as that to trichophytın, histoplasmin, etc, see below) is not related to arculating antibodies and can be passively transferred to a non-sensitive subject only by skin-grafting Thayers . < fully understood Before considering the use of serological methods for the detection of mycoac infections in man, attention must be drawn to the fact that a fungus is not a single antigen and so the angserum prepared against any particular fungus will contain a number of different antibodies, TC. 1 ·64 MEDICAL MYCOLOGY a heterologout antiserum the antibodies for which it has the appropriate antigens and then testing the treated antiserum against the fungus for which it is the homologous anaserum, the presence of anagens common to the two organismis can be detected and by appropriate technique the degree of antgenic similarity can be given a quantitative value This method of cross-absorption has been used by mycologists to obtaui evidence on which to base phylogeneac speculations, she presence of anugers in common being gencraly accepted as indicating a fundamental relatonship Trichophytin During the first decade of the present century the Swiss worker Bloch found that gunca-pigs, after recovery from an experimenta srfection with either Trichophyton qmailcomm or T menfagrophytes, were immune for as long as a year and a half to ren von by the same fungus He found that thus immunity, which was correlated with a hypersensitviry of the sku, could be induced only by cutancous noculation, subcutaneous or intraperitoneal accoon of the living fungus or an extract of the fungus did not give rise to immunity or to skun sensiavity. Further, Bioch sensitized kunself by noculation with T guinckeanum and then grafted a piece of his skin and a piece of skun from a non-sensiuzed person over an ulccr on the leg of a thurd subject. Subsequent testing with a Trichophyton extract gave a positive rcachon on the skin aken from Bloch but not on the skin of the control graft or on the skin of the parent. It was Neisser and Plato in 1902 who first made an extract of a rangworm fungus, which they designated "erichophytin" and which on Introduction into a patient suffering from ringworm caused a local crythematous response around the site of the injection and a generalized reaction accomparaxed by a rise mi tenigerature Bloch found that the sponse to trichophytin appeared a week or so after stafection, an observation since confirmed by others who have shown that the skin sensitivity is sometimes setuned for many years Attempts to demonstrate agglutınıns, preapıtıns, and complemcatfixing anubodies 101 ringworm infections have failed This may be due to tribnical reasons, as Corant et al (1945) suggest, but it may be that zs the mfection is superficial the body cells do not produce detectable amounts of anabodies in the blood Skun sensitivity is thus the only immunological response to infection wluch can be eisested The same effect may sesult saturallyin generalized cutandous ·SEROLOGY OF PATHOGENIC FUNGI os signs in some infected persons, a condition first noted by Jadssohn in 1911 who descabed follcular eruptions in patients with kerion These eruptions or dermatophytrds, which are sometimes distinguished as trichophytids and microsporids according to the genus of the dermatophyte involved, occur on the body, the feet and legs, and, most frequently, the hands, and they disappear spontaneously on the elimination of the primary fungus infection. It is unusual for a fungus to be isolated from a dermatophyod which is commonly thought to be an allergic response to the systemic spread of some metabolic product of the fungus, or perhaps of fungus spores or elements, for there are a number of records of the isolation of ringworm fungi from the blood Recently, evidence has been obtained that sensitization to dermatophytes is one of the factors determining sensitivity to penicillin, the injection of wluch sometimes gives rise to a reaction stmulating that to trichophytin (Peck, 1950) Histoplasmin The inability to obtain iminune serum has hampered investigations designed to clucidate the processes underlying the empirical results of trichophytın testing Skin tests with extracts of other fungi, and particularly with cocadioidin (from Coccidioides immitis) and histoplasmin (from Histoplasma capsulatum), have given valuable results in the diagnosis and epidemiology of other diseases and as an example of modern methods of investigation and as a background for the interpretation of the results of serological diagnosis the salient features and results of a series of recent studies by Salvin on the serology of H capsulatum will be given (Salvin, 1947, 1949, 1950b, Salvin and Hottle, 19484, 19486) The usual method for prepanng a fungal extract for intradermal testing is to grow the fungus in liquid medium for a period of weeks or months, filter off the mycelial mat, and after the addition of I 10,000 methiolate, to store the sterile filtrate in the refrigerator untal needed. The extract is suitably diluted with sterile saline before use I - ! and neither sensitizes man or an experimental animal nor produces non-speafic reactions, was that adopted by Salvin in his study of the factors which influence biscoplasmin formation ·గర MEDICAL MYCOLOGY The composition of this medium is- L-Asparaginc Magnesium sulphate (Mg50.7H2O) Dipotassium phosphate (K,HPO ) Sodium atrate (Na,Cho, SH,0) Ferric atrate (scales) Glycerin Glucose (the grade kupws 25 Cerclose) Dsulled water to 1408 156 1316 098 036 2306 1008 10000 m Enimons and earlier workers estimated the titre of histoplasının by the skin reaction in gunca-pigs moculated with H capsulatum on a basis of the dilution of the lustoplasmin and the drameter of the whcals obtained. Salvin developed an assay by means of a complementfixation technique which he showed to be more accurate and to give Ieproduable results comparable to those of skin testing When thus test was used to evaluate the effect of environment and of nutritive factors on the formation of histoplasman st was found that the maximum yield of Lustoplasmıın was obtained in the glucose-asparaginc medium after eight to un weeks, with an instsal pH of between 7 and 8 a surface to volusie rado of nicar unity, and an uncubator temperature of 28°C While a sagsfactory ate of 10,000 was obtauied with glucose, better yields were obtained by the replacement of glucose by similar amounts of cellobrose (67000), dextrin (64 000), glycogen (128 000) or starch (128.000) The next study was a comparative serological examination of the anogens denved from the yeast-like and mycelial phases of H capsulatum Seven anugens were prepared (a) From the yeast phase (YP) I "whole YP cells” killed by os por cent formalın and washed 2 "ground YP filtrate" obtained by grinding washed live cells in a ball mill and filtering through a Seitz filter 3 "YP residuc," the residue from 2. 'YP broth filtrate" obtained by filtering a VP culture through a Mandler filter (6) From the mycelal phase (21) $ground M filtrate” prepared by grinding the mycelul mat in a ball mull and filtering, o "ground I residue," the residue from "A broth filtrate" (hustoplasmin 4 7 ·SEROLOGY OF PATHOGENIC FUNGI 67 Antiserum against H capsulatum was obtained by infecung rabbits with the yeast phase and bleeding them at intervals In addicon, a 11 fixation test In the precipitin tests, no anabodies were detected for the first eight days after infection of the rabbits With all anagens, peak autres were reached by the 16th or 20th day and the final disappearance of anobody uitre vaned from 49 days after infection with ground M filtrate as the antigen to 76 days with hustoplasorin, the antigen with which the lughest note was obtained In the complement-fixacon tests with antiserum from infected rabbits only whole YP cells, YP residue, and ground M residuc fchc paraculate antigens) fixed complement bue with hypenmmune antiserum only ground M filtrate failed to fix complement, hustoplasının again giving much the highest titre In cross absorption tests hypermmune serum was absorbed with cach of the anngens sungly (with the excepnon of 3) and the subsequent complement-fixation tests showed that the YP cells and ground M residue removed all demonstrable complement-fixation anabodies and that the other four (all soluble antigens) failed to absorb the antibodies which fixed complement in the presence of whole YP cells, YP residue, or ground M residuc It was concluded from these results that the anagens claborated by the mycell phase and the yeast phase were similar and that busto . 1 1 1. le as interesang to note that, whilst as already indicated the preaplan citrc of serum from experimentally infected rabbres cose to a maximum and then fell to zero, the complement-fixation titre with yeast cells 13 the anugen attained its magnum two to threc weeks later and then after a decrease remained constant for at least six months (see Fig 4) The preapıtın titte maximum coaded with the maximum clinical symptoms and so the precipitin and complement-fixation test provide a method for distinguishing the acute and chronic phases of busto plasmosis in rabbits ·68 MEDICAL MYCOLOGY The final group of inveségations related to the cross-reactions obtained between H capsulatum and heterologous sera The data from certain experiments are summarized in Table VII which clearly show the antgeninter cet adu... of IT Cocadioides dermatitidis other three fungi C immitis and C albicans in this series of experiments al - ---PRECIPITIN (H s'oplasm as ant gent COMPLEMENT FIXATION (Yeast cells as ant gen) * & $_$ $ Prec pilottre RECIPROCAL OF TITRE 0644 . O 21 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NUMBER OF WEEKS AFTER INFECTION FIC 4 PRECIPITIN AND COMPLEMENT-FIXATION TITLES OP SERUM 0 RABBITS EXPERIMENTALLY INFECTED WITH H stoplasma kapsularum (After Salvin and Hortie 1948) reacted only with their homologous anaser although the antisera prepared against these two fungi reacted with certain heterologous antgens Other workers, according to Salvin (1949), have reported that C albicans anagen fixed complement in the presence of B dermahindis antiserum but no published record could be found of a crossreaction between c immitis complement-fixing anugen and a heterologous antiserum Cross absorption tests with the four antisera showed that for cach antiserum all three heterologous antigens removed antibodies (that is, the complement-fixation titre of absorbed antiserum against the homologous antigen was lower than that of untreated antiserum against the same antigen) and that B dermatitidis had as great a combining power with ang-H capsulatum serum as had the homologous ·SEROLOGY OF PATHOGENIC FUNGI antgen These results indicated that all four fungi had antigens in common and so cach is theoretically capable of reacting with antisera prepared against the others It should, however, be noted that all the fungal antigens listed in Table VII gave the strongest reaction with their homologous sera In addition, the 1919 experiments included cross-reaction tests wich Aspergillus fumigatus and Absidia corymbifera anugens. No reactions TABLE VII CROSS-REACTIONS OP FUNGAL ANTIGANS Antigen Complement-fixagon tire of antisera prepared against antagens (3) 16 64 IG 16 16 33 O 32 C o O Histoplasma capsulation 3 Blastomyces dormantidis 3 Coccidioides immitis 4 Canada albicans $ Candids stellatokeo 6 Cryptococcus neofonnans 7 Asperg ftus fumigatus ► Absidia corymb fers 16 o 3 o 0 356, 128 64 64 1 024 o 0 2 000 o . . O 0 o 128 0 O o o Data from Salvin, 19496 (titres en roman type) and Salvn, 1950b (nieres in ita! a) Titres of antisera against their homologos antigos 10 bold face type No test. were detected and deather could antisera of significant anobody titre antgen In the same series antisera were prepared against Cryptococcus neoformans, Candida albicans and C stellatoidea All these three reacted with thieu homologous anagens and the last two also reacted, but more weakly, with their respective heterologous Candida anugen. The results suggest that the more specfic the antigen the greater its anubody-producing power (Table VII, anagens 4, 5, 6, 7) Attention may also be drawn to the antigenic dissimulanties of A corymbifera and C immilis, wluch are both phycomycetes, and the failure of A fumo gatus to react with the antisera of other dyphomycetes such as H capsulatum and B dermatitis ·70 MEDICAL MYCOLOGY Serological Diagnosis Specific cutaneous tests or serum reactions would be convenient, simple, and sapid means for the recognition of mycoses and consequently serological diagnosis receives perennial attention Different workers frequently prepare there diagnostic ariagerus by different methods, they use these preparations in different ways, and the inycological data are often inadequate for reasons beyond the investigator's control so that, as might be expected, many conflicting results have been reported The large and confused bterature is difficult to summarize and here it is only possible to indicate certain established facts and to give examples of representative uses of the method Infection by a pathogenic fungus usually results in skin hypersensitivity while the development of demonstrable antibodies in the blood u of less frequent occurrence Cutaneous testung has, therefore, predominated The chief interest in the trichophytı test, the first skin test to be devised, has been an ir use for the rapid dragnosis of infection by a ringworm fungus The evidence so obtained dearly indicates that infection by a dermatophyte usually, but not always, results i skin sensitivity, that paticnes showing dermatophyrids give a postesve reaction with trichophytın with sufficient regulanity for the test to be useful for confirming a chnical diagnosis of this condition, and that patients infected by an "animal' species of ringworm fungs, such as Microsporurn canis, which, as already indicated ( 23). tends to give an inflammatory reaction, most oftea give a strong response to trecho phytu The trichophytın reaction is not, however, speafic, infection by one species will usually induce a reaction to trichophytin prepared from another species of the same or a different genus and at 15 cuscomary for trichophyun to be a blend of several different dermatophytes Also, individuals giving a strong enchophytın response will often give a positive, if weaker, reaction with an extract of another fiuigus such as Candida albicans Many pcople give a posiqve skin reaction to "Odiomyan" prepared from Calbicans and in view of the widespread occurrence of this fungus in the respiratory and digestive tracts of normal individuals (see p 32) this is not perhaps surprising in addition to a positive skun reactios, agglutinin, preapitin, and complement-fixauon rcations may also be demonstrated both in those suffering from morubasis and apparently healthy individuals In general, for moniliasis as for dermatomycoses serological tests have only a confirmatory value in diagnosis Conant et al (1945) do, however, recombiead that the skin ·71 SEROLOGY OF PATHOGENIC FUNGI test should always be made in cases of moniliasis, as potassium iodide therapy, one of the standard treatments for that disease is dangerous to strongly sensitized persons CE Smith et al (1950) found that the combination of preapttın and complement fixation tests can establish the causes of 60 to 99 per cent of infections by Cocadioides immitis in man They also found that. as an experimental hustoplasmosis in rabbits to which reference has already been made (p 68), precipitin tests are most useful in the early, and complement-fixation tests in the later, stages of the disease Complemene fixation attains its maximum titre in disseminated infections and a fall in precipitin atre and a rise in complement-fixation atre may be a useful indication of the dissemination of an infection. Cocadioidomycosis also confers a skin sensitivity Thus may disappear in the final stages of a fatal infection but it persists for many years in those who recover A positive skin rcacaon to cocadioidin is not, therefore, usually indicative of active infection but the extensive cutaneous testing undertaken during recent years is a good example of the important information on the geographical distribution and incidence of a mycosis given by mass serological testing in South Anzona where cocadioidomycosis is endemic, more than 97 per cent of Indian children may scact to coccıdıqıdın and during the Second World War the development of coccidioidin sensitivity in troops after being stationed for training in the desert region of the United States was frequently observed Recently, Mackinnon and his collaborators (1950) have used the skin test to investigate the distribution of coccidioidomycosis in South Ameria Of 62 individuals from the hot and zones of the Chaco and other provinces 8 reacted to cocadioidin Cocadioidin-sensitive individuals were also detected in adjacent regions and confirmed the authors in their view that coccidioidomy- Series of 433 from Buenos Aires It as suggested that these low values are duc to cross-reaction with Histoplasma capsulatum In Buenos Aires 15 per cent of the population is said to be histoplasman postave and when in Uruguay 360 adults were tested with both antigens, 38 reactors to histoplasmin were detected and only one to coccidioidin, the individual who gave the strongest reaction to hiscoplasının Na positive reactors to either antgen were obtained in Santiago, Chile. 6 T.504)-14 pp.

·72 MEDICAL MYCOLOGY Histoplasmun skin-testing affords an example of the use of serological methods to elucidate 2 condinon of uncertain chology lo states of the Mississippi basın, from 27 to 83 per cent of young persons were found to have pulmonary calcfications such as are normally associated with ruberculosis Only approximately one-half of those showing such abnormalities gave a posibve seacuon on testing with tuberculu. Tuberculin sensitivity is considered to be a stable condition and a reliable indication of an attack of tuberculosis Tubercular infections did not, therefore, appear to explain the calafications in tuberculin insensiave individuals. An alternanve explanation was advanced in 1943 by C E. Sruth who suggested that hustoplasmosis might be endemic in the arca This resulted in large scale cutaneous testing with hustoplasmin and lams (1950) has summanzed the resulas of 27.780 recorded tests of these, 38 6 per cent were histoplasmin positive, 61 4 per cent histoplasmin negative, and no patient showed any signs of acuve histoplas moss When the comparative results of hustoplasmin and tuberculin tests were analysed in a series of 2,877 patients exhibiting pulmonary calafications it was found that 13 per cent were bustoplasmin and tuberculin positive while 69 5 per cent were hustoplasının possove but tuberculin negative, and s 3 per cent tuberculin postave and histoplasmin negative That is, 1863 per cent gave a positive tuberculin reaction and 82 5 per cent a possasc histoplasmın reaction These results suggest that a relationship may exist between Sarscomm plasmin sensitivity and the presence of pulsnonary calafications Emmons, Olses and Eldridge (1945) showed, as did Salvan (see Table VII), that hustoplasman gave a cross-scaction with other fungal antigens and paracudarly with blastomyan A doubt must, therefore, reman regarding the interpretation of a positive histoplasmin reaction although Howell (1947) has shown that different batches of histoplasmin vary markedly in their clinical titres and that goad anugens used at their crit artres give few cross-reactions wbule Furcolow (1950) failed to detect a cross-ccaction with blastomyan in cases of human hustoplasmosis. Naturally, a watch is being kept for muild or subclinical manifestapons of histoplasniosis in areas where the madence of unexplamed pulmonary calcifications is tugh Emtisosis, Olsen, and Eldndge reported the isolation of H1 capsulatum from the hular lymph node of a child with pulmonary alafications and recently Christie (1950) has recorded the isolation of H capsulatum from two infants and its microscopical idenafication in the lung of a third, cases which he suggests represent se benign or musmal form of the ·73 SEROLOGY OF PATHOGENIC FUNGI disease Furcolow (1950) has recorded spontaneous recovery from histoplasmosis in a chuld References Lewis and Hopper (1948) give a useful account of the results of trichophytın testing and Skinner (1947) summarizes the serology of moniliasis The papers alted in the chapter give references to additional information on the cocadioidin and histoplasmin tests For details of general serology, see Topley and Wilson's Principles of bacteriology, ed 3, 1947 ·70 MEDICAL MYCOLOGY particles has the reverse effect on fungus spores, presumably due to an increase in the growth of saprophytic moulds under the more humud conditions, and even very heavy ram storms may achieve only a temporary reduction The spore count is, however, maintained at a very low level during periods when the ground is covered by snow (Fig s) Another factor is the wind which is an important determinant of spore storms" One of the most impressive and well-documented of these storms occurred on the 6th-7th October, 1937, throughout the eastern USA when, according to Durham (1938), the weather record showed that air masses from the north-west at an altitude of 2,000-6 000 feet moved rapidly cast and south-cast traversing Minnesota to the Atlantic seaboard in about fifty-five hours During this time thousands of tons of mould spores were transported several hundred miles At nearly every station east of the Mississippi river the catch of Alternaria spores (up to 2,027 per I 8 cm" per 24 hr) was the highest of the year At seventeen of the stations the average increase in spore count was a hundred times that of the daily mean for October Mass movements of cercal rust spores regularly occur in parts of North America and India where they are responsible for initiating outbreaks of plant disease In addition to such major storms, local atmospheric discurbances frequently result in what may be termed "showers On the afternoon of sth June, 1991, at Exeter, for example, durang a period in which the temperature remained constant at 22°C the total number of Cladosporium colorues developing on groups of five malt agar plates exposed for five minutes at 12 noon, 2, and 4 pm were 6, 47, and 3, respectively The spores present in che air are widely distributed for an addition to the usual terrestrial records there are instances of fungus spores having been trapped from aeroplanes, up to 70,000 feet and over polar regions, and from the bows of a liner in mid-Atlantic In such localities the catch is lower than that from outdoor air at low altitudes on land where the spore content is higher than in mountain atr or in still indoor air The spore content of indoor air may, however, attain exceptionally high values in cow sheds and hay lofts or other dusty situations The list of identified species of fungi recorded from air is long and the list of unidentified fungi even longer in North America much attention has been paid to the inadence of Alternana spores This is probably partly because of the case with which Alternania spores can be recognized on gravity slides but theevidence does suggest that thespores of this genus, which often predominate in that region, are particularly !

·238 7604 1407 Days when rann recorded A Days when snow recorded TOTAL NUMBER OF FUNGUS COLONIES ON SIX PLATES Mucha $ 11 21 10 20 9 19 29 20 10 OCTOBER 1946 NOVEMBER JANUARY 1947 FEBRUARY MARCH AG Srou CONTENT or ntr ATNOMA Daily ukatos sa the spore content of the as a Surtos, Surrey, durzes October-November, 1945, und sacury-Febcuuey 1947 ·78 MEDICAL MYCOLOGY important as allergens Altemaria spores regularly occur in the air of this country (Hyde and Williams, 1946, 1949) but in much smaller numbers, Cladosporum spores being the most numerous In Cardiff during 1948 Cladosporium colonies accounted for half those developing on air plates, simular results have been obtained in other localities in the Besash Isles and according to a recent paper by Blackaller (1950) Clafosporium is also the predominating airborne fungus in Mexco In addition to species of Pensallium and Aspergillus, Pullularid 13 frequent and species of Phoma, Botrytis, Tnchoshecsun, etc occur in varying numbers Aerobic actinomycetes and diverse yeasts and bacteria accompany the mycelial forms on plates but phycomycetes such as species of Afucor and Rhizopus are less commonly recorded than their {repuency in soul and other situations mught suggest. Fungus Spores as Allergens By inhaling the spores of the Perucillum, in an involuntary experiment, 2 severe attack of houtseness, going on to complete aplonia was brought ou. This listed for a couple of days, and ended on a sharpsh attack of bronchial catarth, wluch almost unfitted me for duty for a day or two. The sensatons were so unpleasant that I have never cared to reproduce them So wrote Blackley in 1873 of an experience which suggested that fungus spores could give rise to an allergic response in man It us clear from the data summarized in the preceding section that fungus spores are always gresent in the air, someomes in very large numbers What is the evidence that such airborne spores affect mant The connexion between auburne pollen and hay-Fever which was firmly estabbshed by Blackley, if not unanimously accepted ac the ume, was first suggested by Elliotson as long ago as 1832 Blackley's foonnote on hus experiences with moulds passed unnoticed and it is only within the last twenty-five years that the importance of mould allergy has become generally recognized It was in 1924 that Van Leeuwen noted in the island of Zuid-Beveland that o s to 10 per cent of the inhabitants of some villages were asthmatic, an nadence greatly in excess of that prevailag in other parts of Holland Hc failed to associate thus condition with any meteorological peculiarity and attrbuted the cause to "miasmata" or 'chmate allergens" Further, he showed that sufferers were relieved by 21 freed from "mismatc substances" by filtration through cotroo wool or by passage through glycerin and he suggested that these bome ·79 . FUNGUS SPORLES AS ALLER GENS substances were mainly of fungus ongin. Ako in 1924, Cadham in Canada recorded three cases of agricultural workers who developed severe asthma on exposure to dust from tested gram and infected straw He considered the stem rust (Pucanie grammes) sports to be the causal agent and he was able to induce a paroxysia by the inhalaton of a few rust spores According to Feinberg (1948), at a possible that the rust spores were contaminated with spores of Altemarss or Cladon sporrum because most rust spores are ineffective as allerges and are obtained on pure culture with difficulty Whether this was so or not. Cadham was ablc to afford some rclict with a vaccine prepared from the rust (Cadham, 1924) In 1930, in the U.S A, Bertots described a case of Asztma asociated with Aspergillus fumigatus and Hopksris, Benham, and Kesten in the same year described a similar case caused by Alterana spores deaved from vegetables stored in the basement of the paucae's house Smce then many more instances have been recorded and Dura ham (1938) states ckas afecs she storss of Altemaria spores to which ceferetice kuas already been made "2 brief ingiury has disclosed the correlation of clinical symptoms with the advent of the storin LA SOM of the places affected." The most frequent sytriptoms of mould allergy are respiratory and usually take the form of bronchual asthma or thuis Conjunctivitis is anocher comunon manufestations of mould allergy and in 1939 Feuberg (see Fesnberg 1948) reported fourteca cases of scascaal aggravafson of dermanus m mould-sensitive patiens in which there was a positive cortclation of fungus spore counts with the intensity of clinical symptoms Respiratory symptoms usually occur in summer" and may prevail from April to November in contrast to the more sharply defized attacks expenenced by pollen-sensitive subjects Sometimes B-the-year-round symptoms occues or the symptoms may be confined to the spring and autumn and these patterns may possibly be atburad to serislavity to fiwg such as Aspergillus and Penielsum which occur In the air at all times of the year for to co-sensitization to house duse) and to funga showing seasonal opt02, respectively A mould-sensitive subject gives a postave skin reaction to one or more funge at fungus extracts (specific or even genere specificry u tare) and cutaneous testing is the souane method for diagnosis of mould sensitivity Fenberg states test the scratch test with a s 1,000 Extract of the movid (1 gm of dry culture per 1.000 ml nominal saline soluton) resulung in an imeduse aliealing type of reaction, is more conclusive than the incadermal test. 61-T304) ·fo 1 MEDICAL MYCOLOGY Treatment is by desensitizapon by the admiustration of increasing doses of fungus extract given once or twice a week. The first injection 15 Osml of I: 10.000 dilution and the maximum about 1 ml of a ml l9991on The extract uscd depends on the particular case It more usually it is prepared from - Ars Anti- • mptoms but the most gehitlow? Interest in mould allergy has been greaichl u. es where many papers have been published on the subject and whilst the fact that mould allergy us of widespread occurrence and of clinical signuxcance appears to be beyond reasonable doubt much of the data lacks precision This is due in part to the variation in the diagnostic proce dures and in part to the difficulty of obtaining proof of the specific allergens involved. In a summary given by Fernberg (1948, p. 275, Table 19) of the results of eleven investigacions sa de Vanced Seates involving ecsts on more than five thousand individuals suffertag or suspected to be suffering from allergic disorders, the percentage giving 2 posiave reaction to "moulds" vaned from less than 5 to 85 per cent and she reaction of one group diagnosed as suffering from "mould allergy" (75 per cene) was probably not significantly different from that of other groups of "respiratory" and "general allergy" cases which gave 69 and 85 per cent positive mould reactions, respecovely Simslar results have been obtained in other countries Van Lecuwca in Holland found that half the asthmatics he rested gave a positive reacaon to fung Thus compares with is per cent posave in Germany by Hansen in 1928 and 16 per cent in the same country by Fraenkel in 1938 who obtained sj per cent of mould reactors in a series in England In a series of 638 alergic pabenis examined by Fernberg himself, 267 (40 9 per cent) gave a positive reaction to fungi and because a number of patients had failed to respond to therapy cisewhere he considers thar dus figure should be cut to about a half and that on a conserviave estimate za per cent of allergic persons are sensiave to fungi Feinberg also states that 80-90 per cent of his mould-seastave patienu obrain relief from desensitization therapy with mould extracts (and ates claims of 80 and 75 per cent of successes by two other workers) which dearly supports the dam that fungus spores function as allergene. The fungus spores present in ur are normally derved from the şaprophync or parasitic growth of fungi on plants As Hyde and Wilbams (1940) and others have pointed out, the straw of wheat and order ·BI FUNGUS SPORES AS ALLER GENS ccreats would appear to be an ideal medium for the growth of Alter- Ama and the predominance of subome Altesania spores as she states oor adjacent to the wheat belt of central and castern V.5 A. IS, there fore, not surprising while the dommance in other parts of the world of Cladosporium herbarum, an ubiqurous and unspecialized saprophyte, 23 likewise to be expected la addition to allergic disorders caused by spores of such widespread funga there are a number of mstances of allergy to fungt of more localized distribution. Cobe, in 1932, descnbed a case of asthma due to the tomato lafmould fungus (Cladosporum fulrum), the spores of which occur in Lugh concentrations 13 glasshouses concaning affected plants, add similar ases azt ated by Brown (1936) and by Morrow and Lowe (1943) The powdery mildew of oak (Aficiosphaers sms has been associated with allergic disease in Califonua and, according to Fernberg (1948), Sir John Floyer in her Treatise on Asthma, 1726, sand There is Remarkable Instance in Bonetus of an Asthmatic, who fell into a volent Fit by gong isto a we-ceBar where Must was fermeuting wluch is perhaps the first record of mould aletsy Towey, Sucany, and Huron (1932) reported a series of cases of asthma un Mschsgan caused by the ubalacon of a fungus (dentified as Consosponu (Cryprostsoma) corticole) wluch grew on dead maple trees was suggested that is "saplo-bark disease" the fough, fever, night IN cats, and loss of weight were in part caused by a local toxac effect and in part a delayed effect resembimg prorcun seriusstseity Also, during the was the "mal des cannes de Provence" which had been recognized for more than fifty years as an occupational disease of those who handled reeds for thatctung became prevalent in the paper mills of the Muda region of France where the teed Arundo donax was being used for its fibre This disease is characterized by lassitude, stiffness, low fever, and slight scrotal swelling Later a prongenous erythema spreads upwarda from kicshiner surface of the thighs and becomes parucularly sesere in the armpits A cough developi. Work is no longer possiblc The Pa@ent is obliged to rest Hus condition at once improves and recovery # complete in ten to fefuzea days On sexxposwt to the reeds there is fecurrence of the symptoms Ducht (1944) who investigated thus condition attributed the compiunt so the response of a sensuazed individual to Consosporium arundis (Papulanta sphaerostroma) which occurs on she lower leaves of reeds of more than one year old Further, Be suggested thus the actie prinaple was a browsush black visad fund which can be extracted from the fangus IC ·82 MEDICAL MYCOLOGY Moulds and Dast Allergy Dunng recent years increasing interest has been paid to the industhal hazard of dust. Suicosis in muncs is caused by the mechanical action of the mineral particles constituting the dust The cause of bagassosis, an occupational disease of those handling bagasse, the crushed sugar-cane used to make insulating building board and other products after extraction of sugar, is more obscure but this disorder, too, possibly results from some non-alergic cffect Other dusts, and particularly house dust, may, however, at least sometimes owe their ability to induce asthma and other disorders to the allergie action of fungus spores The first published record of dust allergy was that by Cooke in 1922 who described the case of an asthinatic who gave a strong skin scaction and mild asthma to an extract of dust from his room but not to other allergens Cooke was unable to establish the identity of the active fraction in the dust but he found that 109 (or 33 per cent) of a series of 327 asthma patients gave a positive reaction to "dust" (Cooke, 1922) In 1931 Flood tested ss patients suffering from chronic asthma and obtained 8 possove reactors to fungi isolated from house dust in one patent he preapitated an attack of asthma by spraying the nose and chroat with a culture fifcrate of Afucor plumbeus, the mowld to wluch the patient had reacted Brown (1936), who briefly reviened the topic of house dust as an allergen ared further examples and indoned to the view that moulds were the cause of dust allergy The evidence obtained by Romington and lus co-workers in England (see Sallwel, Rimington, and Maunsell, 1947) and by Reymann and Schwarc (1947) en Denmark does not, however, support this view Some of the tests made by these invesagators are summarized in Table VIII from which it can be seen that 37 of the 38 patients sensitive to moulds were also sensiave to dust but that of the 101 sensitive to dust only 37 were sensitive to moulds Only one pacient was sensitive to moulds alone Sullwell et al (1947) prepared a "crude dust-anugen' by the extraction of a ton of dust and they found this antigen at 10-6 to give an intradermal reaction with 6 per cento normal persons andwich 70 per cent of those with allergie symptoms Further it was shown that subjects with a threshold value of 10-* with the dust allergen showed allergic symptoms 33 a dusty atmosphere and treatment by desensitzation with this antigen gave some selsef to 16 of 18 patients Addsaonal evidence of the distinctness of the dust and mould antigens is Feinberg's observation that mould allergy is most frequent in children ·FUNGUS SPORES AS ALLERGENS 83 1 I...8 LC I bese tacts rather suggest that dust and mould allergy are not very closely related phenomena The relationship may, however, at times TABLE VIII SENSITIVITY OP ASTHMATIC SUBJECTS TO DUST AND MOULDS No of Patients Dust Moulds Polysaccharide from Pencil . SPP za 13 + 5+ I + Reymann and Schwartz 1947 9 63 45 + 17- 15 + 17- Stillwell, Remington, and Maunsell, 1947 36 36 + 12 + $ 5 + 5+ + S+ 132 for + 37 + JI- Totals be closer as in the so-called 'farmers' or threshers' lung" which has been noted in country districts of England (Fawatt, 1938) and Scandinavia (Tornell, 1946) This respiratory condition, which References The reviews by Brown (1936) and Morrow and Lowe (1943) and the chapter "Allergy to Fungi" in Franberg (1948) all have long bibliographues. Reference should be made to these publications for the references to work not specfically ated in this chapter and for other details ·CHAPTER VIIS POISONOUS FUNGI A Toxological Problem "That some fungi are edible while others are pouonous has been known Since carkest ames Classical writings contain numerous references to fungi and it is characterisac of human nature that there harmful effects were noted before their use as food tvas recorded. It is among the larger fungi, particularly the Basidiomycetes (mushrooms and toadstools), that most of the edible species are found A few arc Ascomycetes The number of poisonous species as small compared with those which are inocuous Nevertheless, serious illness and even death from cating badly chosen specimens as of frequent occurrence, particularly in countries where the population is less conservative in its taste for fungi chan sa Bricain, so that in parts of western Europe special legislanon segulating the sale of fresh and drsed fungi is an operation There is no general rule for the recognunon of poisonou fung? except the correct depafication of those which past experience has shown to be toxic, Poisonous species are frequently closely related to those which are edible Some genera composed almost entirely of speaes highly esteemed as food include one or more poisonous forms, og the genus Psalliota includes the poisonous P xarichoderma, whick dosely resembles common mushrooms such as P arvensis (the horse mushroom) and P campestris (the field mushroom) On the other hand, most species of a genus may be pouonous while a few are edible The genus Amanita, for example, includes the highly poisonous A phalloides, the poisonous but less dangerous A miscard, and the edible A. rubescens True poisoning should not be confused with wconycricbe caused by cating indigestable or old speamers or with individual idiosyncrasy A poisonous fungus may be defined as one which when eaten fresh and in moderate amounts by normal individuals regularly causes defiuto symptoms of poisoning Cooking or drying alters the poisonous properties of some species (see Gyromitra esculenta, p go) and furiga which are normally edible may become harmful with age dac to the chemcal changes attending decomposition. In the present chapter the range of fungus poisoning is illustrated by 64 ·83 1 POISONOUS FUNGI a brief consideration of the commonet poisonous basidiomycetes sad ascomycetes caucountered in this county and of ergotism induced by the inadvertent ingestion of the scleroba of Claviceps purpurea. Larger Basidiomycetes More than 90 per cent of the recorded deaths from fungas poisoning arc aused by Amanila phalloides Poisoning by this species us always serious and frequently fatal, deaths following poisoning besng placed at from so to 90 per cent. A phallordes is common in the woods of this country and Western Europe in late summer and early autumn It also occurs in North Africa and Japan but appears to be rare in North America. The cap of a well-developed sporophoce ss fleshy and when fully expanded, about 3; in in diameter It is born on a stem approximately 4 in long, vaties un colour from olive or a darker centre cohen - white, and there 21 The gills are crowd out to which is wluce or anged with green, bears a well marked ning and has at the basc a large white or yellowuh papery volva. The mature spores arc white (See Fig 6) The characterissic features of A phellodes pousoning are well marked For a vatuble ame after ingestion, usually 10-12 hours but sometimes as long as 14-20, no inconvenience is felk. Thus period of incubadon is followed by the sudden onset of severe abdominal pains vomiting, diarrhoca, and great thurst. Painful cramp in the calves, coldness of the extremitics, and cyanosis are also characteristic and the clinical picture resembles that of cholera. After this first phase nervous symptoms develop but delimum is rare On about the second day the condicion of the patient shows an apparent improvement but the various symap toms usually return two or three days later with increased severity and it becomes evident that the liver is seriously affected The nervous system next becomes paralysed, che pauent may lapse sto a coma, and death ensues There are many variations of this syndrome one type of symptom commonly picdominaung The gastro-intestinal symptoms are usually the most important but in some cases complete immobility and prostration predominates, in others there w prolonged coma, delirium, or convulsions, while the heart, livet, and kidneys are all affected in varying degrees. Post-mortem exatunauon shows a lack of rigidity and the blood, which is cherry-ted so colour or black and Viscous, fails to coagulate The pupils are dilated fatty degenericon of the liver and kidneys is commor ·86 MEDICAL MYCOLOGY Much work has been done on the chemical nature of the toxic principle of A. phalloides since Boudier in 1846 considered the Poison to be an alkaloid. The foundation of present knowledge was laid by Kobert in 1891 who isolated a complex toxic substance (a glucoside) wluch he named "phallin" and which ford showed to consist of at least two fractions, amaruta-baemolysui and amanita-toxın. The first, Aing 10 Volva a a Fig. 6 Amanita palloides SFOROPHORA 4x6, Dugram of a bas.dura and four cxogcuously developed baudiospores. X 500 a hacmolyac poison, is thermo-lable and destroyed by digestive juices, the second is more stable and is not inactivated by the digestre jusces or boiling water although it is decomposed by boiling ands More recently, in 1937, Lynen and Wieland isolated three poisons. One of these, pluch they named "phalloidın," is a hexapeptide and acts more quickly than the other two. Io animais it causes lesions of the lyer and digestive tract similar to those of A. phalloides poisoning wat man Although one mouthful may prove fatal, recovery from A. phalloides poisoning does occur. The recovery is, however, always slow and the outcome of the various treatments which have been ·POISONOUS FUNGI recommended uncertain The Pasteur Insatute has developed at ants-phallodun serum This is mjected esther intravenously or hypodermically in amounts of 40 ml or more Good results are clumed of the injections we given soon cnough. Since, however, # 15 poc usually known that A skallordes has been calen und the symptoms of posoning appear, and suce the senim is not always Easily procurable, thus carment us of more thcozrucal thar practical interest The observaton that rabbits and sheep cat small amounts of A phelloides without il effects has led to the patient being given the fresh brains of seven rabbits and the stomachs of three chopped up together, the explanation advanced being that the possoning is due to two toxins, one, which acts rapidly on the hver kidneys and latestines, being neutralized by the stomach of the rabbit, the other acting more slowly or the pervous system being neutralized by the tabbit brains Though repulsive to the patient, cutes beste been cficcted by this means to France Glucose anjected stravenously, as used sa Germany agaisse A phallosdes poisoning and thus treatment has met with success both in dinical cases and m cxperiments with animals The reason for its success is not fully understood for though hypoglycaemua os caused by the poisoning this does not seem to be an essential feature Another setle understood treatment for which successes have been clasmed as thae of giving common salt, cher as intravenous injoftions or orally Two other fuaga u kich are closely allied to A phalloides and wbuch cause the same type of poisoning are å vera and & virose in all three the effect of the poison is to cause degeneration of the cells of the miternal organs, parucularly the lives and kidneys and death from quently follows The syndrome of Leptors heh cola porsoning rescinbles that caused by a phalloides but Volcarca giocephala and A citrus, boch at onc asic thought to cause poisoning of this type, are now known to be non-towc Amanita muscaris and A panthening are both responsible for personing of a very different type. They act predominantly on the nervous system and gastro-intesanal sy mproms, though present, are usually of *condary importance of the toyo, A pancherista auses the more Htious possoning and a death rate of 10 to 30 per cent is reported by some authorites A muscara, although the popular prororype of a possonous fungus, is not fazat if the subject us healury Aksion, the dy agaric (so named because it is lethal to fles). $ nell known on account of its bnght scarlet or orange-red cap on the ·88 MEDICAL MYCOLOGY surface of which are scattered whitish, tart-like masses The gills and stem are white There is a sell-developed ang but the volva is represented by only a concentric series of white or yellowish squamules above the bulbous base of the stem The colour of the cap of A pantherına varies from yellowish-brown to brownish-grey Thc stem is white with a bulbous base which shows the remains of a volva and the obliquely attached nng does not persist In contrast to A phalloides poisoning, the onset of symptoms occurs without delay, usually within 3 hours of the meal Vomiting and diarrhoca are accompanied by delirium and hallucination which is both visual and auditory These contnue for about four hours and are followed by a deep stupor and sleep from which the patient wakes feeling much better and with no recollection of hus illness Sometimes the digestive symptoms are more pronounced and in such cases the poisonous matter is quickly climinated from the system and recovery is rapid More rarely there is no digesave upset and then the delirium Is more serious The effect of the Ay aganc on the nervous system has long been known In 1560, thc herbalist Bauhın called this fungus "the fungus of folly" and it is greatly esteemed by the Koryak tribes of north-cast Siberia where it is caten to induce excitement and intoxication The first poisonous principle to be isolated from A miscaria was muscarine (myceto-muscarine) which also occurs in A pantherinaſt has since been prepared experimentally by the oxidation of choline which is also present in the fungus in fairly large amounts and which is probably responsible for the digestive troubles usually accompanying A muscaria poisoning Although muscarine induces characteristic symptoms, parucularly excessive cxcretion by the sudonal and salivary glands, diarrhoca, and slowing of the heart, they arc not the chief sedan 4 erana nosennms These are generally induce - miscaria appears to French workers as the "pantherine syndrome to distinguis al llum the "sudorian syndrome" induced by muscarie In addition to A muscaria and A pantherina, muscandine be the active prinaple in Chitocybe dealbata Crvulosa, and in species of Inocybe, eg 1 patoullardı which may be fatal, while muscarine is present in agancs such as Strophana semiglobala, exceptionally in C dealbata, and in the tube-bearing fungus, Boletus calopus ·POISONOUS FUNGI 89 The trcatmeat for poisoning by A muscarid and other fungs having a like effect w broadly speakng that for violent indigestion. Vomuung s spontanicous and should not be induced bus purganves may be administered to expel any remaining fungus Potassium brotude and chlonde arc gue agarust the pervous symptoms and the injection of ether or other stimulant combats cardiac depression. The North American form of A pisscaria appears to concaun larger amounts of muscanine than do European speamens and açanst thus atropue is effective but this drug should not be adwnistered in cases of poisorung by the fly aganc in Britain. Chanzcal symptoms kave frequently been used as a basis for the classification of poisonous fungi and although such classifications are auscfisl they are very ampliaal Symptoms wisch wually predomanats in pozsarung by a giverz fungus are often modified by idiosyncrasy of the patient so that they are only a guide to the speaes muvolved Microscopsc examinadon of the vonut and stools for spores or fragmear of tungus may provide more reliable dragnostsc evidence The clinical classification devised by Roch has been used by Dujarric and Heim (1918) who recognize three categones of poisonous agare 1 Fung which after a long incubation-period cause the degeneration of the cells of the antemal organs, eg Amonisa pialloides, A verat, A. virosa 2 Fungs which affect the nervous system duectly, eg A muscania, 4. panthertna 3 Fungr causing gastro-enteritas, & Entoloma ke vidum wluch us sobie mes faca! There are many other basidiomycetes wluch have a muldly possonous acton on man and may be considered as indigesable and therefore best avoided with most of these the symptoms are confined to nausea, yomjang, colic (which may be punful), durrhoea and sometimes nervous or other troubles but these last are usually of secondary importance Tncholoma pardınsum causes violent and painful enteritzs which may persist for as long as six days, and several species of Russula and Laclanus have a dendedly irritating effect on the digestive tract. Some European species of Boletus 19€ able to cause gastro-intestinal upress and the polypore Fomes offranalis has long been known for its purgate 3Don. Reports of possorung by other basidiomycetes are not uscosimon but the evidence as to the identin of the species caten is often unreliable and conflicting ·90 MEDICAL MYCOLOGY of a rather different character are the troubles 2310czated with Coprinus Diramentarias one of the common inkcaps Although the fungus can be citer with impuruty by some people with others of taken with alcohol it is said to have produced cardio-vascular ereilussa, congestion and cyanosis of the face and scalp The syraptoms die sway after some hours If however, more alcohol is then drunk they may remappear it has been suggested that the poisonous substance as soluble un alcohol but this does not explain the sporadic nature of the attacks There is no satisfactory explanabon of the facts Larger Ascomycetes The most esteemed esculents among the larger ascomycetes are truffles (the underground fructifications of species of Tuber) and Morchella esculents the more Rather simular to the latter is Gyromettra esculente This fungus which causes pozsonungs which may be faca! has a deeply convoluted cap fawra-coloured when young and dark chestnut in older specimens. The surface of the cap turmus in to meet the whuash stem wuchs is fartened somewhat and longitudinally grooved If cooked or dned the poisonous propertes of G esculenta arc lost though pousonings do occur when the cooking water as served with the dish. For thus ressons the number of cases reported in France where the fungus 13 caten cooked or dred is small Porsonings are more frequent u Germany where the fungus is caten raw or after letle cooking and cases resulting in death have been reported from North America There as always a long incubation perod after the ingestos of the fungus varyug from eghe hours to two days and this as followed by vonucug diarrhoca nervous troubles and ictera and alcomaning periods of decp sleep and convulsions the liver and spleen are swollen and the pulse slow and utrcgulas A coma may precede and continue up to the use of death It was first thought that poisoning 23 due to a haemolype toxos helvelic acid which was solated by German workers before the end of the last century Thac and is destroyed at temperatures of about 60°C and by drying and this would explain why cooked and dred specimens lose their toxiaty On the other hand it us known that the poison docs at times occur u the cooking water and recent work indicates that the problem is a complex one It seems likely that a second thermostable posson as present and that this alone is able to cause death Some workers event state that no haemolytic symptoms OCCUI u man Personal adsosyncrasies bere too would account for ·96 com- POISONOUS FUNGI some of the contradictory evidence (some people are able to at G esculenta raw and children are more lable to poisoning than are adults) but not for all. Onic suggesuot is that possonings Te anaphylactc in nature since poisoning often occurs when 1 second meal of the fungus is taken shortly after the first Ergotum Spores of the ergo fungus (Claviceps purpured, an ascomyccue) mfect flowers of Cereals, partacularly ryc, and of grasses As a result, the ovary is destroyed and the "seed" seplaced by a sclerodium pacted mass of hyphae) which projects from the car as 2 struall, dark, horn-like structure (see Fig 7) These sclerots, when denved from ryc, may be? 5 to 3 s (or more) cm in length and consumate the crgot of commerce They contain several alkaloids able to semulate plass muscle to contract and it As to this property that ergor oncs its employment in gynaccology If inadvertendy caten by cattle or by man character- ISIC signs of poisoning result and death may follow Losses in stock are usually due to wfected grass while poisoning in man normally results from the use of ergot-contamated pre fous Ergos poisoning 1 man Dow rather sare one of the more recent outbreaks pa y EU O Rre Separation was that which occurred in Manchester in Sanota or Curry the autumn of 1928 when there were 3 axy of ergotism among Jewish grants from central Europe whc 1928, Morgan, 1929) TI had been grown in south cent of ergor by bandag of a no-bread citer in broad-sakug was ·9 MEDICAL MYCOLOGY ergot The gehad been grown in Lancasture in 1922, another wee year (Dilling and Kelley, 1928) Formerly ergotsma w more prevalent and more severe and durmg the Aiddle Ages it was known in Europe as St Anthony's Fire or she Fisc of S. Marazh TKO types of ergotism have been distungwshed, the gangrenous the convulsive The former begins with a general Lassstudes vague lumbar pains or paint ar a limb, especially the calf, and the intellect ss dulled in the course of a few weeks the affected extremity becomes swollen and inflamed and attacked by burning pains heat alternating with icy cold Gradually the affected part is numbed and later becomes gangrenow, Inumerufied, and dry Thc gangrenc spreads upwards and the gangrenous limb may separate spontancously without the loss of blood Gangrenous ergotism in Europe occurred west of the Rhine East of that tiver ergotam was usually of the convulsive type in whuch corvulsive twrclung of the lands and feet or of the whole body was accomparued by terrible pains In the intervals between the convisions there was lucede descomfort, a ravenous hunger (there is a secord of two patients cach consuming threc pounds of bread within seven minus) and sesere insomnia If not facal, convalescence is protracted (Barger 1931) Is the first of the British cases mentioned above, the symptoms were of the snuid nervous type while in the second the Liverpool case, there was gangrene of symmetrical tocs It is thought that deficiency in vitamin A is probably a fatror włuch deternunes convulsive crgotism, This would explain repeated outbreaks of this type in orphanages and prisons where the dict was inadequate and there is a positive correlation between the greater availability of dary products (which are the chuet source of vicamun A) in France than in Germany and the type of ergoism characterisaic of the two countries References The monograph by Dujardit de la Rivière and Ham (1938), with is extensive bibliography, gives a comprehensive account of the poisonous basidiomycetes and larger ascomycetes of Europe This may be supplemented by Ford (1923), Rautavaara (1940) and the useful semu-popular booklet by Ratisbottom (1945) Ergos and crgotism are exhaustively treated by Barger (1931) ·EXPLANATION OF THE PLATES PLATE I Black piedra (Pedraia hortai) 1 Naturally infected hair showing black fungus nodules 2-5 Growth of P hortat on Sabouraud's agar after 8 17, and 30 days and 4 mobiths 6 Nodule on har after treatment with caasac potash soluaon 7 Part of a nodule showing development of asci and ascospores. 8-21 Stages in ascus and ascospore development (Horta (1911), plates Reproduced by permission of the author and the Instituto Oswaldo Cruz) PLATE II Trichophycon mentagrophytes (= T (sypseum) asteroides of Sabouraud) I Pomary culture after 40 days on Sabouraud s maltose agar II-III. Overgrowth of the primary culture by the non-sporing pleomorphic form. IV and lyCulture of the pleomorphuc form on Sabouraud's maltose agar after 13 and 20 days respectively (Sabouraud (1910) plate 1 Reproduced by permission of Masson et Cic, Paris) PLATE IT Tinca imbricata (Trichophyton concentricum) 1 Tinca imbrcata on a Brazilian Indian. (Photograph by Dr A E. de Area Leão and Dr M Goto) 7 7 An - A 1 1.A PLATE IV Tinca capitis (Aficrosporum canis) Lesion on boy's head (Photograph by D: Clara M Warren) PLATE V АГістогрorum cais * Naturally infected hair after reatment with caustic pots to show sheath of tegularly arranged arthrospores Unstained x 500 2 Profuse development of macroconidu on fragment of hair after incu bation in a hanging drop for 6 days Unstuned lactophenol mount X250 91 ·94 MEDICAL MYCOLOGY PLATE VI 1 Black gran "Madura fool" External appearance of foot. Black grains may be seen in the exudate. A white bristle has been inserted a one of the openings (Carter (1873) pizre ! (t)) *2 Ažadurella mycetomi granule is assic of foot. *250 (Preparator by Dr Duncan Granule of dainomyces un lung issue X250 (Preparation by Prof Floriana P de Almeida.) PLATE VII Chromoblastomycosis (Plutalophora sp) of leg {Photograph by Dr A. E. de Area Leio) + Cells of Phialophora in tissue X 300 (Preparabon by Prof Forsano P de Almada) 3 Sporotrichoses of 217. Note she primary lesson on the hand and the succession of secondary abscesses along the arm. (Photograph by DE MAR Helm. Reproduod from Sporotrichoses 1949 by permission of the Transvaal Chamber of Mines) PŁATE VIII Anrbome fungus spores, etc , trapped outside the Presidency }ail, Calcutta, by P D Curvungham on 27ch May, 1872 Temp so sº, wand. S by E. and S. raus, oon X270 Cunningham (1873), plate (4) 2 Fungus colonucs oa plate of malc agar exposed to the outdoor at for $ minutes on 23rd Auguss, 1951, at Exeter, and then incubated for 6 days ac 25°C 3 Coppipottus racoformans un human bram tissue Note the wide capuule around cach cello che parasite x 900 (Preparatos by De ) T Duncan. 4. Paracoccidioides brasiliensis Mulaple budding in Essue X 300 (Photograph by Prof J E Mackinnon) Coradiordes iramis spherule is tessac x 800 (Preparation by Prok. Floriano P de Almeida.)

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3 Tien
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PLATE VIII

·BIBLIOGRAPHY ADAMSON H. G (1898) Observations on the parasizes of ningworin. Brusſ Derm 7, 201-II, 337-44. AINSWORTN, G C (1950) List of fungs recorded as pathogenuc for man and higher animals a Barat Trans Brit mycol Soc 32. 338-36 ANSFORTE, G C (1951) A century of medical and veterinary mycology in Distan. Trans Brit mycol Sot 33, 1-16. AJELZO, L., 2nd ZESDNERG, L. D (1951) Isolation of Histoplasm and Allescheria boyde from soul Sesence NS 113, 662-3 ALMEIDA, F P DE (1939) Afycologia Afedid, pp 1-710 (São Paulo) ALMEIDA I P De (1940) Considerações søbre as formações scuno micetoides, radiadas ou maça dos congumelos bos teados Am Fac Med Unwy S Paulo 22, 249-63 ALMEIDA F P De and LACAZ, C Da Silva (1940) Nova técnica para demonstração rápida dos ascospores Foha Chn Esol 12.(4) ALMEIDA, FP De, and LACAZ, C. DA SILVA (1942) Afucoses bronco pulmonares pp 1-98 (510 Paulo) BARCEN, G (1931) Ergot and ergotusta, PP 1-279 (London and Edinburgh ) DNHAM, RHODA W (1931) Certain Monibus parastac on man Their identification by morphology and by agglutinanonj infect Dis 19, 183-215 BENSIAM. NIODA W (1935) Cryptococa-cheu deraficador by morphology and serology J Infect Dis 57, 255-74 DENFAM, RIIODA W, and KESTEN, B (1932) Sporotrichosis 10 transgussion to plants and animals infect Dis $0, 437-58 BERCER, L., and LANCERON, M. (1949) Sur un type nouveau de chromomycosc observé au Canada (Torula bergen o.sp) Ann P'ssasst hum comp 24. $74-99 Desser. E. A. (1950) Morphology and taxonomy of fungs, pp 1-791 Philadelphsa) Biser, G R (1945) da safroduction to the fronomy and nomerulature of fungi, rp 1-117 (kew, Surrey) DUCAUE, F A (1950) Estudio de los hongas atmosfericos en la cudad de Guadalajara, Jalisco Mediana (Mexico) 10, 11-3 ·96 MEDICAL MYCOLOGY BLACKLEY, C H (1873) Experimental researches on the causes and nature of Catarrhus Aestus (hay-fever or kay asıkma) pp 1-202 (London) BRANDT, F A (1950) Early tissue reactions to a South African strun of Histoplasma capsulatum in laboratory animals ) Path Bact 62, 259-69 BROWN G T (1936) Hypersenssovity to fungt. Allergy 7: 455-70 (40 sefs} BRUMPT, E (1906) Los mycetomes Archiv Parasit ro, 489-572 BURKHOLDER, P R and SINNOIT, E W (1945) Morphogenesis of fungus colonies un submerged shaken cultures Anter) Bor 32, 424-31 CADIAM, F T (1924) Asthma due to grain ruses ) Amer med Assn 83, 27 CARRON, A L (1950) Chromodlascomycosis Am NY Ardi So 50, 1255-82 CARTER, H. 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N tysi) dan lial infections complicating the therapeutic use of angbroues, | Amer med Ass 145, 207-11 ·INDEX Absit a corymboa 4 Budryt s 78 Achorion 19 20 22 Botile baclius s Achorton schoenland 22, 24 Bronchomonilusis, 33 Acrochecium faccount 34 Bronchomycosis, a Anmomyces 3 Astutomyces israel 4945 Cand ds S 17 17 44 55 Actinomycetes, 3 4 5 39 Cand da altrans 6 9 12 28 10-16 45 Actinomycosis 2 5 39 68 69 70 Adamson s fringe 19 Candida thalmern 31 As bottc spores 74-83 Candide kruse 23 30 31 Alcunosport 17 Candida stellatardes, 69 Alergy 9 61 78-83 Cond de sopkals 30 3! <3 dust, 82-3 Olamydospore $7 28 39 mould 78-83 Clorampbvscot (Chloromycetin) of infectiort, 20 Allescheria koyd 4742 Chromoblastonycos, 4*- Amand 75 76 78 79 81 Cladospor 1 45 75 76 78 79 Aman la CUTIH 87 Cladosporusom u 57 Bs Amarte #muscaria 84 87- Cladospor wan herbarsim &s Aman & pentherine, 87 81 Clarys purpuro 95 Amon phalloids 84 85-789 CI agbe dealbata, 88 Ancon la nubescens 84 Clitarybe nvulosa 88 Am.tr & vem, 87 89 Coccidio des imm 25 27 34 46 48 SA Aman las 054 87 87 S! 57-0 68 69 72 Anabodics, 61 Coccidiondi 63 77 Antzgm, u Cocxadeordomycotch 2 7 4 37-) Antiktum 62 Complement 63 Artsrospore 319 fixation test, 63 64 Ascomycetes 3 Concarporcum aunt: e Papuloa Akospore s spk scrostromat Aspargloss 7 34 35 Comlosporium cortucale xt Cyr otoma Aspergilus 3. 75 78 sorkak Aspergillus fum 5 %. 34 S 45 46 Coprisus atramonlarcus go 69 79 Crysoco TOSS, ve Torulosis Aspire !! Autul 41 43 Caypixxus Serfus 7 21 34 45 Asforogenous yeasts, 37 SO 57 59 60 61 62 Auscomyaan 38 Corsiostra Cortuale ar Commyces 11 22 Bugisis, 83 Cirinyees mentrophytes 24 Bisdomyertes ) 4 Cipnyats seratus 17 Dised sport ) 36 Berria bastana, I Dandruff so Black Fredsa 47 Dermatofy out $9 Buedemiyus dem du 36 49 31 32 Dktnutog hytes, ti 16-18 SS $7 So, 36 Detratoshytuls og Blastomyou. 73 Dimorskem 50-56 Buktus salopes B3 Dust Allergy sa $0) ·104 MEDICAL MYCOLOGY Ectothxx tachophytons, 20 Mistpides, 20, 23 Endogenous mycoses, S Afecrosphaera alhl. B1 Endomycopsis, 27 Microsporids, os Endothee, 20. 22 Ahcrosporum, 2, 20, 21, 22, 23 Endochrex enchophytons, 20 Microsporum asdouin, 12, 13, 15, 27, 19. Endotrichophyton, 22 23, 14 Entolomd lividuum, 89 Afscrosporum causs, 12, 13, 14. 44.70 Epidermophytos, 19, 20, 22 16788porum felineum, 24 Epidermophyton fioccosum, 12, 19, 20, 24 Alictosporim gypseum, 21 Epidermophyton inguinale, 20, 33, 24 Afittosporim lantosum, 24 Epizoonc lymphangitu of horses, 53 Monika, 31 Ergoum, 91 Monaha pulogs, 32 European blastomycosis, sec Torulons Morultasis, S, 6, 8, 31, 71 - Exogenous mycoses, S Monosporum aprospermum. 41. 42 Mucor, 78 Farmers' lung, 83 Afucor plumbeus, 82 Favotrichophyton, 22 fucor racemoss, SS Favu, 1, 19, 23 Muscardine disease of silk worms, Forces oficmalıs, 89 Myectora, 39 Fuage imperfecta, 3 Mycoses characterspics of 7 Geotrichum, 34 endogenous, Gruby, David, 12 exogenous, s. 385 Gyromitra esculenta, 90 geographucal distribution of, s, 13 incidence of, 1, 3, 56 Hiplosporangsunt parter, 59 nomenclature of, Histoplasma capsulatum, 49. 52, 53, 57 superficial, 8 61, 65-9. 71, 72 Histoplastsat, 47, 65-9,72 Histoplaststosis, 49. ST Nocard.d. 3 Hormoderdrum, 43 Nocardia madurar, 38, 40 House duse allergy. 82 Norordia tenuissima, 7 Nodular orga123, 37 Immunsty Nomenclature acquired, 62 of diseases, 2 of fungs, 23 natural, 03 North American blastomycosu, 26. passive, 03 Inocybe pasoullardus, 88 Oidiomycan, 70 Keros, 13 Ordum pulmoneum. 34 Onychomycous, 2 LACTATIUS, 89 Lepidla helveola, 87 Papularia sphartostroma, BI Paracoccidiordes brasiliensis, $, 34, 46, 49, Macrocorudrum, 17 $3, 55, 57, 60 Madura foot, 38-42, 44-5 Paracordioides cerebriforme, sa Wadurellt, 39.46 Paronychua35 Afadurella grised, 41. 46 Pathogense furg, 3 Madurella mycetomi, 41 nomenclature of, 23 Maduromycos25, 39 numritrost of, 4,6 serology of, 9, 62-73 Megaspore, 20, 22 Microconudium, 17 Pesucilin sentsil vity, os systemic, 8 active, 02 49. 57.00 ·JOS INDEX Streptomyces peliet en 40 Streptomyces somulims 49 Strophans sem globus 88 Pmlos um 75 76 7 cillum glaucum 74 Philophord 45 46 Philophora comptum 43 Phralophora peloso 43 Mlalo kora VETTIKOSE 43 Foma 78 Phycomycetes 3 matrana kortal 4 7 Puryrosporum ovale s 6 28 Pleomorphum, 17 Po sonous fungi 84-93 Pull on arvmsus 84 Psalt ots campestos 84 Palliota xarchoderma 84 Puccinia graminis 79 Pullmlaris, 78 Pulmonary monitoasts 33 Racquette byphic 17 Rhinosporidiosis, 7 Rhundspor dum seeberi 4 7 Rh zopus 78 Rhizopus stolon for Ringworm Ke Tinea Ringworm schools 14 IS Russula 89 Ta tasters cough, 33 Thrush, : 8,31 Tinca ir Tmca capitis 13 Tinca corporis 13 Tinca imbricata, 11 Tinca pedis 12 15 Torult berger 43 Torlopsis 28 Torulopsis glabrala 60 Torvlopsts ut is 37 Torulosis 2 7 8 48 57 61 Tricholomat purdertum B9 Tnchonocardios $ 7 Tnchophyads 65 Tnchopbytın 64 To hophyton 20, 31 32 Trichophyton album a; Trichophyton concentricum 13 Tr chophyton disco drs, 21 3} T shophyton mierd gisle 19 44 Trichophyton mentagrophy es , 21 24 Tn hophyton ochraceum 3T 23 Trichophyton quinckr 64 Trichophyton rubrum 44 Trichophyton schoenkul 21 22 23 24 25 Tr chophyton fonsurans sa Trichophyron v olaceum 17 Tricho hectum 78 I al and glocephala 87 Sahoutwud es ar 22 25 Sabunud ten oudou ni 23 Sabouraud sugar 16 17 Saccharomyces cerevisiae 27 Sclerot um. 44 91 Seborrhocic dermatitas s Serological diagnosis 70 Sun scrisovity 9 64 Skin testing 70, 7? South Amenican blastomycosis, a 37 49 57 60 Srral hyphae 17 Short storms 76 Spores an actges 78 Sporogenow yeases 37 Sporonchosis, 5 1 49 56, 57 Sporotrichum pour 56 Sporotrichum puriosum so Sporotrichum shenk s 46 49 st 35 36 37 Woods Light 14 X-ray spilation 14 Yeasts asporogenot, 17 Black 43 myotlal and non-myalal az forogenou, 27

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