n n HHl AN INTRODUCTION TO MEDICAL MYCOLOGY GEORGE M.LEWIS .. . . MARY E. HOPPER AN INTRODUCTION TO MEDICAL MYCOLOGY Plate I. Development of pigment at the base of a fungus colony growing on an artificial medium. The yellow hue is characteristic of Microsporum lanosum, while the port-wine eolor is characteristic of Trichophyton purpureum. In the lower group, pigment developed only in mediums containing one of certain monosaccharides and was not synthesized when the available sugar was a disaccharide. (See p. 10.) c AN INTRODUCTION TO MEDICAL MYCOLOGY by GEORGE M. LEWIS, M. D. Member of the American Dermatological Association, Inc., of the American Board of Dermatology and Syphilology and of the Mycological Society of America; Fellow of the American College of Physicians, of the American Medical Association and of the New York Academy of Medicine; Member of the New York Dermatological Society and of the Manhattan Dermatolog- ical Society; Associate Attending Physician (Dermatology), The New York Hospital; Associate Professor of Clinical Medi- cine (Dermatology), Cornell University Medical School (I) 1(1 MARY E. HOPPER, M. S. Research Fellow in Medicine, Cornell University Medical School THE YEAR BOOK PUBLISHERS 304 SOUTH DEARBORN STREET • CHICAGO INC. COPYRIGHT, 1939, 1943 AND 1948 BY THE YEAR BOOK PUBLISHERS, INC. Second Edition, September, 1943 Third Edition, September, 1948 PRINTED in THE I . S. Preface to the Third Edition IN THE nine years since the first edition of this book was presented (with some temerity), there has been a considerable advance in the knowledge of fungous disease. Many more workers are now engaged in either part-time or full-time research in this branch of medicine. The knowledge of fungous disease has been more generally disseminated and physicians, particularly dermatologists, have become proficient in the laboratory diagnosis of the various fungous diseases. It is heartening to see that clinical mycology has awakened such an interest among physicians. A glance through the program of almost any regional or national dermatologic meeting will disclose one or more papers of merit on topics related to the mycoses. There are fewer and fewer reports of cases without careful laboratory confirmation. This would indicate that mycology is an important and practical subject. It is hoped that in the revision of the text for this third edition, the many ad- vances which have occurred since 1943 have been sufficiently abstracted without adding too greatly to the length of the book. The main purpose of the book, as its title implies, is to serve as a primer. It does not pretend to include all the many controversial details and involved technical aspects of the subject. The general plan of the book has been retained. The contents are divided into two parts. The first deals with the clinical, theoretical and experimental aspects of the subject; the second outlines the laboratory procedures useful in examining a patient suspected of having one of the various mycoses. The characteristics and habits of the habitual fungous parasites are described. An attempt is made to emphasize important phases of mycology, the com- mon diseases receiving more attention than the rare ones. Since the patho- genic flora varies in different parts of the world, our emphasis on certain fungi as important in New York may not apply to the same degree in other localities. The bibliography is not a complete compilation. It contains articles which we think are important for their originality and their value in teach- vi Preface ing. The majority of the references concern articles available in English. It may be reiterated that pathogenic fungi are rarely found on the normal skin. Thus, when such micro-organisms are present, the finding is of etiologic importance in confirming a diagnosis of fungous disease. It is further notable that pathogenic fungi do not multiply or thrive in the presence of acute inflammation. For that reason the finding of pathogenic fungi in eczematous tissue is of prime significance. It is unlikely that fungous disease would supervene on contact dermatitis. It is a pleasure to repeat words of gratitude to our former teachers, Drs. Fred D. Weidman and J. Gardner Hopkins, for awakening our interest in the problems of medical mycology. During the years preceding the first edition our laboratory was situated in the dermatologic department of the New York Post-Graduate Medical School and Hospital and later in the Skin and Cancer Unit of that institution. Dr. George M. MacKee was our Chief and he provided us with facilities for many of our investigations. In the fall of 1939, we transferred our laboratory to New York Hospital where we have since been. Dr. Eugene F. Du Bois and, later, Dr. David P. Barr encouraged us to continue our work and have given us a splendid opportu- nity under almost ideal surroundings. For seven years our projects were supported financially by the John and Mary R. Markle Foundation. It affords us pleasure to acknowledge the help we have received from col- leagues in many parts of the country both by constructive criticism of former editions and by the submission of supporting material. Dr. Harold L. Temple kindly provided and interpreted several radiographs, Dr. Clement B. Potelunas read the proof and Miss Eleanora Beemer generously provided the requisite secretarial assistance. The Year Book Publishers have been patient with demanding authors. The technical work in the book is all that could be desired. We hope that this edition will be received with no less indulgence than those which preceded it. —George M. Lewis —Mary E. Hopper June, 1948. Table of Contents part ONE. CLINICAL, THEORETICAL AND EXPERIMENTAL ASPECTS i. Historical Review 3 ii. Classification of Fungi 5 in. Structure of Fungi 6 iv. Physiology of Fungi: Requirements for Growth and Reproduction 1. Temperature 7 2. Moisture 7 3. Oxygen 8 4. Light 8 5. Nitrogen Requirements 8 6. Carbon Requirements 10 7. Other Nutritive Needs 10 8. Pigment Formation 10 v. Methods of Diagnosis of Fungous Disease 12 1. The Direct Examination 12 2. Cultural Methods 12 3. Filtered Ultraviolet Radiation 12 4. Cutaneous Tests 13 5. Animal Inoculation 13 6. Fermentation Tests 13 7. Agglutination Tests 13 8. Precipitation and Complement Fixation Tests 13 9. Fusion of Mycelium 14 10. Histologic Examination 14 11. The Therapeutic Test 14 12. Autoinoculation 15 13. Roentgen Examination 15 vu 6D06H \ III. IX. viii Contents 14. Examination of Spinal Fluid 16 15. Clinical Symptoms and Signs 16 vi. Immunity and Cutaneous Sensitization 17 1. The Trichophytin Test 17 2. The Oidiomycin Test 37 3. Other Cutaneous Tests 37 4. Conjoint Sensitization to Penicillin 38 5. Experimental Fungous Infection in Animals 38 MI. NONDERMATOLOGIC ALLERGIC MANIFESTATIONS DUE TO FuNGI . . 41 1. Asthma 41 2. Hay Fever 42 Immune Bodies Circulating in the Blood 44 1. Superficial Fungous Diseases . 44 2. Deep (Invasive) Fungous Diseases 45 The Superficial Mycoses 46 1. Tinea Capitis (Ringworm of the Scalp, Including Favus) . 47 2. Tinea Barbae 75 3. Tinea Glabrosa ( Corporis ) ( Ringworm of the Smooth Skin ) 78 4. Tinea Cruris 93 5. Dermatophytosis ( Dermatomycosis, Including Onychomy- cosis) 97 6. Moniliasis 145 7. Tinea Versicolor 157 8. Erythrasma 164 9. Tinea Imbricata 166 10. Otomycosis ( Myringomycosis ) 168 1 1 . Lepothrix ( Trichomycosis Axillaris ) 171 12. Tinea Nodosa (Piedra) 172 13. Chromoblastomycosis (Dermatitis Verrucosa) .... 173 The Deep Mycoses (Essentially or Potentially Systemic) . . 177 1. Actinomycosis ( Streptothricosis ) 177 2. Mycetoma ( Maduromycosis ) 186 3. Nocardiosis (Actinomycosis without Granules) .... 187 4. Sporotrichosis 189 5. Blastomycosis 197 6. Histoplasmosis 203 7. Coccidioidomycosis 206 8. Granuloma Paracoccidioides 213 Contents i\ f). Torulosis (European Blastomycosis) 215 10. Rhinosporidiosis 21'i 11. ^pergillosis 219 12. Mycoses of the Lungs . * 220 xi. Fungous Diseases and Compensable Dermatoses 222 1. Primary Dermatophytosis of the Hands 222 2. Dermatophyte! Secondary to a Fungous Focus .... 223 3. Nonmvcotic Disease 223 4. The Rare Mycoses 223 PART two. LABORATORY METHODS xii. Introduction 227 xiii. Precautions Against Laroratory Infections 229 xiv. The Microscope 230 xv. Collection of Diseased Tissue 231 xvi. Care of Instruments 233 xvii. Care of Glassware 234 xviii. The Dfhect Examination 235 1. Solvents and Stains 235 2. Making the Preparation 236 xix. Appearance of Fungi on Direct Examination 238 1. Hair 238 2. Scales 239 3. Macerated Skin 239 4. Roofs of Vesicles 239 5. Nail Tissue 239 6. Pus 241 7. Sputum 241 8. Feces 241 9. Blood 242 10. Stained Sections 242 xx. Durious Fungous Forms and Artefacts 243 1. The Mosaic Fungus 243 2. Saprophytes 246 3. Artefacts 246 xxi. Cultural Methods 249 1 . Formulas 250 2. Inoculation of Medium 254 x Contents xxii. Characteristics of Fungi on Culture 256 1. Routine Examination 256 2. Pleomorphism 258 xxiii. Preservation of Fungus Colonies 259 1. Reasons for Preservation 259 2. Method of Preservation 259 xxiv. The Culture Mount 260 1. Cover Slip Method 260 2. Culture Chamber Method 261 3. Wet India Ink Preparation 261 4. Binding Agents 262 xxv. Microscopic Characteristics of the Dermatophytes .... 263 1. Vegetative Forms 263 2. Reproductive Forms 264 3. Features of Different Genera 266 xxvi. Animal Inoculation 267 xxvh. Technic of Passive Transfer Test 269 1. Technic 269 2. Interpretation 270 xxvni. Testing the Fungistatic and Fungicidal Power of Drugs and Chemicals 271 1. Testing Fungistatic Power 271 2. Testing Fungicidal Power 272 xxix. Filtered Ultraviolet Radiation (Wood's Light) 273 1. Source of Ultraviolet Rays 273 2. Filter 274 3. Exclusion of Unwanted Rays 274 4. Use of the Rays 275 xxx. The Trichophyton Test: Technical Details 279 xxxi. Other Specific Skin Tests 281 1. The Oidiomycin Test 281 2. The Coccidioidin Test 281 3. The Blastomycin Test 281 4. The Sporotrichin Test 281 xxxi i. Characteristics of Pathogenic Fungi 282 1. Microsporum Audouini 283 2. Microsporum Lanosum 286 3. Microsporum Fulvum (Microsporum Gvpseum; Achorion Gypseum) 288 Contents xi I. Microsponim Ferrugineum 290 5, Achorion (Trichophyton) Schoenleini 292 (i. Trichophyton Alba (Faviforme) 294 7. Trichophyton Violaceum .' 296 8. Trichophyton Crateriforme 298 9. Trichophyton Sulfureum 300 10. Trichophyton Gypseum 302 11. Trichophyton Purpureum (Hang) 305 12. Epidermophyton Inguinale (Epidermophyton Cruris; Epi- dermophyton Floccosum) 308 13. Monilia (Candida) Albicans 310 14. Malassezia Furfur (Microsporum Furfur) 312 15. Actinomyces Minutissimus (Microsporum Minutissimum ) . 315 16. Endodermophvton Tropicale 315 17. Hormodendrum Pedrosoi 317 18. Hormodendrum Compactum 318 19. Phialophora Verrucosa 320 20. Actinomyces Bovis ( Hartz; Wolff and Israel ) 320 21. Sporotrichum Schencki 323 22. Blastomyces Dermatitidis 326 23. Histoplasma Capsulatum 329 24. Coccidioides Immitis 332 25. Paracoccidioides Brasiliensis 334 26. Torula Histolytica ( Cryptococcus Hominis) 336 27. Rhinosporidium Seeberi 338 xxxiii. Other Pathogenic Fungi 339 1. Microsporum Equinum 339 2. Achorion Quinckeanum 339 3. Achorion Gallinae 339 4. Microsporum Simiae 340 5. Trichophyton Acuminatum (Endothrix) 340 6. Trichophyton Cerebriforme (Endothrix) 340 7. Trichophyton Rosaceum (Endothrix) 340 8. Actinomyces Tenuis 340 9. Trichosporum (Piedraia) Hortai 341 10. Trichosporum Giganteum 341 xxxrv. Fungi Probably Pathogenic 342 1. Aspergillus Fumigatus 342 2. Pityrosporum Ovale 342 xii Contents xxxv. Fungi Questionably Pathogenic 347 1. Saprophytes Assuming Pathogenicity 347 2. Inadequate and Conflicting Evidence 350 xxxvi. Common Contaminants 352 1. Aspergillus 352 2. Penicillium 353 3. Mucor 353 4. Alternaria ( Macrosporium ) 353 5. Hormodendrum 353 6. Fusarium 356 7. Scopulariopsis 356 8. Dematium 356 9. Mycoderma 356 10. Torula ( Cryptococcus ) 356 11. Chaetomium 356 Reference Books 357 Index 359 Plate I. Plate 11. Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. Fig. / . Fig. 8. Fig. 9. Fig. 10. Fig. 11. Fig. 12. Fig. 13. Fig. 14. Fig. 15. Fig. 16. Fig. 17. Fig. 18. Fig. 19. Fig. 20. Fig. 21. Fig. 22. Fig. 23. Fig. 24. Fig. 25. List of Illustrations Pigment at base of colony on artificial medium . . .Frontispiece Characteristic colors of fungous cultures facing 227 Sabouraud's classification of the ringworm fungi 2 Growth of fungi in artificial medium and on human skin ... 9 Hyphal fusion between strains of identical species .... 15 Specific reactions to trichophvtin test 25 Age incidence in tinea capitis due to M. audouini 49 Tinea capitis due to M. audouini 51 Tinea capitis caused bv M. lanosum 53 Tinea capitis due to endothrix Trichophyta 55 Kerion 56 Favus of the scalp 57 Favus 59 Favus 60 Ringworm infection 61 Diseases confused with tinea capitis 65 Activation of tinea capitis after x-ray therapy 69 Tinea capitis treated with x-rays 70 Tinea capitis— localized infection treated with x-rays .... 72 Tinea barbae 77 Tinea barbae and sycosis barbae 79 Tinea glabrosa (circinate type) due to M. lanosum .... SI Tinea glabrosa due to M. audouini 82 Tinea glabrosa and pityriasis rosea 83 Tinea glabrosa due to \l. fulvum 85 Tinea glabrosa 86 Tinea glabrosa due to T. alba (faviforme) 87 xiii xiv List of Illustrations Tinea glabrosa caused by T. purpureum 88 Tinea glabrosa 91 Disorders confused with fungous eruptions 92 Tinea cruris 95 Tinea cruris 96 Acute dermatophytosis of hands and feet 103 Acute dermatophytosis 104 Acute dermatophytosis (T. gypseum) 105 Acute dermatophytosis of the hands 107 Chronic dermatophytosis of the feet 109 Ringworm infection due to T. purpureum 110 Infection due to T. purpureum Ill T. purpureum infection— sites of involvement 112 Chronic dermatophytosis of hands and nails 114 Chronic dermatophytosis due to T. purpureum 115 Dermatophytid secondary to tinea pedis 117 Nonmycotic diseases simulating dermatophytosis 122 Diseases to be differentiated from dermatophytosis .... 123 Nonmycotic rashes simulating dermatophytosis 125 Treatment of nails infected with fungi 137 Moniliasis of feet and hands 147 Moniliasis— types of skin involvement 149 Moniliasis of generalized type 151 Tinea versicolor, or chromophvtosis 158 Tinea versicolor (papular follicular variety) 159 Hidden lesions of tinea versicolor 161 Erythrasma 165 Erythrasma 167 Tinea imbricata 169 Chromoblastomycosis 174 Actinomycosis 179 Actinomycosis 181 Actinomycosis of the chest 183 Nocardiosis (actinomycosis without granules) 188 Sporotrichosis 191 Sporotrichosis 193 Blastomycosis 198 Blastomycosis (secondary involvement) 199 Blastomycosis affecting lungs and bones 201 s- 26. 27. g- 28. g- 29. g- 30. g- 31. g- 32. g- 33. g- 34. g- 35. g- 36. g- 37. g- 38. g- 39. g- 40. or 41. g- 42. g- 43. g- 44. g- 45. g- 46. g- 47. g- 48. g- 49. g- 50. g 51. g" 52. g- 53. 6" 54. g- 55. g- 56. g- 57. g- 58. l g- 59. 'g- 60. g- 61. g- 62. g- 63. 'g- 64. <> {3 65. g- 66. 07. (is. 69. 5" 70. a Id. g" 74. g- 75. 70. g- 77. g- 78. g" 79. 80. a 81. g- 82. g- 83. g- 84. 85. g- 86. & 87. g- 88. g- 89. 90. g" 91. g- 92. 'g- 93. 'g- 94. g" 95. g- 96. 'g- 97. g" 98. g o 99. 'g- 100. l g- 101. 'g- 102. 'g- JOS. List of Illustrations \\ Histoplasmosis 205 Coccidioidomycosis 207 Coccidioidomycosis 209 Paracoccidioides . 214 Appearance ol ringworm fungi 240 Foreign material in skin scrapings 244 Elastic fibers confused with hyphae 245 Nonmycotic hairs 247 Comparison ol cultural growths 251 Vegetative variations in dermatophytes 265 Microsporum audouini 285 Microspornm lanosum 287 Microsporum fnlvnm 289 Microspornm ferrugineum 291 Achorion schoenleini 293 Trichophyton alba (faviforme) 295 Trichophyton violaceum 297 Trichophyton crateriforme 299 Trichophyton sulfureum 301 Trichophyton gvpseum 303 Trichophyton purpureum 307 Epidermophyton inguinale 309 Monilia albicans 311 Malassezia (Microsporum) furfur 313 Actinomyces minutissimus 316 Hormodendrum pedrosoi 319 Actinomyces boyis 321 Granule of Actinomyces 323 Sporotrichum schencki 325 Blastomyces dermatitidis 327 Histoplasma capsnlatum 330 Histoplasma capsnlatum and Leishmania donovani .... 331 Coccidioides immitis 333 Paracoccidioides ( brasiliensis ) 335 Torula histolytica ( Cryptococcus hominis) 337 Pityrosporum ovale 345 Aspergillus niger 349 Common contaminants 354 Common contaminants 355 PART ONE CLINICAL, THEORETICAL AND EXPERIMENTAL ASPECTS TUtl.KUJ -YYIIIKTInl P ; |,|> |t||(\| \ I h|'|IVTI> M, ,,.., Am***"* ''• Mtftwiw miw i'i it- id- t \ | . . • \ \i iniiiiixi.iiiiin. liiiin.'iiii t \l. I.inliiiii I MICRO- SI'UIII \|S. ' \l m-Im-Ii. / Mirni-|Mii win />,.i'>-'"'>- . M li-liiii-iini \» 1 1- Mil lto.l-.illl M. nil (I i'i Ik'IIM' \ M i-i|llllllllll ainmali-. ri.n-f t \.inl |i>nuli-iii|>- < M IiiImiiii li-nr l%|»<- |>.iia«itaiif ji- J \|. villi,. urn f M. |.iiIm - in-. M Iniiii-iil.-iiiii .. . i lrn li.mlnl '■''<•" /••""'• ! *■?"•" - >!•«- •,,,.,.,:,,,,,.,, I fi'i-iim- nlf «. / ... . . I \l»>l 111:1V H in*. IN IM> TIIIIIV I K»|i«'ff . r,iir« mi \ i-lr.-iMKrrt-- I r. •• ITi.-hIiiiii I i fiimahiiii 1*1. It umliiliratiim. I I ppjniten*, Tr. ntlfwrrnm. I I | > < > I N U • > ■ ■ • • 1 1 1 1 Tr f \.iiiatilin. 1 1. i inoiiMiliiliiin Tr. |>iI,,.iiiii Tr. Blabnun. - \ 1 1 in ItlfilV I \|MH III IV MM i mii.i i j )| „-,,... a-lair.-*,.,,. ,,;.„,,,. * In |M-n<>«li- ji'iiiii-. ■ I \|>«- gyp*rum. f I \ llf iiirriiin . mi i.x-i-mii r \ . llllllll- r,l,.ulr III M :no- IIIONS / \ •iiiiun { (..,,,„: \i liMimn tin fa YIN liumaiii \i li«nii>li» ; 1 1 1 1 1 1 1 . m I \ . . . I IH lii.plivlMli tvtteni&lr*. \ Tr. r.iiliiil.iliiui. \ Tr. I.i. in ..I. >i. , Tr. «r.iiiiili»«iiiii. I Tr. r.M imili-iiiiiin Tr. |n-i-n Him. ^ 1 in li<'|ili*l'>ii nuUtmt t Tr. ili-iiiH'iil.'iiiiiii ,:!•" • \ I r. \ iiii'-iiiii '/■''•'•'/ ' I in Impln Inn i .minimi . I I li l|il|>ll\ lull •"/" •'■ -11111. '"""] Tr. allium Tr. «li- I.-/,.., ,. .1.-. <.l,i,ul* \ ( Mlllli ki'.'llllllll \ \ u-.illlll.i.- I \ U>|>- II i ii >~|i< H .i raiiinn. 1 l.r> f.|>f«f. If. |ihi. iiii|>ihI.iiiIi-. nut I • in mi i-ii ilaln|ilf . i'i A ii'ilf ilu Vrirhttphyhm fit mill urn, p-t, i-ii lulll ,a-. |>.irim If. 1 1 i,lm|ili\ lmi» iinli,lliii\ il f.iiiilia liifiiini fairr |il.n f a ilfu\ imIIi-. f-|iiii-.. i.ult-f. a Vfin.f. ilan- If .fiM.f id- M. I.- Prof. | h.ii... par If l»' Miii.i..i.in I. urn- : /.<- rkupkgloM in/titiim a i iilliui- i fi.-luilm- potldlt 1 i|.,- i-l . ia,|ii<-lf <-. pi.-.i-nlf i-ii -mi ffiilrt' uiif iMim.inilluif l,|.m, li.iliv. ililTmim- . i ai.utf ri.lh|iif mir inilifii iTAprPUV*. I.anlro : Irir/utfihylim >/,,,„,/,,,,/,.. |irtWhti< inn- liulll -millurf . fiilralf iii.'iIml'iii' main ilf i mill- m Itiartrc. iifiilrf. hull |>mi\ Nickerson (Biology of Pathogenic Fungi, Chapter 10). BIBLIOGRAPHY Dodge, C. W.: Medial Mycology (St. Louis: C. V. Mosby Company, L935), p. 466. The physiology of the dermatophytes is discussed here in some detail. Foster, J. W.: The heavy metal nutrition of Fungi, Bot. Rev. ):2()7. L939. Goddabd, D. R.: Phases of the metabolism of Trichophyton interdigitale Priestly, |. Infect. Dis. 54:149, 1934. Lewis, G. M., and Hopper, M. E.: Pigment production by fungi: I. Nutritive requirements, Arch. Dermat. & Syph. 44:453, 1941. MoSHER, W. A.; Saunders, D. H.; Kingery, L. B., and Williams, R. J.: Nutritional require- ments of pathogenic mold Trichophyton interdigitale, Plant Physiol. 11:795, 1936. \n kerson, W. J.: Biology of Pathogenic Fungi (Waltham, Mass.: Chronica Botanica Com- pany, 1947). Chapter 9 on nutrition and metabolism is recommended for supplementary reading. Bobbins, \Y. J., and Ma, R.: Growth faetors for Trichophyton mentagrophvtes, Am. J. Bot. 32:509, 1945. CHAPTER V Methods of Diagnosis of Fungous Disease THE procedures to be described are the chief methods by which it is possible to determine the presence of fungi in specimens, to identify species and to decide on their pathogenicity. 1. THE DIRECT EXAMINATION This is the simplest and yet the most important single means of labora- tory investigation. It is the first step in establishing a diagnosis. Its limita- tion is that it rarely permits one to identify species. The method consists in mounting specimens of skin, hair, nail scrapings, pus or exudate and examining them under the microscope. 2. CULTURAL METHODS (a) Giant colonies.— Material containing fungi, if planted on suitable culture mediums, yields characteristic colony growths. In many instances identification of species can be satisfactorily made in this way alone. (b) Culture mount (hanging-drop, slide culture).— The character of the spores and the presence of any vegetative variations can be studied. A small amount of material from a cultural growth is mounted and imme- diately examined or inoculated in a thin medium, which can be studied as growth progresses. 3. FILTERED ULTRAVIOLET RADIATION The phenomenon of fluorescence may be used in the examination of patients to determine the presence of tinea capitis or of tinea versicolor. It may also be used in the study of fungus colonies. 12 Mel hods of Diagnosis of Fungous Disease L3 4. CUTANEOUS TESTS The use of Fungus vaccines in diagnosis and treatment has not been entirely clarified. We believe trichopliytin to be specific in that it denotes sensitization In infection with a dermatophyte. Not every patient with a fungous infection is sensitized, since many virulent fungi do not have the capacity to sensitize the skin. The test, then, is not always diagnostic, although it is specific. Oidiomycin elicits so many reactions that it is useless in diagnosis. The reactions to coccidioidin, blastomycin and sporotrichin are considered to be specific. The subject is dealt with in more detail in Chapter VI, "Immunity and Cutaneous Sensitization." 5. ANIMAL INOCULATION In order better to establish the pathogenicity of a given strain of micro- organism, inoculation of the fungus into various laboratory animals may be helpful. It may also be used to obtain pure strains of a fungus which is also pathogenic to animals, It is used chiefly when one is working with the deep fungous infections, if negative results are obtained from the direct examination or from cultures. 6. FERMENTATION TESTS Hopkins and Iwamoto found that fungi of the ringworm group utilize certain sugars by a process of acid fermentation but do not ferment lactose, saccharose, xylose or 1-arabinose. All of the saprophytes which they studied fermented one or more of these sugars. In a later study Hopkins and Iwamoto were able to divide fungi of the ringworm group into three classes, which were based on speed of fermentation. Castellani, Benham and others have classified the \ easts and yeastlike fungi according to their fermentation reactions. 7. AGGLUTINATION TESTS These are useful in the identification of the monilias (Benham). Conant also uses the agglutination reaction as a diagnostic test for blastomycosis. 8. PRECIPITATION AND COMPLEMENT FIXATION TESTS These are also used with certain of the rare mycoses. Greenbaum inves- tigated the Kolmer complement fixation test as applied to a group of serums 14 An Introduction to Medical Mycology obtained from patients who were suffering from a variety of superficial ringworm infections. The negative results showed the test to be valueless here and indicated that few or no antibodies develop in the course of super- ficial ringworm. 9. FUSION OF MYCELIUM This method was devised by Davidson and his co-workers to establish the identity of an unknown species. Only strains of the same species will fuse with each other when myceliums of two or more species are allowed to mingle. The myceliums of two strains of M. lanosum fuse, but no fusion takes place between M. lanosum and Microsporum audouini. 10. HISTOLOGIC EXAMINATION This reveals the nature of the reaction of the host to the invasion of the pathogenic micro-organisms. The fungi themselves are rarely seen. In the superficial chronic infections the lack of pathologic changes may be help- ful in the differential diagnosis from other dermatoses. In the deep forms of infection, there is no specific picture and granulomatous changes are the rule. Moore showed the close similarity between tuberculosis and many of the deep invasive fungous infections. In the acute form of each, a highly inflammatory reaction occurs, often leading to abscess formation. In the chronic forms, there are granulomas containing giant cells arranged in tubercle-like formation and plasma, epithelioid, lymphoid and polymor- phonuclear cells. In fungous disease there are usually fewer epithe- lioid cells and more plasma and polymorphonuclear cells than in tuber- culosis. In some cases, histoplasmosis may only be established by postmortem examination of internal organs or tissues. 11. THE THERAPEUTIC TEST When the diagnosis cannot be definitely established but the clinical features point to a fungous disease, it may be considered expedient to institute therapy. Improvement of the disorder following fungicidal ther- apy is evidence that the disease is mycotic. We advise against beginning therapy before the diagnosis is established by recognized laboratory meth- ods. It is thus frequently advisable to delay treatment for several days or even weeks. Methods of Diagnosis of Fungous Disease IT) 12. AUTOINOCULATION Recovery of a recognized pathogen from a characteristic lesion is suffi- cient to establish the organism as the cause of the infection. II the lesion is atypical, particularly if the isolated fungus is of a variety not usually patho- Fig. 3. Hyphal fusion between two strains of identical species. This does not occur when strains of dissimilar species are in proximity. A, T. gypseum. B, M. audouini. (Courtesy of Harold Orr and Silver Keeping, Edmonton, Alberta, Canada.) genie or not usually isolated, further proof of pathogenicity is ordinarily required. Here the use of animals may be instructive but is not in itself conclusive, since variation in susceptibility with the species of animal shows that the response in human beings also varies. As mentioned by Weidman and others, the more frequent use of experimental autoinoculatiOn is advis- able. It is common knowledge that there is a considerable flora of contami- nants, and it is possible that on occasion pathogenic strains may appear among them. 13. ROENTGEN EXAMINATION This may give the first clue to the nature of the pathologic process. Pulmonary mycoses usually affect the base of the lung, and cavitation is 16 An Introduction to Medical Mijcologi/ not commonly found. Metastatic growths in the bony framework may be detected. 14. EXAMINATION OF SPINAL FLUID The routine inoculation of all specimens of spinal fluid on a suitable culture medium is advisable in all cases in which symptoms referable to the nervous system are present. It may be noted that the diagnosis of torulosis is rarely proved ante mortem. The chief reason is that the syn- drome is not well delineated, but undoubtedly a contributory factor is the unawareness of physicians. 15. CLINICAL SYMPTOMS AND SIGNS Perhaps the most important diagnostic aid of all is the clinical knowledge of the symptoms and signs of the invasion of pathogenic fungi. BIBLIOGRAPHY Greenbaum, S. S.: Immunity in ringworm infections: Active acquired immunity, with note on complement fixation tests in superficial ringworm infections, Arch. Dermat. & Syph. 10:279, 1924. Hopkins, J. G., and Iwamoto, K. : Fermentation reactions of ringworm fungi: Differentiation of Trichophyta and allied genera from other fungi, Arch. Dermat. & Syph. 8:619, 1923; Fermentation reactions of ringworm fungi: Characteristics of three divisions of Trichophyton group, ibid. 8:838, 1923. Moore, M.: Mycotic granulomas and cutaneous tuberculosis: Comparison of histopathologic response, J. Invest. Dermat. 6:149, 1945. CHAPTEk VI Immunity and Cutaneous Sensitization 1. THE TRICHOPHYTON TEST AT THE outset it should be mentioned that a most welcome method 1\, for the diagnosis of a fungous infection would be a test based on specific acquired cutaneous sensitization to a fungus after infection. While sensitization often occurs shortly after infection, it does not do so invariably, and cutaneous tests based on the assumption that the phenomenon is con- stant often cause confusion. Since sensitization may have been produced by a previous infection, a test based on its demonstration cannot be regarded as unqualifyingly diagnostic. An eruption which is caused by fungi or their products and is due to cutaneous hypersensitivity is designated in this book as dermatophytid. Further discussion of the subject will be found on pages 58 and 116 to 119. Most of the work in this field has been done with trichophytin, made from common dermatophytes. Oidiomycin, made from Monilia albicans, has also been investigated, and coccidioidin and sporotrichin are said to elicit specific reactions in patients infected with Coccidioides immitis and Sporotrichum schencki, respectively. According to Martin and others, pa- tients with blastomycosis may or may not react to an extract made from Blastomyces dermatitidis. Negative reactions to the extract are always found in normal individuals. Because of the controversial nature of the subject and because we believe that knowledge of previous investigations of allergic and immuno- logic phenomena relating to fungous disorders may assist in the develop- ment of better methods of diagnosis and treatment, we have here reviewed the literature somewhat more extensively than for some other subjects treated in this work. (a) Review of the literature.— In 1902 Neisser and Plato made an extract of fungi isolated from patients with ringworm and called the prod- uct "trichophytin." They found that when this substance was administered 17 18 An Introduction to Medical Mycology by injection into a patient who was suffering from a deep-seated fungous infection, a general reaction resulted, with malaise, a rise of temperature and a local erythematous response at the site of the injection. No reactions occurred in normal persons or in patients with superficial fungous infec- tions. They also prepared an extract of Achorion schoenleini, but patients with favus did not react to this or to trichophytin. Bloch inoculated animals with Achorion quinckeanum and Trichophyton gypseum and showed that an animal so infected recovered spontaneously. The animal was then immune for as long as a year and a half and during that time could not be infected by either of the fungi just mentioned. The animals all exhibited a hypersensitive response to trichophytin. Bloch found that immunity could not be obtained except by cutaneous inoculation; it did not result from subcutaneous or intraperitoneal injection. Bloch and Massini found that immunity was obtained only from the inocu- lation of the living organism which produced an actual infection. Injection of trichophytin and favin (an extract of A. schoenleini) did not confer immunity, nor did the animal become hypersensitive. Bruhns also found that the inoculation of A. quinckeanum or T. gypseum caused immunity, while the injection of some other fungi in culture did not. Bruhns and Alexander confirmed the work of Bloch and found that fungi which pro- duced deep-seated lesions had a greater power to immunize than those which produced superficial infections. The difference may have been partly due to the individual reaction, since the same fungus could produce a deep infection in one person and a superficial glabrous infection in an- other. Immunity was produced in the former but not in the latter instance. Citron failed to confirm the work of Neisser and Plato and did not observe any cutaneous reactions following the administration of trichophytin, even in the cases of patients with deep-seated ringworm infection. Kusunoki was able to produce immunity in guinea-pigs with all types of fungi; this immunity was complete for any member of the same group of fungi. However, a strongly sensitizing fungus was capable of immuniz- ing against all fungi, while the weaker infections did not prevent sub- sequent infection with a virulent fungus. He had more difficulty in producing immunity in rabbits than in guinea-pigs. He found that im- munity may be transferred to the offspring when the mother is immune before conception or during pregnancy and that immunity is relative and not necessarily absolute. Prytek found that after the infection of guinea-pigs with fungi, further inoculations produced either a modified form of the disease or no mani- festations. Truffi noted the invariable response to the subcutaneous injection of trichophytin in patients with a deep-seated infection. Lombardo con- Immunity and Cutaneous Sensitization 19 sidered that a second infection following a deep infection was an allergic reaction due to the previous sensitization of the skin. Lombardo could not produce allergy by the injection of trichophytin. An attack of the disease was necessary to cause sensitization and immunity. Saeves also found that Epidermophyton inguinale and M. audouini had little power to sensitize the skin. He was able to find these fungi on the skins of inoculated animals 10 to 15 days after inoculation. This showed that the rapid death of the fungus was not the cause of its nonpathogenicity. These experiments indi- cated that a carrier of nonsensitizing fungi may pass the infection to an- other person without exhibiting a visible cutaneous reaction. Saeves inocu- lated guinea-pigs intracardially with suspensions of fungi and produced widespread cutaneous eruptions when the infecting fungus was A. quinck- eanum or T. gypseum. No lesions appeared after the injection of A. schoen- leini and E. inguinale. Sabouraud also found that guinea-pigs inoculated with different ringworm fungi became sensitized and remained so. Ribbert injected Aspergillus intravenously into rabbits. When spores of Aspergillus were then injected into the anterior chamber of the eye, less reaction occurred than in rabbits not previously so inoculated. According to Marten- stein, the skin cells and the blood serum of a guinea-pig infected with A. quinckeanum contained certain specific bodies. If these were brought into contact with spores of A. quinckeanum in vitro, a toxic substance was produced. When injected, this produced a local inflammatory nodule. Martenstein show r ed that A. quinckeanum produced a specific antibody, first present at the site of the injection and later in remote areas of skin. If fungous elements were injected and came in contact with the specific antibody and with the resultant toxin, an inflammatory reaction was produced. The nature of the trichophytin test was studied by Bloch, who sensi- tized himself to trichophytin by inoculation with a fungus. A piece of his skin and a piece of skin from a nonsensitized person were used in a graft to cover an ulcer of the leg of another subject who was not hypersen- sitive to trichophytin. Subsequent trichophytin tests elicited a reaction on the skin taken from Bloch but not on that from the control or on that from a remote area of skin of the recipient. This revealed a sensitivity of the skin cell itself as the basis for the immune reaction. Bloch found that the trichophytin reaction appeared seven to eight days after infection with a fungus. Peck, in an experimental reproduc- tion of tinea pedis with a downy type of T. gypseum, found that a reaction to trichophytin could be elicited 13 days after the inoculation of the organism. Amberg noted that the test may produce a positive reaction long after the disease has become cured and cited a case in which sensi- 20 An Introduction to Medical Mycology tivity was retained for 29 years after a deep tinea infection. Amberg also noted a reaction delayed as long as eight days after the test was made. Bloch regularly obtained positive skin reactions in patients with kerion and also in those with tinea barbae. He found that the more inflammatory the disease, the greater the reaction to trichophytin. The superficial tinea infections gave slight or no reaction. Hanawa found that animals immune as the result of a previous infection exhibited well marked reactions to trichophytin. Bruck and Kusunoki found that the intensity of the reaction gradually decreased when trichophytin was repeatedly injected intracu- taneously. Normal subjects always gave a negative reaction to this sub- stance. Sutter, Amberg and Kusunoki each reported the occasional occur- rence of a positive reaction in persons free from any type of ringworm. Low questioned the type of reaction in subjects free from fungous infec- tion, suggesting that in these cases the reaction was nonspecific. Bloch warned against the possibility of pseudoreactions, which occasionally occur unless the proper technic is followed. Sutter demonstrated that the number of positive reactions to trichophytin increased with age. Accord- ing to Sutter, the reaction to the trichophytin test is negative during attacks of pneumonia, scarlet fever, measles or typhoid fever but may be positive subsequently. During chronic diseases, no change in the reaction to tricho- phytin from that experienced by normal persons may be expected. In cachexia, the reaction may be absent. The reaction to trichophytin was also less on a paralyzed than on a normal limb. Scholtz stated that he obtained a few false positive reactions and found that the reaction to trichophytin was also positive in lupus vulgaris. This observation has not been substantiated by others. Patients with lupus vulgaris, pityriasis rosea and other diseases of the skin may also harbor a fungous eruption or may have been previously sensitized by such an infection. Fuhs obtained a positive reaction to trichophytin in deep ringworm but not in the superficial varieties. Pedersen demonstrated that the test gave a stronger reaction on the abdomen, a common site for the development of trichophytids, than elsewhere. Pedersen and also Sutter found that a heightened reaction to trichophytin was obtainable in areas around active fungous lesions rather than at more remote sites. Arnold found 14 positive reactions in 130 healthy children with no history of ringworm. He also found that 58 per cent of children with superficial ringworm infection reacted to trichophytin. Many of the superficial infections gave more marked reactions than the deep infections. Arnold confirmed the work of Sutter, observing that the reaction to trichophytin was diminished or absent during eruptive fevers, and also agreed with Bruck and Kusunoki that a diminution in the strength of the reaction results from repeated Immunity and Cutaneous Sensitization 21 injections oi trichophytin. Wise and Sulzberger also noted this phenomenon. Vrnold considered trichophytin less specific than tuberculin l>nt more specific than some bacterial products. Stein Found that patients with lavns Tailed to react to trichophytin. Low obtained only two positive reactions in 26 cases of proved ringworm infection and was disappointed in the results, lie used vaccines made from strains ol Microspornm, Trichophyton and Achorion. His positive results were obtained in a case of Microspornm infection of the scalp and in a case of favus. Negative reactions were obtained in cases of kerion and of tinea barbae. It was noted by Walthard and by Jadassohn and Peck that patients with allergic secondary eruptions ( dermatophy rids ) regularly reacted to trichophytin. Sulzberger and Lewis demonstrated that in some persons an eczematous reaction was obtained to a patch test with trichophytin. Rosen, Peck and Sobel, who studied the reaction to trichophytin in 102 patients, concluded that the test was specific. They compared the relative merits of the intracutaneous, scratch and patch tests and found the intra- cutaneous test to be the most reliable. No cultural studies were undertaken. Van Dyck, Kingsbury, Throne and Myers reported the cases of 100 patients who presented eczematous eruptions and others which suggested fungous infections. In each instance the reaction to a commercial extract of trichophytin (Metz) was positive. They used a 1:10 dilution, whereas we later found that a 1:100 dilution of the same extract was capable of producing reactions in susceptible subjects. Van Dyck and his associates inferred that the reaction to trichophytin may displace other methods in the diagnosis of fungous infections. It was later reported that 117 of 317 subjects had positive reactions to trichophytin similar to those previously reported. Although not specifically stated, it was implied that the remain- ing 200 subjects also exhibited positive reactions. The presence of a positive reaction was held as the diagnostic equivalent of demonstration of the micro-organism. The high concentration of trichophytin (1:10) used as testing material and the absence of cultural studies, as well as the lack of a suitable number of patients as controls, weaken the value of these reports. Williams and Carpenter evaluated trichophytin in diagnosis and re- ported that the reaction was positive in 51 cases of clinical fungous disease in 36 of which there was microscopic verification. There was a negative reaction to the test in 19 cases of clinical fungous disease, in five of which the microscopic test gave positive results. In 36 control subjects, clinically free of fungous disease, there was only one positive reaction to trichophytin, and this could not be accounted for by the history or the physical findings. Williams and Carpenter stated that false positive reactions to trichophytin 22 An Introduction to Medical Mycology may occur if the extract is contaminated with bacteria. They noted that many superficial tinea infections gave positive reactions. Although other authors noted a reaction to trichophytin in patients who also had pityriasis rosea, they were unable to confirm this observation. They concluded that "intradermal tests with trichophytin are an aid in diagnosing mycoses of the glabrous skin." Later Williams reported that "the trichophytin test ap- pears to be specific and on careful examination of the patient and of his history exceptions are usually found to be only apparent." Sulzberger and Wise stated that an overwhelmingly large majority of patients who have trichophytids react to the intradermal injection of trichophytin with an inflammation not to be observed in normal persons who have had no prior contact with fungi. They warned against relying on the test as a positive means of identifying an eruption on the hands, since the reaction may be positive because of a prior infection or an infection in another part of the body. The specificity of trichophytin when compared with oidiomycin was demonstrated by Sulzberger, who injected serum from a patient who was known to have circulating antibodies into the skin of normal young women who were previously without sensitiveness. The sites were then tested, and reactions were obtained to trichophytin but not to oidiomycin. Pels and Schlenger used trichophytin in testing 230 subjects. They found the reaction to be positive in 83 per cent of 65 patients who showed the clinical characteristics of the disease. Of 165 subjects who were clin- ically free of the disease, 35 per cent had positive reactions. In some of the cases fungi were demonstrated. Pels and Schlenger were not entirely convinced that trichophytin is specific in its effect. Muskatblit and Director made their own trichophytin and tested 350 patients. Of 49 patients with fungous infections proved by culture, 41 had positive reactions and eight no reaction. The results of the tests were as follows: Epidermophyton interdigitale, 22 positive, one negative; Epider- mophyton rubrum, six positive, three negative; E. inguinale, three positive, none negative; M. lanosum, seven positive, one negative; Trichophyton violaceum, two positive, none negative; T. gypseum, one positive, none negative; A. schoenleini, one positive, one negative; Microsporum minu- tissimum, none positive, one negative. These authors warned against "depot" reactions in which the response was not greater than the original injection of material. Goodman and Marks used the nitrogen content of trichophytin and various bacterial products as the basis for their standardization. They found that when like amounts of the antigens, on the basis of this stand- ardization, were administered intraeutaneously, some patients reacted indis- Immunity Oidiomycin \\i> Catarrhal Vaccine oi Patients with Strong Kkaction to Tmchophytin* 1 TlUCHOPHYTIN Oidiomycin Catahhji \i V u i im Patient 48 Hr. lWk. ' 48 Hr. 1 Wk. 48 Hr. 1 Wk. B.J + + + + + + + + + + + + + + + + + o + O W. \ o A.T + + . + + + + + + + + + L.I + + + + + ± ± ;+; S.N + + + + + + + ± O o T.R + + + + + -£ ;+; ;+; S.M + + + + + + + + o S.T + + + + + + + + + + + + + + + + + + + + + + + + + + + + O + + + + + + o G.E ;+; G.B o C.A ;+; P.A + + + + + + + o o H.T + + + + + + + + + + + + + + + + + o o j W.H o W.A + + + + + + + -+- o H.C + + + + + + + + + + + + + + + + o M.H o F.W + + + + + + + ^H G.G + + + + + + + + + + + + + + + o + + o M.I C.W A.M + + + O o F.E + + + + Hh ± o S.C + + + + + o + o B.B + + + + + Total patients 25 Total positive reactions 25 24 22 15 9 1 'For all patients, cultural examination yielded fungi. stance common to all species of Trichophyton but that each species has a component peculiar to itself. However, the greatest portion of the extract is undoubtedly the same, no matter what the source of the extract. In testing we have used monospecies extracts made from M. audouini, M. lanosum, Trichophyton purpureum and T. gypseum and are able to sub- stantiate the conclusion of Tomlinson and others that a patient who reacts to one type of trichophytin will usually also react to a type made from another species. Thus patients whose skin was sensitized by an infection with T. gypseum had a comparable response when the skin was tested with extracts 28 An Introduction to Medical Mycology of T. gypseum and of T. purpureum. Conversely, patients with infections due to T. purpureum who did not react to an extract made from that organism failed to react to a vaccine made from T. gypseum. Similarly, one may observe the variations (usually minor) which occur when two com- mercial trichophytins are administered to the same patients. A study of TABLE 2.— Reaction to Trichophytin and Catarrhal Vaccine of Patients with Strong Reaction to Oidiomycin* Patient Oidiomycin 48 Hr. lWk. Trichophytin IS ||i-. lWk. Catarrhal Vaccine 48 Hr. lWk. B.B. R.E. T.E. W.F. G.B. A.Y. D.C. G.R. S.I. M.I. G.P. S.E. D.J K.J S.J. M.S. D.A. M.I. D.R. A.Y. + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + O O + + o + + + + + + o + + + + + + + + + o + + + o o o o + + o o + o + + + + o + + o o o + + o o + + o o + + o + o o + + o o o + + + + + o + + + + + + + o o o o o o + o o o + + o o o o o o o o o o Total patients 20 Total positive reactions . . . 19 11 6 'For all patients, fungous examination showed M. albicans. these variations has already been published but may be briefly referred to here. Of 57 reactions to one or more of three trichophytins, 53 (93 per cent) were elicited by Metz (1:100), 43 (75 per cent) by Lederle (1:30), and 25 (43 per cent) by Bischoff trichophytin ( dermatomycol undiluted). After additional experience we noted agreement between the Metz and the Lederle trichophytin in 80 to 95 per cent of cases. It would appear that the specificity of the test is chiefly due to the component in the vaccine which is common to all members of the genus. Immunity and Cutaneous Sensitization 29 (cl) Infection does not always mean sensitization to trichophytin. -Perhaps the lack of understanding of this fact has led to the belief of many physicians that trichophytin docs not elicit specific reactions. Saeves noted that E. inguinale and M. audouini failed to sensitize the skin, and TABLE 3.— Reaction to Trichophytin \\i> Oidiomycin of Patients with Strong Reaction to Catarrhal Vaccine* Catarrhal Vaccine Oidiomycin Trichophytin .Patient 48 Hr. 1 Wk. 48 Ilr. | lWk. 48 Hr. 1 Wk. JH K.M M.N M.C M.F R.V R.L M.E O.A + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + O o + + + + + o o o + o o o o + + + + + + + + + o + o + + + o + + + + o + + + + + + + + + + + + + + + + + + + + + + + + + + O o o + + o o o o o + + + + + o + o + O o o o o + + o o o o o o o + + o + + o o o ± o o o o o o o o + o o o o o o o o + + o + + + M.C B.A R.S R.P S.L B.S MR R.M K.B G.B 4- B.V D.H G.R o + A.A o S.I A.H o + + Total patients 25 Total positive reactions 25 12 19 8 3 7 "For all patients, fungous examination gave negative results. Stein reported that patients with favus reacted negatively to trichophytin. Muskatblit and Director reported the reaction of a series of 48 patients with culturally proved fungous infection and noted a variation in the response according to the species of infecting organism. In Table 4 may be found our results in testing with trichophytin 254 patients who had ■m 30 An Introduction to Medical Mycology fungous infections. It is here shown that a patient with a severe infection may yield a negative response to trichophytin. When the infecting organism is T. purpureum or A. schoenleini, for example, there is little likelihood of cutaneous sensitization and response to therapy is usually poor. Another TABLE 4.-Reaction to Trichophytin, after 48 Hours, of 254 Patients with Proved Fungous Infection Fungus M. lanosum . . . . M. audouini . . . A. schoenleini . T. purpureum . T. gypseum . . . T. violaceum . . M . f ulvum .... T. niveum E. cruris T. crateriforme . No. OF Cases No. of Negative Reactions O No. of Positive Reactions + + + + + + Percentage of Positive Reactions 39 48 10 50 88 6 4 4 3 2 4 18 7 25 13 3 1 1 5 15 1 13 12 15 8 2 8 35 2 1 1 1 14 7 2 23 1 2 3 1 76 31 20 24 71 50 75 75 33 100 possibility is that in a case of recent infection the test may be undertaken before sensitization has occurred. In experimental work, the time necessary for sensitization may vary between one and two weeks. We have found that approximately 53 per cent of patients with infec- tions due to T. purpureum who exhibited negative reactions according to TABLE 5.— Comparison of Immediate and Delayed Reactions to Trichophytin for Three Species of Infecting Micro-Organisms Fungus No. OF Cases Positive Immediate- Negative Delayed, % Both Positive, % Negative Immediate- Positive Delayed, % Both Negative, % 100 150 19 53 1.5 15.8 32 15 10 72.9 26.3 5 10.6 57.9 examination of the test site after 48 hours showed a positive response when the site was examined 10 minutes after the test. An additional 32 per cent of patients reacted both after 10 minutes and after 48 hours (Table 5). In some instances this immediate wheal reaction is associated with circu- lating antibodies, as evidenced by passive transfer tests. In the other cases we are unable to demonstrate circulating antibodies. It is interesting that in the latter cases a second injection into the site of the first fails to elicit Immunity and Cutaneous Sensitization ;>l any immediate response, whereas in the first group (with circulating anti- bodies) there is no difference between the responses to the first and those to a subsequent injection in the same site at various intervals between the two. Our studies on this important subject of immediate wheal reactions have not been completed, but it seems that some so-called negative reactions may be attributed to a laek of observance of the immediate response. We have so far noted the wheal reaction not only in cases of infection due to T. purpureum but also in a few instances when only E. inguinale and T. gypseum have been found on culture. We have also observed an immediate wheal reaction to oidiomycin. In the cases in which there are no circulating antibodies, the sensitized tissue appears to be situated in the upper cutis with increased permeability of the capillaries of the skin. (e) Does a patient with a trichophytid always react to trichophy- tin?— It is theoretically possible that the vaccine (trichophytin) may lack some of the components of the living fungus which are capable of eliciting reactions. However, in practice such an occurrence must be rare. If the patient's skin is sensitized so that a trichophytid reaction is produced, it is hardly likely that it will fail to react to the extract. We subscribe to the principle that a positive reaction to trichophytin is requisite to a diagnosis of dennatophytid. Some observers have reported negative reactions to trichophytin in cases of typical dermatophytid. They state that they have demonstrated anticutins to trichophytin to explain the anergic phase. In TABLE 6.— Reaction to Trichophytin Test of Patients with Eruption on Hands and Feet for Whom Culture from Feet Yielded T. Gypseum No. OF No. OF Negative Reactions No. OF Positive Reactions Percentage Cases o ;+; + + + + + + Reactions Trichophytin Lederle 48 hr. 38 1 wk 29 Metz 48 hr. 34 1 wk 29 1 1 1 1 4 4 3 20 15 12 13 11 8 15 12 2 1 3 3 87 83 88 97 Table 1 are listed the cases of trichophytid in which we are reasonably certain that no other diagnosis could explain the rash. Our diagnosis was based on an evident inflammatory focus preceding the eruption and was proved by culture and by the subsequent development of vesicles which were sterile for the growth of fungi. Irritation of the original focus some- times caused an exacerbation of symptoms; the test dose of trichophytin 32 An Introduction to Medical Mycology always elicited a response (usually strong) and sometimes caused a focal reaction. In Table 6 are listed cases in which cultures of T. gypseum were isolated from the feet by culture and in which there was a concomitant eruption on the hands. Although some of these rashes were considered non- mvcotic, it is interesting that in 87 per cent of the cases the test with trichophytin showed a positive reaction. (f) Variations in reactivity to trichophytin according to clin- ical type.— We find no difference in the reactivity of the skin to tricho- phytin between cases of inflammatory infections without evidence of trichophytid and cases of trichophytid. In all instances the patients react to the test. Likewise, all patients with acute tinea pedis due to T. gypseum TABLE 7.— Reaction to Trichophytin Test of Patients with Eruption on Feet for Whom Culture Yielded T. Gypseum No. OF No. of Negative Reactions No. OF Positive Reactions Percentage of Positive Cases O ± + + + + + + Reactions Trichophytin Lederle 48 hr 50 1 wk 28 Metz 48 hr 45 1 wk 27 12 6 8 6 8 6 7 2 15 9 13 8 12 5 15 9 3 2 2 2 60 57 67 70 have positive reactions. The reaction to trichophytin in patients with infection of the feet due to T. gypseum is shown in Table 7. Only 60 per cent of these patients showed hypersensitivity to trichophytin. In the patients with infection due to T. gypseum but with a negative reaction to trichophytin either the cutaneous manifestation was a slightly inflammatory focus or the organism was isolated from an infected nail. We conclude, therefore, that some factor or factors are responsible for a trichophytid other than infection with a potentially sensitizing organism. Some of the factors which may precipitate a trichophytid are (1) heat, (2) severe trauma (to hands), (3) intense anxiety and (4) administration of penicil- lin. That a patient exhibits a positive reaction to trichophytin does not necessarily mean that a trichophytid will develop. (g) "False" positive reactions.— We have not been able to confirm the statement of Tolmach and Traub that a false positive reaction may follow if one test site receives more than one test dose of trichophytin. To 10 patients who were not reactive to trichophytin, from two to five injections of trichophytin were administered at the same site at intervals of from two days to two weeks without evidence in any case of the development of Immunity and Cutaneous Sensitization 33 cutaneous sensitivit) to the vaccine. We consider this an important observa- tion, since it has been the experience <>l a number of investigators that the initiation of cutaneous sensitivity to fungi is only possible when the living organism invades the living tissues. The results of our tests seem to confirm this opinion. Tn another report it was noted that occasionally a tendenex to a response 1 had developed 48 horns after an initial delayed response to trichophytin. It was undecided, however, whether this tendency could be elassified as initiation of sensitivity. (h) Graded trichophyton tests.— A small percentage of patients do not react to trichophytin even in concentrated solution (1:10 or undiluted), and another small group react to a highly dilute 1 solution (1:300). In neither of these groups, which we have studied, do the patients have well defined clinical peculiarities or family histories of allergy, and we are unable to account for their different responses or as yet to attach any significance to the finding. With the largest number of persons trichophytin undiluted or in concentrated solutions (up to 1:10) is primarily an irritant, and more dilute solutions are requisite for determination of hypersensitivity or the lack of it. The optimal dilution varies somewhat with the product. (i) The patch test with trichophytin.— It has been known for a num- ber of years that some persons react to a patch test with trichophytin. This has led to the belief that some of the eczematous eruptions on the hands may be toxic fungous eruptions ( dermatophytids ) or that the infection may be primarily eczematous, simulating contact dermatitis. Our studies in regard to this point are as yet incomplete, but from our observations to date we conclude that both possibilities must be uncommon. In our experi- ence the patch test with trichophytin has less significance than the intra- cutaneous test. Even in cases of undoubted dermatophytid the patch test with trichophytin frequently shows a negative reaction. This may be inter- preted to mean that in these rashes the epidermis is not the tissue pri- marily sensitized. (j) Does the site of injection of trichophytin influence the size OF the response?— When the arm, the leg and the abdomen were used for test sites no appreciable difference was noted in the size of the reaction, nor did we find one site reactive when one or more of the others were non- reactive. In some instances a moderate increase in the size of a reaction was noted when skin adjacent to an active fungous infection was tested and the reaction was compared with that in skin at a remote point. This, however, was not invariable, and we have even noted a diminution in the size of the reaction near an active fungous focus. In routine practice the upper, outer arm is the usual test site. (k) Reliability of the [ntractjtaneous test with trichophytin.— We 34 An Introduction to Medical Mycology have found that when the triehophytin test is employed as part of a thor- ough study of the case, including clinical and other laboratory examina- tions, it is of confirmatory value both in diagnosis and in prognosis. It has been said that the test cannot be useful in diagnosis since it simply denotes sensitization to a dermatophyte, which may have occurred at a previous time and thus have no significance in connection with a given eruption. The second important disadvantage of the test is the undisputed fact that it may produce a negative reaction in a patient from whose skin pathogenic fungi have been isolated. Finally, the correlation of positive reactions and a presenting dermatosis should be carefully interpreted, both as to exist- ing probabilities and as to the presence of an active inflammatory fungous disease in the past. It is our belief that the first criticism is not altogether founded on accu- rate clinical or laboratory proof. It is probable that an inflammatory re- sponse to a fungous infection is necessary before the skin becomes sensi- tized. A careful study of the history for rashes will determine whether such an eruption previously occurred. A thorough search usually reveals traces of the condition, since spontaneous cure of most fungous diseases is rare. Microscopic and cultural studies will aid in the appraisal. If the examination is thorough, few instances of inability to interpret the results of the test will occur. We do not believe that the test can take the place of other investigations, such as the cultural determination of the pathogenic micro-organism, but it may yield information which cannot otherwise be elicited. The reason for the seeming unreliability of the test in the face of proved fungous infection has already been explained (Table 4). Such a fungus as A. schoenleini has a low sensitizing index, while one like T. gypseum has a high index. Few patients having favus react to triehophytin; with T. gyp- seum infection such a reaction is usual. (1) Interpretation of the intracutaneous test with trichophy- tin.— When a pathogenic fungus is isolated, a positive reaction to the test is additional evidence that an eruption at a remote point is also fungous. In cases in which the response to triehophytin is vigorous the prognosis is favorable. A strong reaction to the test should lead to conservative methods of treatment, such as application of bland wet dressings, soaks, powders, soothing lotions, pastes or ointments, and when there is exudative derma- titis the use of roentgen rays may be considered. In a small percentage of cases, the reason for the development of cutaneous sensitivity to triehophy- tin cannot be determined from the history, the examination or concurrent laboratory investigation. Of 111 patients who presented inflammatory erup- tions on the feet but no other rashes and lor whom the microscopic and Immunity and Cutaneous Sensitization 35 cultural tests yielded negative results, from 50 to 58 per cent showed a positive reaction to trichopliytin. Iu many of these cases previous treat- ment had masked the infection and made the isolation of fungi difficult. In others the primary disorder was definitely determined to be nonmycotic. The test was of little value for this series of patients, except that a doubtful TABLE 8.— Reaction to Thichophytin Test of Patients undeh 20 Years, Examination for Fungi Having Given Negative Results No. OF No. OF Negative Reactions No. OF Positive Reactions Percentace Cases O ± + + + + + + Reactions Tiichophvtin Lederle 48 hr. , 106 1 wk 75 Metz 48 hr 105 1 wk 75 79 61 74 60 11 3 15 5 9 8 12 5 5 3 o 5 2 2 15 15 15 13 reaction to trichophytin led us to repeat the cultural studies. Of 106 patients under 20 years of age who had rashes which were not considered fungous, only 15 per cent reacted to the trichophytin test (Table 8). We therefore wish to stress the diagnostic value of a positive reaction to trichophytin in children and young adults. In tests of 45 patients over 50 years of age who TABLE 9.— Reaction to Trichophytin Test of Patients over 50 Years, Examination for Fungi Having Given Negative Results No. OF No. OF Negative Reactions No. OF PosiTrvE Reactions Percentage of Positive Cases O ± + + + + + + Reactions Trichophytin Lederle 48 hr 45 1 wk 39 Metz 48 hr 45 1 wk 39 20 16 18 18 11 10 11 10 9 9 10 7 4 4 5 4 1 1 31 33 35 28 were clinically free of fungi, 31 to 35 per cent of the reactions were posi- tive (Table 9), over twice the percentage of patients under 20 years. The possibility of error therefore increases with age. In tests of 77 patients of miscellaneous ages with various cutaneous disorders not considered to be mycotic, from 16 to 20 per cent of the reactions were positive (Table 10). In a series of 216 cases in which an eczematous eruption was confined to the hands and in which incidental examinations for fungi on both the 36 An Introduction to Medical Mycology hands and the feet gave negative results, only 20 per cent of the patients showed a positive reaction to trichophytin (Table 11). It is interesting to note that for all 557 patients for whom fungous examinations gave negative results, the incidence of the reaction to trichophytin was approximately 29 TABLE 10.— Reaction to Trichophytin Test of Patients with Miscellaneous Eruptions, Examinations for Fungi Having Given Negative Results No. OF No. OF Negative Reactions No. of Positive Reactions Percentage Cases O ;+; + + + + + + Reactions Trichophytin Lederle 48 hr 77 1 wk 53 Metz 48 hr. 76 1 wk 53 46 34 45 33 19 7 16 9 7 8 9 7 5 4 6 4 16 23 20 21 per cent. In half of these cases the clinical evidence suggested mycotic infection. Since we believe the test to be specific in the majority of instances and have noted that patients with primarily inflammatory eruptions proved by culture to be fungous inevitably show positive cutaneous reactions to TABLE 11.— Reaction to Trichophytin Test of Patients with Eruption on Hands rut Not on Feet, Examination for Fungi Having Given Negative Results No. of No. OF Negative Reactions No. OF Positive Reactions Percentage of Positive Cases o ± + + + + + + Reactions Trichophytin Lederle 48 hr 216 1 wk 141 Metz 48 hr 205 1 wk 135 129 90 121 80 42 23 43 18 32 14 24 23 12 13 15 12 1 1 2 2 20 20 20 28 trichophytin, we believe that a positive reaction is of value but a negative reaction of even greater value when one is trying to decide whether an inflammatory eruption is of mycotic origin. If the rash is of several weeks' duration (which would allow ample time for sensitization), if neither microscopic nor cultural studies show fungi and if the intracutaneous test to trichophytin gives a negative result, an exudative inflammatory eruption m;i\ be declared to be nonnivcotic. Immunity and Cutaneous Sensitization 37 2. THE OIDIOMYCIN TEST In an investigation ( in which Royal Montgomer) collaborated ) of the tost with oidiomycin, a commercial vaccine made from M. albicans, we concluded that the information obtained from the test was rarely useful. Sensitization of the skin might occur from a focus in the intestinal tract or from a lesion which had subsequently resolved. Of 42 patients having some form of localized cutaneous moniliasis, a positive response to the test was noted in 57 per cent. Of 91 patients with an infection due to a fungus other than M. albicans, 45 per cent showed a positive reaction, while of 192 patients with no evidence of any type of fungous infection, 46 per cent reacted. In a second series of tests ML albicans was found to be present in cultures of material from the tongue, skin or stool of 52 of 100 patients. The test produced a positive reaction in 58 per cent of the patients with positive cultures and in 54 per cent of those with negative cultures; the similarity of results is noteworthy. From these findings, which substantially agree with those of Biberstein and Epstein and of Staehelin and his co-workers, it is obvious that the test has no practical value in the diagnosis of infections due to M. albicans. We advise that the oidiomycin test be abandoned. 3. OTHER CUTANEOUS TESTS We came into the possession of a supply of coccidioidin through the courtesy of the late Ernest C. Dickson, of Stanford University, and have tested the cutaneous sensitivity of over 400 patients who had various dermatoses, many with some form of infection due to a dermatophyte. In only one instance we observed a weakly positive reaction to the test. This is important, since the patients tested lived in New York and gave no history of a prolonged stay in the part of California where granuloma coccidioides is endemic. There is ample proof that the coccidioidin test is highly specific. The same conclusions may be drawn with respect to blas- tomycin and sporotrichin. With blastomycin, in contradistinction to coc- cidioidin and sporotrichin, negative reactions to the test may be encoun- tered in the presence of the active disease. The histoplasmin test may be negative in a patient with active histoplasmosis. Positive reactions usually may be found in patients with the rapidly fatal type and also in patients who apparently have an abortive form. Occasionally cross-sensitization or false positive reactions may be noted for blastomycin and histoplasmin. Fishman stated that 60 per cent of several hundred patients with coc- 38 An Introduction to Medical Mycology cidioidomycosis showed a positive skin reaction to histoplasmin. Katzenstein concluded that cross-sensitization occurred frequently with blastomycin. 4. CONJOINT SENSITIZATION TO PENICILLIN Recent clinical and experimental studies suggest that penicillin, a derived product of the mold Penicillium, contains antigenic properties similar to those elaborated in superficial fungous disease. The local applica- tion of penicillin in patients with acute fungous disease may provoke a local exacerbation. Injection of the drug parenterally may result in the reactivation of a previous dermatophytid, produce in patients with present or previous active dermatophytosis a vesicular eruption of the hands and/or feet identical with the id reaction, or bring forth erythematovesicular lesions in areas of previous dermatophytosis. Cross-sensitization experiments in the guinea-pig, utilizing both skin and uterus as test tissue, disclosed an intimate relationship between sensitiza- tion to penicillin and to T. gypseum infections. Whereas the nature of this relationship is still obscure, available evidence indicates that animal tissues with an induced sensitization to penicillin have likewise developed an allergic reactivity to trichophytin. Clinical reactions to penicillin may be classified as ( 1 ) contact dermatitis; (2) sensitization of the vascular bed, resulting in urticaria, angioneurotic edema, serum sickness-like syndrome, erythematovesicular dermatitis, erythroderma id-like reactions and erythema nodosum (shocklike reactions are included in this group); (3) sensitization of other structures, e.g., asthma; (4) toxic effects, causing convulsions (especially after local cere- bral application), peripheral neuritis and possibly agranulocytosis, and (5) indirect effects, precipitating an unrelated infection by destruction of antagonistic bacterial flora. 5. EXPERIMENTAL FUNGOUS INFECTION IN ANIMALS This subject is considered partially in the first part of this chapter under The Trichophytin Test. It is further dealt with in Chapter XXVI. Not all fungi capable of being inoculated into laboratory animals cause a resultant "take." The dermatophytes, or fungi causing superficial infections in man, are about equally divided in regard to their capacity or lack of ability to infect laboratory animals. Bloch and his school did most of their work of establishing basic immunologic principles using a strain of A. quinckeanum. DeLamater and also Henrici used strains of T. gypseum as well as other species of fungi. Immunity and Cutaneous Sensitization 39 When a virulent strain <>l T. gypseum is inoculated cutaneously intp guinea-pigs, the incubation period is lour to six days, and the period of spread or development lasts seven to 10 days. A climax is reached 1>\ the twelfth to sixteenth day. The lesion then begins to disappear spontaneously, and healing is complete in 30 to 35 days. Considerable variations in the time factors occur when different species of fungi are used and even with different strains of the same species. The susceptibility, time for develop- ment of a reaction it the animal is susceptible and the appearance of the reaction are also variable when other laboratory animals such as kittens or rabbits are employed. When guinea-pigs and rabbits are subjected to addi- tional inoculations, the incubation period is shortened and the reaction greater. Henrici found that intraperitoneal reinoeulation of live spores or of trichophytin when the first infection had not quite healed resulted in a diffuse generalized reaction of the skin. If interested in experimental prob- lems in which laboratory animals are to be used, the reader is referred to the original articles mentioned in the bibliography. BIBLIOGRAPHY Biberstein, H., and Epstein, S. : Ininiunreaktionen bei der menschlichen und tierexperimen- tellen Oidiomykose der Haut, Arch. f. Dermat. u. Syph. 165:716, 1932. Bloch, B., in Jadassohn, J.: Handbuch der Haut- und Geschtectitskiankliciten (Berlin: Julius Springer, 1928), vol. 11, pp. 300 and 564. Cormia, F. E., and Lewis, G. M.: Experimental aspects of penicillin sensitization, with spe- cial reference to conjoint sensitization to superficial fungous disease, J. Invest. Dermat. 7:375, 1946. ; Lewis, G. M., and Hopper, M. E.: Experimental aspects of penicillin sensitization: II. With reference to Schultz-Dale phenomenon, J. Invest. Dermat. 8:395, 1947. DeLamater, E. D.: Experimental studies with dermatophytes: III. Development and duration of immunity and hypersensitivity in guinea-pigs, J. Invest. Dermat. 4:143, 1941; IV. Influence of age upon allergic response in experimental ringworm in guinea-pig, ibid. 5:423, 1942. , and Benham, R. W.: Experimental studies with dermatophytes: I. Primary disease in laboratory animals, J. Invest. Dermat. 1:451, 1938; II. Immunity and hypersensitivity in laboratory animals, ibid. 1:465, 1938. Fishman, H. C: Discussion of Katzenstein. Goodman, H., and Marks, I.: Reaction to trichophytin compared with reactions to othei bacterial products, Arch. Dermat. & Syph. 31:819, 1935. Henrici, A. T.: Experimental Trichophytid, in Proceedings of the Third International Con- gress for Microbiology (Baltimore: Waverly Press, 1940), p. 567. Jadassohn, W., and Peck, S. M.: Epidermophytide der Hande, Arch. f. Dermat. u. Syph. 158:16, 1929. ; Schaaf, F., and Wohler, G.: Analyses of composite antigens by Schultz-Dale technic: Further experimental analyses of trichophytons, J. Immunol. 32:203, 1937. Katzenstein, L.: Specificity of skin tests in deep fungous infections, J. Invest. Dermat. 9:249, 1947. k\n her, W.: Ueber den diagnostischen Wert der intrakutanen Trichophy tinreaktion, Deutsche med. Wchnschr. 62:138, 1936. Lewis, G. M., and Hopper, M. E.: Ringworm of scalp: IV. (a) Comparative reactions to cutaneous tests with trichophytin in children with and without ringworm of the scalp; (b) Evaluation of therapy with stock vaccines in types of infection resistant to treatment, Arch. 40 An Introduction to Medical Mycology Dermat. & Syph. 36:821, 1937; Infections of skin due to Monilia albicans: II. Immunologic, etiologic and therapeutic considerations, New York State J. Med. 38:859, 1938. ; Hopper, M. E., and Montgomery, R. M.: Infections of skin due to Monilia albicans: I. Diagnostic value of intradermal testing with commercial extract of Monilia albicans, New York State J. Med. 37:878, 1937. MacKee, G. M., and Hoppeh, M. E.: Trichophyton test: Its value as diagnostic aid, Arch. Dermat. & Syph. 38:713, 1938. Sulzberger, M. B., and Wise, F.: Trichophytin and allergy to trichophytin: II. Ob- servations on variability of cutaneous responses to trichophytin, Arch. Dermat. & Syph. 36:548, 1937. Low, R. C: Anaphylaxis and Sensitization (New York: William Wood & Company, 1925), p. 124. We are greatly indebted to this text. References to authors whose works were printed prior to 1925 will be found here. Marcussen, P. V.: Relationship of urticarial to inflammatory reaction to trichophytin, Arch. Dermat. & Syph. 36:494, 1937. \li skatblit, E., and Director, W.: Trichophytin test: Report of 350 cases, Arch. Dermat. & Syph. 27:739, 1933. \i isser, A.: Plato's Versuche iiber die Herstellung und Verwendung vom Trichophytin, Arch. f. Dermat. u. Syph. 60:63, 1902. Peck, S. M.: Epidermophytosis of feet and epidermophytids of hands, Arch. Dermat. & Syph. 22:40, 1930; Allergic manifestation of fungous diseases, New York State J. Med. 36:1237, 1933. Pels, I. R., and Schlenger, L.: Incidence of dermatophytosis of feet, with comment on use of trichophytin, South. M. J. 25:1066, 1932. Robinson, G. H., and Grauer, R. C.: Use of autogenous fungus extracts in treatment of my- elitic infections, Arch. Dermat. & Syph. 32:787, 1935. Rosen, I.; Peck, S. M., and Sobel, N.: Hypersensitivity to trichophytin in casual dermatologic patient: Study of 102 cases, Arch. Dermat. & Syph. 23:1041, 1931. Staehelin, A.; Mu, J. W., and van Schouwen, M.: Beitriige zur Klinik und Pathogenese der Oidiomykosen, Arch. f. Dermat. u. Syph. 165:294, 1932. Sulzberger, M. B.: Dermatologic Allergy (Springfield, 111.: Charles C Thomas, Publisher, 1940). ■ — — , and Lewis, G. M.: Trichophytin hypersensitiveness demonstrated by contact tests, Arch. Dermat. & Syph. 22:410, 1930. -; Lewis, G. M., and Wise, F.: Trichophytin and allergy to trichophytin: I. Comparison of cutaneous responses to two standard preparations of trichophytin and to dermatomycol (da Fonseca and de Area Leao), Arch. Dermat. & Syph. 34:207, 1936. and Wise, F.: Ringworm and trichophytin, J. A. M. A. 99:1759, 1932. Tolmach, J. A., and Traub, E. F.: Epidermophytids and trichophytin reaction, Arch. Dermat. & Syph. 28:560, 1933. I omlinson, W. J.: Trichophytin hypersensitiveness: Report of case with immediate or reagino- genic type of reaction, J. Allergy 6:573, 1935. Traub, E. F., in discussion on Peck (1936). Van Dyck, L. S.; Kingsbury, J.; Throne, B., and Myers, C. N.: Use of trichophytin as diagnostic and therapeutic agent in mycotic infections of skin, New York State J. Med. 31:611, 1931; Further experiences with trichophytin, ibid. 32:1101, 1932. W \i i'hard, B.: Zur Pathogenese des dysidrotischen Symptomenkomplexes: Ueber cin unter dem Bilde einer Dysidrosis verlaufendes Epidermophytid, Dermat. Ztschr. 53:692, 1928. Wn.ii wis, C. M.: Trichophytid of the hands, Arch. Dermat. & Syph. 27:973, 1933. . v\i) Carpenter, C. C: Trichophytin in diagnosis, Arch. Dermat. & Syph. 25:847, 1932. CHAPTER VII Nondermatologic Allergic Manifesta tions Due to Fungi THERE is reason to believe that sensitization and immunity phenomena are of great importance not only in the development of the response of the patient with a fungous infection (symptoms and signs) but in the rate of response of the patient to most therapeutic measures. The subject of secondary allergic manifestations of the skin ( dermatophy tids ) is dis- cussed in Chapter IX in the sections on tinea capitis (pp. 58 ff.) and dermatophy tosis (pp. 116 ff. ); moniliids are discussed in the section on moniliasis (p. 150). It has been shown that specific sensitization to some genera of fungi occurs after infection, and this fact may be demonstrated by tests with fungus extracts. The possibility has also been considered that fungi may act as sensitizers without causing an actual infection. From this point of view we have investigated a number of cases of eczema of the hands in which the cause was obscure. Patch tests with trichophytin did not reveal any consistent sensitivity either on the affected area of skin or at a site remote from the eczema. We had the same negative results when we tested such patients with extracts of saprophytic air-borne fungi. From a theoretical standpoint, an immediate wheal and flare response to a sus- pected fungus allergin given by intracutaneous injections would speak in favor of a direct relationship. 1. ASTHMA There have been investigations of other allergic diseases and their pos- sible cause by the spores of air-borne fungi. Cooke found that house dust was a cause of asthma. The activity of the dust was diminished by heating. Van Leeuwen noted that in localities where patients with asthma were free of an attack there were few air-borne molds and yeasts. Cadham in 41 42 An Introduction to Medical Mycology 1924 reported three cases of asthma in which the disease was due to the spores of a wheat rust. He found positive reactions to an extract of the organism, and acute attacks resulted on the inhalation of a small quantity of the spores. Hansen found several species of Aspergillus and Penicillium to be excitants capable of producing a paroxysm. Hopkins, Benham and Kesten reported that in a case of asthma under their observation the at- tacks occurred in locations in which mold spores were abundant. There was cutaneous sensitivity to a strain of Alternaria present in the patient's home, and attacks were provoked by inhalation of the extract. Feinberg, Brown, and Conant, Wagner and Rackemann pointed out the importance of molds in the patient's environment as a cause of asthma. They per- formed many tests with the extracts of cultured air-borne fungi, and these resulted in a high percentage of positive reactions. Wagner and Rackemann noted that many patients with asthma obtained relief when kapok was removed from their immediate environment. Fresh kapok did not cause trouble; most of the reactions observed were produced by old material. They found that the principle in commercial kapok active in skin tests depends on the growth of molds in the kapok (vegetable) fibers. Wagner and Rackemann also found that steam sterilization of both cotton and kapok effectively changed the materials so that molds did not grow well on them. Rowe recently stated that all patients with possible bronchial asthma or allergic bronchitis should be tested with fungus extracts as well as with other allergens. Waldbott and Ascher consider sensitivity to rust and smut an important cause of seasonal allergy of the upper respiratory tract. In two cases they were able to reproduce asthmatic attacks by in- halation of rust. They consider the development of the attack during the rust and smut season and strong reactions to their antigens to be reliable features in diagnosis. Further detailed and controlled work in this subject appears to be necessary in order to clarify the concepts. Few proved instances of true bronchial allergy to fungi have been reported. 2. HAY FEVER Correlation between the incidence of attacks of hay fever and prev- alence of air-borne fungi has been recorded. Difficulty may be experi- enced in ruling out air-borne pollens. BIBLIOGRAPHY Brown, G. T.: Hypersensitiveness t<> fungi, J. Allergy 7:455, 1936. Cadham, F. T.: Asthma due to grain rusts, J. A. M. A. 83:27, 1924. Nondermatologic Allergic Manifestations Due to Fungi 43 Conant, N. F.; Wagner, II. ('.. vnd Rackemann, F. M.: Fungi found in pOlows, mattresses and furniture, J. AJlergj 7:234, L936. Cooke, H. A.: Studies in specific hypersensitiveness: New etiologic factors in bronchial asthma, J. [mmunol. 7:147, 1922. Feinberg, S. M.: Mold allergy: lis importance in asthma and hay fever, Wiseonsin M. J. 34:254, L935; Seasonal haj lever and asthma due to molds, J. A. M. A. 107:1861, 1936. Hansen, K.: Ueber Schirnmelpilz— Asthma, Verhandl. d. deutsch. Gesellsch. f. inn. Med. 40:204, 1928. Hopkins, J. G.; Benham, R. W., and Kesten, B. M.: Asthma due to a fungus— Alternaria, J. A. M. A. 94:6, 1930. ROWE, A. H.: Bronchial asthma: Its diagnosis and treatment, J. A. M. A. 111:1827, 1938. Van L EE U WE N, W. S.: Allergic Diseases (Philadelphia: J. B. Lippincott Company, 1925), p. 58. Wagner, H. C, and Rackemann, F. M.: Kapok, J. Allergy 7:224, 1936; Kapok and molds: An important combination, Ann. Int. Med. 11:505, 1937. Waldbott, G. L., and Ascher, M. S.: Rust and smut, major causes of respiratory allergy, Ann. Int. Med. 14:215, 1940. CHAPTER VIII Immune Bodies Circulating in the Blood 1. SUPERFICIAL FUNGOUS DISEASES GREENBAUM investigated the Kolmer complement fixation test as applied to a group of serums obtained from patients suffering from a variety of superficial ringworm infections. The negative results indi- cated that the test is valueless and that few or no antibodies develop in the course of superficial ringworm. Precipitins were demonstrated in rabbit serums after infections with several different dermatophytes ( Citron, Sharp, etc.). Kusunoki failed to demonstrate either precipitins or complement- fixing antibodies in experimental animals or in man infected with ring- worm fungi. As we have mentioned, Marcussen and others have demonstrated circu- lating antibodies, evidenced by passive transfer tests. In our observations this finding was obtained only in patients with infections due to T. pur- pureum. Per and Braude, Jessner, and Ayres and Anderson have demon- strated antibodies in patients exhibiting allergic rashes due to fungi. Ayres and Anderson showed that serum obtained from a patient with a tricho- phytid, if mixed with Sabouraud's agar in the proportion of 8 per cent, was completely fungistatic. Control tests which utilized serum of subjects free from infections or with infections localized to the feet showed no inhibition of fungi seeded on the medium. Traub achieved partial success with the therapeutic administration of serum obtained from patients who had been cured of trichophytid. Our unreported experiences have not entirely confirmed the reports of these investigators. When serums ob- tained from patients with trichophytid were added to dextrose agar, we noted partial inhibition, evidenced by a diminution in the diameter of the resultant growth. However, in a few instances retardation of the cultural 44 Immune Bodies Circulating in the Blood 45 growth resulted when normal scrum was added to the agar. We could not obtain complete fungistasis. Therapeutic use of serum in patients with fungous disease lias been uniformly unsuccessful. 2. DEEP (INVASIVE) FUNGOUS DISEASES Whereas in main of these deep fungous infections it is possible to demon- strate agglutinins, precipitins, opsonins and complement-fixing antibodies, such tests have not come into popular use, nor are they considered as reliable as other methods for diagnosis. This subject is considered further under the various individual diseases. BIBLIOGRAPHY Avhks. S.. and Anderson, N. P.: Inhibition of fungi in cultures by blood serum from patients with •phytid" eruptions, Arch. Dermat. & Syph. 29:536, 1934. Greenbaum, S. S.: Immunity in ringworm infections, Arch. Dermat. & Syph. 10:279, 1924. [essner, M., in Jadassohn, J.: Handbuch der Haut- und GescMechtskrankheiten (Berlin: Julius Springer," 1928), vol." 11, p. 361. Per, M., and Braude, R.: Diagnostic and therapeutic value of triehophytin in dermatomycoses in light of present knowledge of specific allergy and immunity, Acta dermat. -venereol. 9:1, 1928. Sharp, W. B.: Extraction of antigen from molds, J. Invest. Dermat. 4:205, 1941. Traub, E. F., in discussion of Peck, S. M.: Allergic manifestations of fungous diseases, New York State J. Med. 36:1237, 1936. CHAPTER The Superficial Mycoses IN THE majority of cases of fungous infection the eruption is confined to some part of the skin. There are two large groups of the mycoses: (1) ringworm, or tinea, in which the site of invasion and propagation of the fun- gus is keratin (stratum corneum, hair, nails) and in which, while dissemi- nation by the blood stream may occur, the involvement of visceral organs is unknown, and (2) moniliasis, in which the yeastlike micro-organism is found in intertriginous areas but is also a common silent inhabitant of the gastrointestinal tract. Included also are tinea versicolor, erythrasma, myringomycosis, tinea imbricata and several other tropical mycoses and other fungous diseases which do not produce granulomas. Some workers subdivide the superficial mycoses into parasitic and saprophytic types, according to the degree of cellular reaction in the adjacent tissues. We do not share their point of view, since some of the more virulent (difficult to cure) infections caused by organisms such as T. purpureum or A. schoen- leini show little reaction in the tissues, invoke little or no immunologic response and yet, therapeutically, are the opprobrium of dermatologists. To call these organisms saprophytes might be correct in the sense that they do not provoke reaction in the host, but this would be misleading from the aspect of response to treatment. As a group, the superficial mycoses show a wide diversity of types and characteristics, and no generalization may be offered regarding their re- sponse to treatment. They constitute the bulk of fungous infections which plague the general population. The incidence of species varies in different parts of the world. We shall consider the various phases of the subject, including the clinical features and the treatment, under the respective titles. It is of interest, but so far of not much practical importance, that multiple fungous infections involving different species of dermatophytes are not uncommon. Muskatblit and we also have recorded a number of instances in which one infection antedates another, in which the different 46 The Superficial Mycoses 47 species of Fungi are working together or in which they arc causing entirel) independent infections. In our discussion of ringworm we shall follow conventional lines, with some variations which seem indicated. We believe that the ideal approach is etiologic (according to Sabouraud), and we have tried to correlate this point of view with the time-honored division into clinical groups. It is our opinion that an exposition of the characteristics and habits of such a fungus as T. purpureum will be helpful, simplifying rather than confus- ing the subject. Dowding and Orr described three clinical types of T. gvpseum; this seems to be another step in the right direction. Analysis of data compiled from the study of specimens from a particular locality is also valuable. Fowle and Georg reported on inflammatory infections in patients exposed to ringworm in cattle. They found that 14 of 25 cases of deep suppurative ringworm were caused by faviform Trichophyta. We find it convenient to divide ringworm into five regional varieties, keeping in mind that a patient may have more than one variety at the same time. Table 12 indicates the predominant micro-organism of each. TABLE 12.— Types of Ringwobm Infection Diagnosis Organism Tinea capitis Microspora Tinea barbae Variable Tinea glabrosa Variable Tinea cruris E. cruris Dermatophytosis T. gypseum ( Onychomycosis ) and T. purpureum BIBLIOGRAPHY Fowle, L. P., and Georg, L. K.: Suppurative ringworm contracted from cattle, Arch. Dermat. & Syph. 56:780, 1947. Lewis, G. M., and Hopper, M. E.: Concurrent, combined and consecutive fungous infections of skin: Cultural experiences, Arch. Dermat. & Syph. 47:27, 1943. Muskatblit, E.: Combined fungous infections: Beport of six cases with review of 36 cases from literature, Arch. Dermat. & Syph. 44:631, 1941. 1. TINEA CAPITIS (Ringworm of the Scalp, Including Favus) Tinea capitis is a superficial fungous infection observed mainly in chil- dren before the age of puberty. In certain forms, the infection may persist into adult life, but it is unusual for the disease to appear then for the first time. The condition is characterized by loosening and partial loss of scalp hair in patches, breaking off of the infected hair, which loses its luster, and 48 An Introduction to Medical Mycology inflammation varying in degree from fine, branny scaling in some cases to phlegmonous localizations in others. (a) Etiology.— During the past few years, a widespread epidemic of scalp ringworm affected children throughout the United States. At this time ( 1948 ) there is some evidence that it is slowly resolving, but in many communities the problem is still acute. The predominant micro-organism is Microsporum audouini. Except under epidemic conditions, tinea of the scalp is usually due to one of two Microspora, M. audouini and M. lanosum. In New York under ordinary conditions the incidence of these micro- TABLE 13.— Cause of Tinea Capitis As Found in New York City before AND DURING THE EPIDEMIC Nonepidemic Years 1935-38 Epidemic Years 1943-46 Organism No. of Cases % No. of Cases % M. audouini 114 39.0 351 77.0 M. lanosum 115 39.4 79 17.3 T. violaceum 22 7.5 3 0.7 A. schoenleini 17 5.8 5 1.1 T. craterifonne 5 3 1 1 1.7 1.0 0.3 0.3 7 6 1.5 M. fulvum 1.3 T. gypseum T. sulfureum No growth or not diagnosed 14 4.8 5 1.1 Total 292 100 456 100 organisms is almost equal; they are the cause in about 80 per cent of all cases (Table 13). The remainder of the infections are caused by a scatter- ing of micro-organisms (Table 13). In California and in most parts of the Western and Southern states, M. lanosum is the predominant organism. No definite statement, however, is possible without cultural studies. Leh- man, in San Antonio, Texas, has observed that a greater percentage of infections were due to M. audouini, whereas Smith, in El Paso, reported that he rarely encountered this organism and that in most of his cases ringworm of the scalp was caused by M. lanosum. In the Midwestern and Eastern states, M. audouini probably is the most frequent cause of tinea capitis. In Europe, M. lanosum is uncommon; in most cases, ringworm of the scalp is caused by M. audouini. The condition is more often observed in cities than in the country and is seen chiefly among the poor, particularly when there is overcrowding. It affects more boys than girls, the ratio being about 3:1. Crocker stated that in 600 cases the disease was 6 per cent more prevalent in boys. Beeson noted that 85 per cent of his patients were boys. In Pardo-Castello's series, there was only one girl to 31 boys. However, Fk;. 5. Age incidence of 444 children with tinea capitis due to Microsporum audouini. Solid line represents 317 white children; broken line, 127 Negro children. 49 50 An Introduction to Medical Mycology Fox and Fowlkes found that in 48 recorded instances of ringworm of the adult scalp, 32 women were affected (66 per cent). In our experience the highest peak of infection is reached at age 8. The disease may occur in epi- demics in schools, orphan asylums or camps or wherever a number of chil- dren congregate; it is spread by direct contact with an infected person, with an infected comb, barber clippers, plush (movie) seat, hat or other article or, TABLE 14.— Incidence of Species of Fungus Causing Nonepidemic Tinea Capitis in the United States and Canada Authority White Corlett Wende Beeson Greer wood Burgess Pardo-Castello Davidson and Gregory Cleveland Mook Weidman Anderson Smith Binkley Location Boston Cleveland Buffalo Chicago Boston Montreal Havana Winnipeg Vancouver St. Louis Philadelphia Los Angeles El Paso Cleveland No. OF Cases M. Au- DOUINI, % M. Lan- OSUM, % Other Species, % M. audouini stated to be the pre- dominant organism 40 25.0 67.5 7.5 62 32.2 33.9 33.9 32 75 100 In majority of cases acquired from animals 25.0 67.5 32.2 33.9 100.0 57.0 43.0 100.0 36 41.7 50.0 Most frequent Rarely found 70.0 30.0 8.3 in case of certain types of infection, with kittens or other pets. It is inter- esting that with animals, as with human beings, only the young are sus- ceptible to the infection. The chief danger, then, of dissemination of the infection from animals lies in young pets of unknown origin, particularly kittens. Race does not appear important except that with favus most pa- tients are either native-born Russian, Polish or Italian or descendants of immigrants from these countries. (b) Types of infection.— The infecting micro-organism first invades the stratum corneum, later enters the hair follicle and finally attacks either the superficial or the deep parts of the hair. The cardinal symptoms of tinea of the scalp are partial loss of hair in patches, breaking off and lack of luster of the infected hair and varying degrees of inflammation. Atrophy and scarring may follow certain types of infection. In most textbooks a separate section is devoted to kerion. We do not Fig. 6. Tinea capitis due to M. audouini. A, scattered scaly patches of pseudo-alopecia containing hair stumps in a boy aged 7. B, the same patient, showing extension of infection to the smooth skin of the forehead. C, regrowth of hair lias masked the disease. D, luminogram of the patient shown in C, revealing infected hairs. Examination of patients under filtered ultraviolet rays often brings to light hidden foci not detectable during the ordinary clinical examination. E, pustular ringworm of the type more commonlj caused by M. lanosum. F, complete epilation of scalp hair following roentgen treatment. This is the therapy of choice in most instances of tinea capitis caused by M. audouini. 51 52 An Introduction to Medical Mycology consider kerion to be more than a marked tissue reaction to the infecting micro-organism: at the top of the list, so to speak, with simple scaling at the bottom. Kerion is a painful, elevated, boggy, erythematous, local- ized tumefaction due to one of several species of fungi. We have records of kerion due to M. lanosum, M. audouini, Microsporum fulvum, Tricho- phyton crateriforme, T. gypseum and Trichophyton niveum. In the main, the characteristics of kerion are the same, irrespective of the causal fungus, and in most instances cure of the fungous infection follows the disappear- ance of the kerion. In another particular we deviate from the customary teaching. We cannot see any logic in the traditional respect paid to favus when it is considered more than a type of tinea capitis. The clinical findings of favus are frequently characteristic, so the retention of the name is useful. Since the clinical findings and the course of the disease vary a great deal, according to the infecting micro-organism, we shall discuss tinea capitis further under the headings of the causative fungi as follows: (1) Microsporum audouini.— This fungus is responsible for the classic type of scalp ringworm known as the "gray patch"; it is the common cause of epidemics in orphanages and other institutions. The onset is usually insidious, and the duration of the infection averages over eight months. When the condition is first detected by the parent, guardian or teacher, there are several small areas in which the hair is dull and broken off. The surface of the patch is usually scaly. As a rule little redness is noted, but occasionally a considerable degree of inflammation may be present. We have observed that the infection frequently begins along the part of the hair or where the hair is short. When first examined, the lesions are usually in the occipital and temporal regions. Usually a number of lesions spread peripherally, finally becoming as large as a silver dollar or larger. There is not much tendency for the infection to spread to other parts of the body. In the cases observed in New York during an epidemic ( 1943 to 1947 ) there was a tendency for the infection to localize to the occipital region. The lesions were more frequently inflammatory than in the ordinary spor- adic disease, and associated lesions on the glabrous skin were more com- monly observed than in the sporadic cases. Montgomery and Walzer re- ported a case of infection of the eyelashes in a patient with tinea capitis. (2) Microsporia)! lanosum.— There may or may not be a history of contact with a stray or newly acquired kitten or other young animal. Various home and proprietary remedies have usually increased the inflammation. In other members of the family, particularly the mother or other children, lesions ma\ develop on the glabrous skin. The infection tends to show con- siderable inflammatory reaction. The first patch to develop is frequently Fig. 7. Tinea capitis caused by M. lanosum. A, typical acute inflammatory involvement with follicular pustules. B, areas of complete alopecia due to the severe follicular inflammation. In such cases spontaneous cure results. C, extension of the infection below the hair line, an occurrence not uncommon in this type of infection. D, extension of the infection to the glab- rous skin of the face. 53 54 An Introduction to Medical Mycology the largest; secondary lesions are usually smaller. The duration is usually short ( under three months ) . There is noticeable loss of hair in the affected patches with slight or, more commonly, marked inflammation and tender- ness. Broken-off hairs may be found at the periphery of a lesion. (3) Microsporum fulvum— An infection due to this fungus may or may not be acquired from an animal. The duration is usually short (one month or less). There is a tendency for the infection to remain localized to only one part of the scalp. Inflammation is usually marked, and kerion is not unusual. In our experience there is always noticeable edema of the affected tissues. (4) Trichophyton violaceum.— In this type of ringworm of the scalp, small scattered patches develop insidiously. The duration of the infection is frequently many months or even years. The disease may not be cured at puberty. The fungus invades the cortex of the hair (endothrix infection), and the hairs break off close to the scalp. The appearance of the infected scalp has led to the name "black dot" ringworm. In many instances, the hairs break off just below the surface of the scalp, which results in a minute secondary pyogenic infection with subsequent crusting, not unlike that due to ingrowing hairs of the beard. We have never found T. violaceum in the pus in these lesions, although we have tried innumerable times. After many months there is usually some atrophy or scarring. (5) Trichophyton craterifonne — The clinical appearance and course of tinea due to this organism differ materially from those of infection due to T. violaceum, since the infection may appear in one or more patches and the infected hairs usually do not break off at the surface of the scalp; rarely the clinical appearance is that of "black dot" ringworm. In addition there is usually secondary infection; crusting and kerion are seen in three of five cases. As in kerion due to other fungi, the infected hairs are shed because of the inflammatory process, and cure may be spontaneous. The organism invades the cortex of the hair ( endothrix infection ) and is not transmissible to laboratory animals. Infection with T. craterifonne may be of several weeks' duration when first observed. (6) Trichophyton sulfureum.— -The only scalp which we observed to be infected with this fungus presented a diffuse reddened scaly rash over the occiput. Throughout this area were numerous small stumps, inter- spersed with normal hair. (7) Achorion (Trichophyton) schoenleini.— This micro-organism (essen- tially an endothrix Trichophyton ) is the cause of an infection designated as favus. The clinical manifestations are usually characteristic. The usual focus is the scalp, from which the disorder may spread to the nails or to the glabrous skin. At first there is a small spot of scaly inflammation. Around Fig. 8. Tinea capitis due to endothrix Trichophyta. A, severe inflammation producing boggy infiltrations caused by T. crateriforme. B, the subject shown in A, after cure by simple topical measures. There was eventually a complete regrowth of hair in the areas of alopecia. C, D and E, examples of "black dot" ringworm, caused by T. violaceum. In E the hair has been cut in a patch around the infected site. The black dot is caused by breaking off of the hair near the surface. Small pyogenic superinfections arc common. Tinea capitis due to T. violaceum is the most difficult type of all to cure. Fig. 9. Kerion, which may be due to any one of many species of Fungi. Four instances of kerion arc shown, each caused by a different fungus. A, M. fulvum. B, T. crateriforme. C, M. Ianosum. D, M. audouini. 56 Fig. 10. Favus of the scalp. A, early single patch with trusts but no alopecia. Regrowth oi hair occurred, and there was no resultant atrophy. />. untreated involvement of short dura- lion, showing thick crusts but no demonstrable atrophy. C, multiple foci ot infection with crusting. The areas of alopecia are the result of manual epilation. Complete regrowth of hair occurred without atrophic changes of the scalp. D, scutula with small atrophic areas; the process was of 15 years' duration. E, condition of long duration, showing an atrophic patch with active spreading infection. F, result of neglected infection, with atrophy ol the scalp and permanent alopecia. 57 58 An Introduction to Medical Mycology the hair follicles may be noticed yellow points which are soon observed to be crusts. These yellow crusts increase in size and finally become cup- shaped, when they are known as scutula. The convex side of the scutulum presses down on the skin; the concave side faces outward. They are sulfur colored, friable and pierced with hair. A distinctive mousy odor may be readily detected. The infected hair is brittle and lusterless, but not neces- sarily fractured, certainly not as extensively as with infections due to Microsporum. Owing to pressure of the scutula the hair in the affected sites loosens and falls out and may not return. The skin in the affected patches is atrophic. When untreated, the disease spreads slowly to cover a large part of the scalp. After several years there may be spontaneous cure, but permanent alopecia in patches is the final result. In another manifestation of favus on the scalp there may be a diffuse superficial but adherent scaling, with little, if any, alopecia or evidence of follicular involvement. The resemblance to seborrheic eczema may be striking. Since most of our patients have been adults, it is our impression that this form is more apt to appear after puberty, when there is more resistance to follicular infections of the scalp. It is well to keep in mind the possibility of favus when a scaly condition of the scalp refuses to re- spond to the remedies commonly employed in the treatment of seborrheic eczema. Whittle reviewed the clinical features of cases presented in Great Britain during the past few years. He concluded that atypical and minimal manifestations, with scutula rarely present, may lead to an error in diagnosis. (8) Trichophyton gypseum.— While rare in New York, instances of in- fection with this micro-organism are observed more commonly in other parts of the country, particularly in the Middle West. The chief charac- teristic is a violent inflammatory reaction, ordinarily with the development of kerion. There is usually a history of contact with an infected animal. Familial infections may occur, in which case each member may have a particular manifestation unlike the others. In a family which came under our observation a boy had a widespread infection simulating psoriasis and involving, among other areas, the hands, feet and face; another child had kerion and a third child tinea glabrosa of an eczematous type (Fig. 13). (c) Dermatophytid ( microsporid, trichophytid).— Jadassohn, in 1911, before the Swiss Medical Congress, first described an eruption in patients with kerion which consisted of small, follicular elevations, occurring either in groups or diffusely, in large or small numbers, and which disappeared spontaneously. There was a resemblance to lichen scrofulosorum, but the histologic picture was different, and a patient's skin did not react after the injection of tuberculin. There was a symmetrical distribution; the trunk was the usual site, and often the extremities were involved as well. In some Fig. 11. Favus in a boy aged 6. Other members of the family were also affected. A and B, typical neglected crusted lesions (scutula). C and D, following daily use of soap and water and application of salicylic and sulfur ointment for one week, the crusts have disappeared. E, epilated scalp, showing residual erythema at sites of former lesions. 59 Fig. 12. Favus. A, ill-defined scaly lesion above the eyebrow, tt, onychomycosis of one toenail. C, onychomycosis of a fingernail. 7) and E, scutula on the smooth skin. F and G, extensive involvement of the scalps of two patients; in both eases the disease had been unrec- ognized and untreated. When lesions are present on the smooth skin or the nails are affected, the scalp is usually concomitantly involved. 60 Fig. 13. Ringworm infection of three members of a family, showing variations in the site of involvement and in the degree of inflammation. The source of the infection was not deter- mined. All three patients responded readily to fungicidal therapy. The culture in each ease revealed T. gypseum (granular). A, pustular tinea capitis of one month's duration in a boy aged 5. B, tinea glabrosa (eczematous type) <>t two weeks' duration in a girl aged 4. ('. /). /■; ■ lll(1 I- involvemenl of the right hand and forearm, face, toes and right elbow, of one year's duration in a hoy aged 8; in all sites the lesions showed mild inflammation. 61 62 An Introduction to Medical Mycology instances horny spikes, or spines, capped the lesions, when the appearance was similar to that of lichen spinulosus. The work of Jadassohn, Bloch, Gnth and others of their school soon showed that these rashes ( and others resembling erythema toxicum, erythema multiforme or the like) were ex- pressions of cutaneous allergy due to a hematogenous spread from an in- flammatory focus on the scalp. We designate a rash of this character as dermatophytid. Fungi or their products caused sensitization of the skin, and this altered reaction resulted in lesions which in themselves were sterile. We have observed a number of instances of dermatophytid in children with tinea capitis in which the appearance of the rash coincided with or followed a depilating dose of roentgen rays. We studied a rash on a child who received trichophytin therapeutically. In all instances the patient exhibited a strong reaction to the intracutaneous test with tricho- phytin. The origin of the rash was always an inflammatory lesion or lesions, most frequently being frank kerion. Sometimes strong topical applica- tions causing marked inflammatory changes have resulted in dermatophytid. The subject is further discussed in the section on dermatophytosis, pp. 116 ff. (d) Reaction to trichophytin.— Patients with ringworm of the scalp vary in their reaction to trichophytin, mainly in accordance with the type of infecting micro-organism. There is usually more response when the fungus is also pathogenic to animals. The reaction may be valuable in helping the physician to determine the type of therapy. In infections due to M. audouini the response to the intracutaneous test with trichophytin is usually slight. With endothrix infections, such as those due to A. schoen- leini and T. violaceum, the reaction to the test is commonly negative or only slightly positive. When tinea of the scalp is caused by M. lanosum, M. fulvum, T. crateriforme or T. gypseum, a moderate or marked reaction to trichophytin is the rule. (e) Filtered ultraviolet rays.— The nature and use of these rays has been mentioned elsewhere. Since under the rays a suspected scalp will show a characteristic fluorescent effect whenever infected hair is present (except in the rare instances of ectothrix infection), it is apparent that the use of ultraviolet rays is important in revealing not only the presence but the extent of the infection. One is frequently surprised to find widespread involvement when clinical inspection has led one to believe that only one or two areas of infection were present. Furthermore, we have observed several patients in whom regrowth of hair in patches of partial alopecia due to a tinea infection was sufficiently vigorous to mask the disease. Numerous infected hairs were observed by the test of fluorescence. Hairs infected with one of the commonly found Microspora (M. lanosum, The Superficial Mycoses 63 M. audouini or M. fulvum) arc all revealed as bright green stubs under the- rays. In the very early stage of infection the color may be noted only in the portion ol the infected hair nearest the scalp. No fluorescence will be revealed in infections due to M. ferrugineum. Hairs infected with A. schoenleinii vary from lighter green to dull gray; when T. violaceum, T. crateriforme or T. sulfureum is the infecting micro-organism the hair is dull gra\ and yet to be differentiated from normal hair. Light brown or gray hair fluoresces somewhat. This might lead to confusion as also might the fluorescence due to petrolatum or to some drugs. We believe use of filtered ultraviolet rays to be of the utmost impor- tance in the diagnosis and management of tinea of the scalp. Their use to determine when cure has taken place is indispensable; if the patient is being treated by topical applications, progress may be noted under the rays. Cleveland raised the question whether a child might show fluorescence but be noninfectious when the disease was asymptomatic. He found that such is not the case, being able to reproduce the disease from such cases in animals. He points out the danger to others when children who are clinically cured and yet have infected hairs, as revealed by the fluorescence test, are not treated or whose treatment is lapsed. This method of exam- ination, however, should not entirely supersede the older procedures. It is important to observe fungous elements under the microscope, and it is desirable to culture the causative micro-organism. (f) Differential diagnosis.— It is taught at the Cornell University Medical School that patchy loss of hair from a child's scalp denotes ring- worm until repeated laboratory investigation has failed to substantiate the diagnosis. When there is little inflammatory reaction, alopecia areata may be simulated. In alopecia areata, however, there is a sudden complete loss of hair with no scaling on the surface of the patch. Trichotillomania and trichokyptomania have proved puzzling to us in a few instances, but in such cases the child is usually neurotic, the apparent or actual loss of hair is near the front of the scalp, and again there is no scaling. Seborrheic dermatitis may be differentiated by the presence of greasy scales and the absence of patchy loss of hair. The superficial form of favus may so closely resemble seborrheic dermatitis that only the lack of response to therapeutic agents may favor the diagnosis of favus. When marked inflammation is present, pyoderma is the chief condition to differentiate. Pyodermic lesions on the scalp of a child usually spell pediculosis, and an inspection of the scalp ordinarily reveals nits. Pustular lesions, however, ma}' appear secondarily to a focus of infection such as a dis- charging ear. We have observed an instance of pustular lesions of the scalp^., due to the ingestion of iodized salt. /yS*Z~- 64 An Introduction to Medical Mycology Tinea amiantacea (asbestos-like tinea) was first described by Alibert in 1832. The disease has lately been reviewed by Becker and Mnir. It should probably be classed as a pseudomycosis, since no constant fungous flora is demonstrated. It is important, since the clinical signs simulate those of tinea capitis. It is thought by some to be a form of seborrheic eczema and by others to be an aberrant form of psoriasis. The disease is manifested on the scalp by a binding together of the proximal portions of the hairs by asbestos-like laminated scales. It may be localized to one area or distrib- uted over the entire scalp. Scaling is present on the involved surfaces, but usually with little visible inflammation. The disease is said to occur most frequently in children. There is no tendency to loss of hair, nor is the struc- ture of the hair altered. The peculiar large yeastlike bodies which have been noted are probably artefacts caused by the action of potassium hydroxide on grease. The condition is usually helped by frequent washing of the scalp and by the application of a salve containing sulfur or tar. Recurrence is common. Trichorrhexis nodosa is a disease in which the hairs show one or more nodular enlargements. Microscopically, these nodules are due to partial transverse fracture. When the fracture is complete, the end is frayed. A certain amount of thinning of the hair may result. Monilethrix, a congenital disease, also produces a variable degree of alopecia. The affected hairs have a peculiar undulated appearance due to regular variations in their diameter. Where the diameter is reduced, a fracture is apt to occur. Keratosis pilaris is often associated, and general- ized scaling of the scalp is common. In all cases of suspected infection, one is not justified in being content with a clinical diagnosis. Examination of the scalp under filtered ultra- violet rays and microscopic examination of material such as hair and scales are mandatory- It is also highly desirable to inoculate a culture medium and determine the specific diagnosis. Such procedures are simple to perform and yield exact information. (g) Prognosis.— There is a marked difference in the prognosis with dif- ferent types of ringworm of the scalp. In general, infections caused by fungi which are also pathogenic to animals are quickly cured, and often cure is spontaneous. The causative fungi not pathogenic to animals cause infections which are resistant to treatment and which, if unchecked, re- main for an indefinite period. Microspora in general are responsible for benign infections; Trichophyta produce either infections rebellious to treatment (endothrix ) or severe inflammations (ectothrix). The infections dwe to Microspora tend to clear up spontaneously at or about the age of puberty. Rotlunan and his co-workers have demonstrated that this spon- Fig. 14. Diseases often confused with tinea capitis. A. seborrheic dermatitis. B, psoriasis. ('. trichotillomania. D, folliculitis decalvans E, alopecia areata. F, trichorrhexis nodosa. 65 66 An Introduction to Medical Mycology taneous cure of M. audouini infections (and also the immunity of adult scalps) is due to the secretion, at puberty and later, of sebum which con- tains, in higher concentration than before, low-boiling saturated fatty acids with selective fungistatic and fungicidal effect on this fungus. We believe that an entirely different mechanism of cure (hypersensitivity; inflamma- tion; epilation of hair) is responsible for the cure of M. lanosum infections and for those due to other fungi capable of sensitizing the skin. Favus and the manifestations of the endothrix organisms persist for an indefinite period unless treated. We have seen instances of infection with A. schoen- leini which lasted over 20 years. It seems that eventually even here the fire burns out, but cinders (in the form of atrophy) may be noted. The most resistant conditions which we have treated were caused by T. vio- laceum (an endothrix). In our experience, 90 per cent of patients with M. audouini infections may be cured in nine weeks if roentgen epilation is undertaken. (h) Treatment of nonresistant infections.— In several publications we have called attention to the tendency to spontaneous cure and to the success of local measures alone when tinea capitis is caused by M. lanosum. The series of patients reported cured by Poth and Kaliski following ther- apy with estrogens were not controlled by filtered ultraviolet ray studies, nor were cultures done. The estrogens were rubbed on the scalp in most cases, probably assisting cure by rubbing out the infected hairs. Unless there are special reasons, one may not wish to subject a child with this type of ringworm to epilation of the entire scalp by means of thallium ace- tate or roentgen rays or to the administration of estrogens. This also applies to infections due to an ectothrix Trichophyton, to markedly inflammatory conditions (at least until the process is less severe) and to states of vigorous reaction to trichophytin, irrespective of the cultural diagnosis. In all such cases the treatment should be conservative. We use one of several topical applications, such as an ointment containing 5 per cent ammoniated mer- cury or one containing 1 per cent thymol, 0.5 per cent oil of cinnamon and 0.5 per cent iodine crystals. Salves containing any antiseptic in a not too concentrated form would probably be of equal benefit. We have previously pointed out that cure of these infections invariably occurs because the infected hair comes out and not because of any direct fungicidal action of an applied medicament. Because of this the salve should be mildly stimulating, to assist in loosening the hair but not strong enough to cause 1 too much inflammation, and fungicidal, to prevent the spread of the infection. Besides the drugs just mentioned, sulfur in an oint- ment base (5 to 10 per cent) and iodine crystals (10 per cent) in wool fat will be found equally effective. We advise against the use of salicylic The Superficial Mycoses 67 acid, chrysarobin, croton oil, oil of turpentine and the like as unnecessarily hazardous. The loosened hair is best removed by frequent shampoos. The use of a mild soap applied with a brush has been found effective. If the shampoo is carried out too vigorously or too frequently, the infected hair may be kept rubbed off close to the scalp instead of being epilated. The result is that the infection does not respond as rapidly as expected. The remedy is to lengthen the interval between shampoos and to use less vigor in applying the hand brush. (i) Treatment of resistant infections.— When the infecting micro- organism is M. audouini, A. schoenleini or one of the endothrix Trichophyta (chiefly T. violaceum), unless there is a vigorous response to the test with trichophytin, some type of depilating treatment is usually required. Livin- good and Pillsbury have shown that even M. audouini infections will often become spontaneously cured if left long enough. In practice it is not con- sidered wise to defer active treatment. There are three methods which may be used: (1) manual epilation with salves and adhesive plaster, (2) roent- gen epilation and (3) epilation by the thallium salts. If the infection is due to M. audouini and the patient is near the age of puberty, expectant treatment rather than depilating measures may be undertaken. We have attempted to cure the resistant infections by means of vaccinotherapy (trichophytin), substitution of another fungus capable of producing an inflammatory response in the scalp, short wave ultraviolet radiation and other modalities and methods without any consistent effects. The poor results which we obtained from the therapeutic use of trichophytin were similar to those reported by other observers who studied their cases from the etiologic point of view. Cures attributed to trichophytin for the most part concern infections due to M. lanosum, M. fulvum or T. gypseum, and since these have a tendency to spontaneous cure, the role of trichophytin is debatable. We have not been able to substantiate the claims made by a commercial concern for an imported trichophytin which has been exten- sively advertised as a certain cure for ringworm of the scalp. The cases of patients reported cured with estrogens by Poth and Kaliski were prob- ably due to M. lanosum. In a study by Lewis, Hopper and Reiss of the effect on fungi of estrogenic and androgenic substances, an in vitro effect was apparent, but clinical results were poor when such agents were applied locally to areas of infection. (I) Manual epilation and local applications— When there is only a small patch (as revealed by examination under filtered ultraviolet rays), epila- tion of the infected hairs with forceps may be attempted. The process is repeated at intervals of three or four days. During the interval between treatments, adhesive plaster, larger in diameter than the infected patch. 68 An Introduction to Medical Mycology should be kept constantly over the treated area. We have found that this not only prevents spread of the infection but tends to set up follicular irri- tation valuable in furthering cure. If the reaction to the adhesive plaster is too severe, it may be applied only part of the time. When the adhesive is left off the scalp, some fungicidal ointment should be used and a linen cap applied. The rest of the scalp should be treated with ointment containing 10 per cent ammoniated mercury applied morning and night. Shampoos are allowed, but the ointment is reapplied immediately after them. If the area of infection is large or if there are many different patches, manual epilation is not practicable. Schwartz reported successful treatment of tinea capitis due to M. audouini using the following formulas: 1. Salicylanilide 5 Hyamine 1622 (25 per cent) 5 Carbowax 1500 100 2. S. S. copper undecylenate in carbowax 1500 3. Pentaehlorphenol 1 Carbowax 1500 100 One of these remedies is applied daily for at least 40 days before improve- ment should be expected. Cure may not be obtained before 100 or more applications. A better effect was obtained in some instances by alternating the prescriptions. (2) Roentgen epilation.— The use of roentgen rays by those competently trained has proved of infinite worth in the treatment of the resistant forms of tinea capitis. The incidence of infection in France, England and other countries has been materially reduced, and this treatment has been of marked economic importance in controlling the disease. A word of caution, however, is in order. The epilation of hair by means of roentgen rays is a most delicate operation, requiring considerable patience, special training and skill. The ma- chine must be accurately standardized, and the technic of the operation should be learned thoroughly under the personal supervision of an authority. The reader is referred to Chapter XXVII in MacKee and Cipollaro's X-Rai/s and Radium in the Treatment of Diseases of the Skin for further details of technic. It may be emphasized that after the epilating dose of roentgen rays, the patient should be given an ointment containing 3 per cent am- moniated mercury. When the hair begins to loosen (after 18 to 21 days), daily shampoos are in order, and the hairs which cannot be epilated readily (as noted under the filtered ultraviolet rays) should be removed manually. The removal of adhesive tape applied to the scalp assists depilation at 1 1 lis time. The patient should not be discharged before two examinations under the filtered ultraviolet rays, made one week apart, have indicated normal conditions. A final inspection one month later is advisable. In pa- Fig. 15. Activation of tinea capitis which may follow x-ray therapy or develop spon- taneously. A, tinea capitis due to M. audouini before x-ray therapy, showing gray-patch, rela- tively noninflamrnatory lesions. B shows severe inflammatory, pustular eruption which appeared over the scalp three weeks after epilating dose of x-rays. Erythematous papular lesions were noted on the trunk and extremities. Such a complication occurs in less than 1 per cent ol patients treated with x-rays. C and D, tinea capitis clue to M. lanosuin. In C, the flare-up ol lesions with development of ids on arms and trunk was spontaneous; in D, the occurrence followed an epilating dose of x-rays. 69 Fig. 16. Tinea capitis in an adult, showing results of x-ray therapy. A, 10 weeks after administration of epilating dose. B, six weeks later, showing uniform return of hair. Length from scalp is approximately 1.6 cm. 70 The Superficial Mycoses 71 tients with a limited infection of short duration we have used roentgen ray epilation to only the affected site (one or two exposures). Care should be exercised that small foci of infection arc not overlooked; we USliall) examine our patients several times, using filtered' ultraviolet rays. The dose of roent- gen rays administered should be one-tenth higher than that used with the TABLE 15.— Return of Scalp Hair Follow inc. Administration of Epilating Dose of Roi \ m.i \ R \is (figures based on average Endings) Elapsed Time, Length of Hair, Mo. Cm. 2 soft down 3 1.0 4 1.3 5 1.9 6 2.7 7 3.8 8 . 4.4 9 6.7 10 7.0 11 8.6 five point technic. Following the treatment, a salve containing 3 per cent ammoniated mercury is used and should be reapplied twice daily to the entire scalp. The scalp should not be washed. After 21 days the grease may be removed by soap and water and by benzene and all loose hairs extracted by adhesive plaster. Negative findings from two Wood's light examinations one week apart should be recorded before the patient is discharged. It should be emphasized that this method is suitable only for special cases of limited infection, particularly in girls for whom total epila- tion of the scalp is a minor tragedy. Despite all precautions, the result may be a failure, in which case three months should elapse before further ex- posures are given. (3) Epilation by thallium salts.— It a mistake is made in the dose of roentgen rays, permanent alopecia may result. A mistake in the dose of thallium acetate, however, may result in the death of the patient. Several instances of fatal mistakes are to be found in the literature. There is also the possibility of a number of other bad effects. The method consists in the oral administration of thallium acetate in a single dose of 8 mg. of the salt, dissolved in a glass of water, per kilogram of body weight. The exact weights of both the child and the drug should always be rechecked. There is definite contraindication to the treatment in the face of illness, particu- larly a renal ailment, in patients showing a disproportionate age-weight ratio and in adults. The after-treatment is that described for the use ot Fig. 17. Tinea capitis (M. audouini) of limited extent and recent origin treated success- fully with x-rays to the localized infection. Careful attention to detail is necessary (see text). A and B, before and after preparation lor treatment. C, two obscure lesions in occipital region outlined to reveal extent of fluorescent hairs. D, small localized lesi ver left temple follow- ing epilation. 72 The Superficial Mycoses 73 roentgen rays. Thallium epilation has been particularly recommended For the feebleminded and lor those to whom the services ol a trained roentgen technician arc 1 not available. It should again he mentioned, however, that the method is potentially dangerous, -and one niav question whether it should ever he used in the treatment ol tinea capitis. (j) Treatment ok associated cutaneous lesions.— The patient should always be inspected lor concomitant lesions. If any evidence ol them is found, the use of an ointment containing 5 per cent ammoniated merenrv or 0.25 per cent anthralin (dihidroxy-anthranol) will usually be sufficient. (k) Home care.— The 1 following outline in mimeographed form is given to the parents of patients with scalp ringworm coming to the New York Hospital. (1) The disease is contagious to other children. Because of this, bring to the clinic all Other children in the family. They should he examined every three weeks even if will, until there is no more ringworm in the household. The patient should not go to the movies or barber shop and must not he sent to camp or plav indoors with other chil- dren. He may plav outdoors (with the scalp covered) provided an adult is present and no wrestling or games with personal contact are played. Please live up to these rules and help to stamp out this disease. As a precaution, any children in the family who are well should be cautioned against using the patient's comb, brush, hat or cap and should not sleep in the same bed with the patient. You should also rub through their scalps every night the salve which you will be given. (2) The infection is deep in the hair and cannot be cured until the infected hair comes out. Sometimes x-ray treatment is necessarv and sometimes not. The doctor will decide what treatment is best. (3) You can help a lot in curing the patient by bringing the patient to the clinic at the appointed time and by following these directions. (4) Rub in the salve, thoroughly, to all the areas outlined by the pencil. The re- mainder of the scalp should also be treated. Do this twice daily, morning and night. (5) Do not wash the scalp with soap and water. This tends to spread the infection. The excessive accumulation of salve may be removed with mineral oil and absorbent cotton twice weekly. (6) Make several linen skullcaps so the head can always he covered— even at night. Boil the caps for 10 minutes and change at least once daily. (7) One type of ringworm is spread by infected pets, such as kittens and pups. If any animal pets are in contact with the patient, do not give the animal away or allow the animal his freedom so that other children may be exposed. The fluores- cence test will decide if any infection is present. Careful attention to directions will bring earlier cure and prevent infection of other children. (1) Prophylaxis.— The main consideration is to stamp out the resistant forms of the disease. Since these are usually spread by contact of one child with another, detection of all infected scalps is most desirable. The follow- ing precautions are important. 1. The medical examination before admittance to school should always 74 An Introduction to Medical Mycology include a careful examination of the scalp. The use of filtered ultraviolet rays simplifies the examination and increases its accuracy and its rapidity. 2. Patients with ringworm should be excluded from school provided there is intelligent supervision of the child's activities at home. The danger to other children in the home or elsewhere is minimized if the patient constantly wears a linen cap. 3. Barbers should be told that infected combs and brushes will spread the infection. If the comb and brush were washed with soap and water after each use, this would probably be sufficient to prevent infection. The physician should not send a patient with tinea capitis to the barber shop. He might better remove the hair himself with hair clippers which he can sterilize. Barbers should be instructed not to cut the hair of a child with evidence of tinea capitis. 4. As this edition is being written, an epidemic of scalp ringworm due to M. audouini has been present for over four years in New York City. There is some evidence that the infection was spread in part from contact with the backs of theater seats, through the medium of barber shops and because of the overcrowding incidental to war and postwar conditions with rapid change of residence and lack of housing facilities. Some form of quarantine of infected children, so that other children are not exposed, may be requisite when such an epidemic occurs. 5. Parents should be instructed always to wash the child's scalp imme- diately after each haircut. The use of 5 per cent ammoniated mercury ointment before the shampoo would be additional protection. 6. Before admittance to a home or orphanage a child should be free from ringworm of the scalp, as shown under filtered ultraviolet rays. 7. Pets, particularly kittens, should be inspected under filtered ultra- violet rays, since they may be carriers of ringworm. The danger is probably greatest with stray animals. 8. Children must avoid persons known to be infected. This admonition would seem trite were it not for the many instances in which little concern was shown until the infection had been transferred from one person to another. BIBLIOGRAPHY Arzt, L., and Fuhs, H.: Ueber durch Trichophyton violaceum hervorgerufene Pilzerkrankun- gen (Ein Beitrag zur Pilzflora in Wien), Dermat. Wchnschr. 76:409, 1923; Zur Entstehung der Allgemeinexantheme bei Mikrosporie, Arch. f. Dermat. u. Syph. 143:52, 1923; Ueber Allgemeinerkrankungen bei Andouinischer Mikrosporie, Acta dermat.-venereol. 4:59, 1923. Becker, S. W., and Mum, K. B.: Tinea amiantacea, Arch. Dermat. & Syph. 20:45, 1929. Blumenfeld, A.: Kerion microsporicum with hematogenous and ectogenous microsporids, Arch. Dermat. & Syph. 24:607, 1931. Cleveland, D. E. H.: Infectix itv of fluorescent hairs in scalp ringworm, Canad. M. A. J. 49:280, 1943. CUMMER, C. L.: Tinea capitis with kerion in an adult caused by Trichophyton gypseum- lacticolor, Arch. Dermat. & Syph. 36:844, 1937. The Superficial Mycoses 15 Dowdinc, E. S., \\D Orr, II.: Three clinical types "I ringworm due to Trichophyton gypseuru Brit. J. Dermat. 19:298, L937. l'i i hk\, B.: Epilation with thallium acetate in treatment ol ringworm ol scalp in children, \uh. Dermat. & Syph. L7:182, L928. Iiwinn, C. W.: Stml> ol generalized eruption caused bj Microsporon audouini, lichen microsporicus, Brit. J. Dermat. 37:63, 1925. Fox, II.; Ringworm ol scalp in adult: Report of case ol kerion due to Microsporon audouini, Vrch. Dermat. & Syph. 13:398, 1926. , and Fowlkes, R. W.: Ringworm of scalp in adults. Arch. Dermat. Crawford, G. M.: Measurement of roentgen therapj for tinea capitis: Correlation of epilation dose with the roentgen, Arch. Dermat. & Syph. 37:62, 1938. Lewis, G. M.: Ringworm of scalp: II. Curability, without depilating measures of infections caused bj "animal" microsporons, Am. J. M. Sc. 189:364, 1935. , and Hopper, M. E.: Ringworm of scalp: III. Clinical and experimental studies in types ot infection resistant to treatment. Arch. Dermat. & Syph. 35:460, 1937; IV. (a) Compara- tive reactions to cutaneous tests with triehophytin in children with and without ringworm of scalp; (b) Evaluation of therapy with stock vaccines in types of infection resistant to treatment, ibid. 36:821, 1937; V. Mechanism of cure of infections caused by Microsporon lanosum, ibid. 36:1194, 1937; Successful use of roentgen rays to epilate local areas of infec- tion, ibid. 49:107, 1944. ■; Hopper, M. E., and Reiss, F.: Ringworm of scalp: Clinical data on recent cases: Experiences with local endocrine therapy, J. A. M. A. 132:62, 1946. -, and Miller, H. C: Ringworm of scalp: I. Report of three cases due to Microsporon lanosum with tendency to spontaneous recovery, Arch. Dermat. & Syph. 29:890, 1934. -; Silvers, S. H.; Cipollaro, A. C; Muskatrlit, E., and Mitchell, H. H.: Measures to prevent and control epidemic of ringworm of scalp, New York State J. Med. 44:1327, 1944. Livingood, C. S., and Pillsrury, D. M.: Bingworm of scalp: Prolonged observation, family investigation, cultural and immunologic studies in 130 cases, I. Invest. Dermat. 4:43, 1941. Low, R. C. : Some cases of trichophytides and microsporides and their connection with lichen spinulosus, Brit. J. Dermat. 36:432, 1924. Montgomery, R. M., and Walzer, E. A.: Tinea capitis with infection of eyelashes: Report of case, Arch. Dermat. & Syph. 46:40, 1942. Pernet, G. : Ringworm of scalp: Report of case in adult, Arch. Dermat. & Syph. 12:267, 1925. Poth, D. O., and Kaliski, S. R.: Estrogen therapy of tinea capitis: Preliminary report, Arch. Dermat. & Syph. 45:121, 1942. RasCh, C: Secondary lichenoid trichophytids in association with kerion celsi (lichen spinulo- sus trichophyticus), Brit. J. Dermat. 28:9, 1916. Rothman, S.; Smiljanic, A.; Shapiro, A. L., and Weitkamp, A. W.: Spontaneous cure of tinea capitis in puberty, J. Invest. Dermat. 8:81, 1947. Sabouraud, R., and Noire, H.: Traitement des teignes tondantes par les rayons X a L'Ecole Lailler (Hopital St. Louis), Presse med. 2:825, 1904. Schwartz, L.: Public health aspects of treatment of tinea capitis, New York State J. Med. 47:1782, 1947. ; Peck, S. M.; Botvinick, I.; Leirovitz, A. L., and Frasier, E. S.: Control of ring- worm of scalp among school children in Hagerstown, Md., 1944-1945, J. A. M. A. 132:58, 1946. Thomson, M. S.: Cat ringworm, Brit. J. Dermat. 37:269, 1925. Whittle, C. H.: Atypical favus: With notes on three cases and review ol cases published in last 15 years, Brit.' J. Dermat. 59:199, 1947. 2. TINEA BARBAE Ringworm of the beard is rarely seen in the United States and is uncom- mon in New York. The infection is follicular; infection of the skin alone in the bearded region is not considered here. 76 An Introduction to Medical Mycology (a) Etiology.— In the majority of cases the condition is due to T. gyp- seum. In a scattering of cases it is caused by M. lanosum, Trichophyton rosaceum, T. violaceum and T. purpureum. It is chiefly men who are vul- nerable, and in many instances the barber shop has apparently been respon- sible for passing along the infection. Animals also play a part as carriers of T. gypseum or M. lanosum. In some instances the infection is caught from another person, not uncommonly a child with infection of the scalp or of the glabrous skin. ( b ) Symptomatology.— There are two types of infection, with dissimilar clinical pictures. (1) Kerion type— -There is usually a history of contact with a diseased animal. When the infecting organism is T. gypseum or M. lanosum, the response is usually the development of one or more boggy infiltrations, par- ticularly around the angle of the jaw. Any part of the beard may become infected, but the upper lip is an unusual site. The resemblance to kerion, as noted with ringworm of the scalp, is frequently striking. Hairs in the affected tissue loosen and either come out spontaneously or are readily extracted. (2) Sycosis type.— When T. violaceum or T. purpureum causes tinea barbae, the infection gradually spreads, resulting in a mild pustular (crusted) folliculitis with breaking off of the invaded hair (T. violaceum) or similarly without the formation of hair stumps (T. purpureum). (c) Reaction to trichophytin.— Here, as with the other types of super- ficial fungous infection, the result of the intracutaneous test with trichophy- tin is dependent on the type of infecting micro-organism. If T. gypseum or M. lanosum is the causal fungus, there is usually a vigorous reaction; if T. purpureum or T. violaceum is responsible for the infection, negative or slightly positive reactions may be expected. (d) Filtered ultraviolet rays.— If M. lanosum or T. violaceum is pres- ent, fluorescence of the infected hair under these rays may be noticed. Since both T. gypseum and T. purpureum are eetothrix organisms, no fluor- escence will be observed when they are present. ( e ) Differential diagnosis.— The kerion type of tinea barbae has to be differentiated from sycosis barbae, iododerma or bromoderma and syphilis. In sycosis barbae the lesions are rarely kerionic, the upper lip is fre- quently affected, and the hairs in the affected follicles are epilated with difficulty. Pustular reactions to one of the halogens is determined by the history, the tendency to bilateral involvement, the presence of the disorder elsewhere on the body and detection of the substance in the urine. Pustular syphilis is rare, doubly so if confined to the beard alone. In all cases of tinea barbae the demonstration of the causal micro- 3 • ■ ffigflj s Fig. ] T. purpureum. /), M. laiiosnm infection in a delicatessen worker. 77 78 An Introduction to Medical Mycology organism is necessary to establish the exact diagnosis without equivocation. (£) Prognosis.— If the condition is of the kerionic type, there is good prospect of an early cure. If it is caused by T. purpureum or T. violaceum, other sites, such as the nails, are usually involved. The prognosis is to be reserved, depending on the co-operation of the patient and the type of therapy. (g) Treatment.— When marked inflammation is present, the appli- cation of mild wet dressings, with use of such remedies as a 1:15 dilution of aluminum acetate (Burow's solution), hypertonic saline solution or solution of boric acid for as long periods as possible will assist drainage and prove soothing. The use of fractional roentgen therapy may be of value. Epilation by means of roentgen rays is seldom necessary or advis- able. One should not use strong topical applications, particularly in the form of ointment. A number of other remedies, such as trichophytin and foreign protein shock, have been advocated but should be used with cau- tion, since there is usually enough inflammation to cause the hair to loosen and cure to take place. With infections of the beard caused by T. purpureum or T. violaceum, manual epilation repeated once weekly and the use of a fungicidal oint- ment, such as one containing 10 per cent ammoniated mercury or 0.25 per cent anthralin, may prove curative. Wise advocates manual epilation followed by hot dressings of Vleminckx's solution diluted 1:10. Unless attention is also paid to any other cutaneous manifestation, the condition will surely recur. If other foci of infection are present, it is questionable whether epilation of the beard by means of roentgen therapy should be undertaken. With this type of infection the use of trichophytin and foreign protein shock may be tried but will probably be ineffective. BIBLIOGRAPHY Davidson, A. M., and Dowding, E. S.: Tinea barbae of upper lip, Arch. Dermat. & Syph. 26:660, 1932. Lawless, T. K.: Tinea sycosis of upper lip, Arch. Dermat. & Syph. 34:118, 1986. Williams, C. M.: Tinea barbae involving upper lip and accompanied by dermatophytid. Arch. Dermat. & Syph. 23:213, 1931. 3. TINEA GLABROSA (CORPORIS) (Ringworm of the Smooth Skin) Superficial fungous infection of the smooth skin may occur as a scaly lesion, as a circinate patch, as a solid plaque or in a gyrate configuration. The manifestation may also simulate eczema, or deep granulomatous le- sions may develop; We do not here include the intertriginous forms of Fig. 19. Tinea barbae and sycosis barbae. A and B, tinea barbae due to T. gypseum. C, tinea barbae due to T. purpureum. D and E, chronic localized pyoderma. F, sycosis barbae 79 80 An Introduction to Medical Mycology infection ( dermatophytosis, tinea cruris) or secondary allergic eruptions ( dermatophy tid ) . In many instances concomitant lesions will be found in the scalp, the nails, the bearded area, the inguinal region or the feet. A patient with an infection of the glabrous skin should be carefully exam- ined for other foci. (a) Etiology.— One of a number of different organisms may be found. The commonest is M. lanosum. The infection may be caught from a kitten or other pet, a playmate or another member of the household. Finding the source of infection here is usually comparatively simple. In other instances infection may be due to A. sehoenleini, the condition almost always being secondary to an infection of the scalp; to T. gypseum, in which case the infection may have been caught from an animal, from a focus on the pa- tient's feet or from another person, or to T. purpureum, the lesion in this instance almost always being part of a syndrome involving the nails and feet. During two years (1943 to 1945) we observed 18 cases of tinea of the nonhairy skin due to M. audouini, indicating that tinea glabrosa due to this fungus is more common than was formerly thought. There are a few T other organisms which may at times produce eruptions on the smooth skin, but they are relatively unimportant. While these manifestations may appear at any age, children are particularly prone to exhibit circinate lesions due to M. lanosum. Adults, on the other hand, show a preponderance of infections due to the other organisms. Women occasionally become in- fected from their children or from new pets (kittens). One of the most obstinate cases of tinea glabrosa in our experience was that of a woman on whom developed over 100 circinate lesions and in whom the thera- peutic response to various types of treatment was poor. (b) Clinical types.— (i ) Tinea circinata (M. lanosum and M. audouini). —The classic form of ringworm is evidenced by an erythematous ringed lesion gradually increasing to a diameter not over 6 in. (15 cm.). There are usually minute vesicles along the border; the surface is scab - , and the center appears unaffected. Sometimes two or more concentric rings may appear in a single lesion. If the condition is untreated, new lesions develop on skin adjacent to or remote from the original focus. The lesions are com- monly seen on the faces or necks of children with tinea capitis; while the infection is commonly due to M. lanosum, we have recently seen more cases than usual of tinea circinata due to M. audouini. The backs of the hands and other exposed parts arc the usual sites of the first lesions in pa- tients who catch the infection from an outside source. Ringed lesions are sometimes caused by T. purpureum. The subjective symptoms are usual!) mild, although the infection is itchy and subsequent scratching may con- tribute to its spread. Fig. 20. Tinea glabrosa (circulate type) due to M. lanosum. A, B and C reveal dissemi- nated lesions with a tendency to coalescence and double rings (an interesting immunologic phenomenon). D, common location for this type of ringworm. E, a dog belonging to the patient shown in D; these lesions yielded M. lanosum on culture. F. lesions of impetigo contagiosa. The ringed lesion on the forehead is suggestive ol tinea, but there wire typical trusted lesions elsewhere. 81 Fig. 21. Tinea glabrosa due to M. audouini. The lesions may be ringed or of the solid plaque type. Examination of lesions with filtered ultraviolet rays may reveal presence ol infected lanugo hair; such hairs are difficult to epilate and contribute to ehronicity. 82 Fie. 22. Tinea glabrosa and pityriasis rosea. .V. typical circinate patches on the neck and chest with secondary satellite lesions ( M. lanosum ). B, ringed lesions with clearing centers. C, disseminated erythematous scaly lesions with accentuated border and clearing center. D, pityriasis rosea; the symmetry ol the rash, the appearance ol lesions in showers, the tendency ot the lesions to Follow the lines ol cleavage and the negative results of examination For fungi usually serve to differentiate this disease from tinea circinata. 83 84 An Introduction to Medical Mycology (2) Eczematous type.— There are two forms, primary and secondary. In the first, the initial response to infection ( usually T. gypsemn ) is a vesicle, and vesicles continue to form, rupture and become crusted. The infection spreads peripherally; the lesion may remain ill-defined or become circulate, with active vesiculation along the periphery. There is no tendency to cen- tral clearing. Lesions are commonly solitary and rarely numerous. In- cluded here is favus herpeticus, a rare manifestation of favus. The markedly inflammatory and rapidly spreading eruption due to Trichophyton alba may also be mentioned as an uncommon form. The secondary form of eczematous patch is caused by sensitization to applied medicaments or by treatment producing primary irritation, which transforms a circulate lesion into a vesicular, oozing patch. (.3) Scaly type.— A small area of ill-defined branny scaling with slight redness at the base may be the only manifestation of A. schoenleini or of one of the endothrix Trichophyta, such as T. violaceum. Trichophyton purpureum also causes such a lesion, but usually more typical areas are present in addition. Microscopic and cultural studies are necessary for differential diagnosis. (4) Crusted type.— Favus of the glabrous skin may manifest itself by the formation of scutula similar to the cup-shaped crusted lesions com- monly noted with the scaly type. Crusts may be formed by the drying of an exuding surface, particularly if the lesions are eczematous, but there is much more inflammatory reaction than is associated with favus. (5) Solid plaque type.— Trichophyton purpureum is the cause of lesions which are not unlike certain lesions of psoriasis, being dull red and scaly on the surface, with slight thickening. Bleeding points are usually not present when the scales are removed. The intensity of the color may vary in different portions of a single patch. The shape of the lesions is not neces- sarily regular. The size of the patches varies from that of a pinhead to that of a half-dollar or larger. There is no tendency to central clearing. Lesions have been noted on various portions of the trunk, on the extremities and, in a single instance, on the face. (6) Bizarre and configurate type— -In this type, T. purpureum is the cause of an eruption which may involve large surfaces of skin of the trunk. The infection begins at one or more points and migrates in a thin line over an ever-widening area. The affected skin is dull red and shows slight infiltra- tion and scaling on the surface. Behind the advancing border the skin is lighter than normal. This suggests partial achromia. Persistent itching is a constant feature, and excoriations are usually seen. (7) Tinea imbricata-like type— Kittrcdge described a widespread scab Fig. 23. Tinea glabrosa due to M. fulvum. There is usually a solitary lesion, predomi- nantly observed in children. 85 Fie;. 24. Tinea glabrosa. A, disseminated erythematous scaly lesions on the arms and legs (M. lanosnm). B, acute inflammatory ( eczematous ) lesions due to T. gypseum. C and D 7 gyrate and ringed lesions ( T. violaceum). There were also lesions on the scalp. E, deep-seated infection on a wrist, the only lesion ( T. violaceum). F, solitary ringed lesion on a wrist ( T. sul- fnremn ). 86 4 Fig. 25. Tinea glabro.su due to Trichophyton alba (faviforme) in sisters, aged 13 and 17. Rapidly spreading, boggy, inflammatory lesions are present. Since interchange of clothes was common, the development of lesions on identical locations (left shoulder) in both girls was considered to result from wearing an infected dress. 87 Fig. 26. Tinea glabrosa caused by T. purpureum. A, well defined, solid plaque type with little tendency to clearing. B, subacute, dull red plaque with vesicopustules at the periphery. C, annular and gyrate Lesions. D, small, dull red, scaly, ill-defined patches. E, crusted, dull red lesions on the leg with involvement of the hair follicles. 88 The Superficial Mycoses 89 eruption due to T. purpureum. The similarity to tinea imbricata was strik- ine. We have observed several similar cases. (8) Granulomatous type (Majocchi), or tinea profunda— This is a rare but classic form of involvement in whio v the smooth skin may be invoked separately or concurrently with the scalp or with the bearded area. There may be nodules and plaques, characterized by their indolent nature. Pus may collect and finally be discharged. Ulcers may develop, and small discrete nodules may appear in adjacent areas of skin also. (c) Immune reactions.— The trichophytin reaction is usually negative in cases of uncomplicated tinea of the glabrous skin. This applies even to tinea circinata due to M. lanosum. For this reason the test is not of much practical value. Although we have no experience with reading the test when the condition is granulomatous, it is more than likely from analogy that there is an initiation of sensitivity in such a case. (d) Differential diagnosis.— Tinea circinata is simulated by pityriasis rosea when the herald patch is on the face or on an exposed portion of the bodv. The absence of a vesicular border, of clearing in the center or of the subsequent sudden development of secondary lesions is evidence against a diagnosis of tinea circinata. The eczematous type is confused chiefly with contact eczema and some- times with infectious eczematoid dermatitis or parasitic eczema. Contact eczema is usually differentiated by the history of exposure to a substance capable of causing the eruption, by the lack of circinate outline and at times by the patch test. In infectious eczematoid dermatitis there is a focus of infection, such as a boil or a discharging ear. The lack of definition of the lesions is a major point against tinea. Parasitic eczema consists of circum- scribed vesicular erythematous patches, spreading apparently by auto- inoculation. We recognize it as an entity but have never demonstrated fungi in material taken from the lesions. For this reason we doubt that the infection is fungous. The lesions, if examined closely, are seen to be studded with vesicopustules, and there is not the tendency to be present more abundantly along the border of the lesions. The scaly type may be confused with seborrheic dermatitis, contact eczema or excessive dryness of the skin. The manifestation is so mild that a definite clinical diagnosis is usually impossible. In order to prove the diagnosis of any of the types mentioned, one must demonstrate the causative micro-organism by microscopic and preferably by cultural studies. The clinical course may often be helpful, and the re- sponse to medication may be the only definite indication of the correctness of the clinical diagnosis when the mycologic examinations yield negative results. 90 An Introduction to Medical Mycology Little difficulty will be experienced in the diagnosis of favus when typi- cal scutula are present. The solid plaque type must be differentiated from psoriasis and from neurodermatitis circumscripta. The irregular distribu- tion and the lack of bleeding points, together with other evidence of the infection on the feet and lack of involvement of the scalp, will serve to rule out psoriasis. Neurodermatitis circumscripta is more pruritic; there may not be a history of another allergic disease, and there is usually evi- dence of other forms of infection on the feet. The bizarre and configurate type may be simulated by erythema annulare centrifugum (Darier), but the scales on the surface of the lesions, the intense itching, the absence of edematous plaques and the lack of tempo- rary remissions are against the latter diagnosis. Majocchi's granuloma may be mistaken for pyoderma, bromoderma or iododerma, one of the deep mycoses, such as sporotrichosis, or tubercu- losis. The mycologic study may be the onlv definite method of determining the true nature of the condition. (e) Prognosis.— This varies with the infecting micro-organism. Ordinary tinea circinata usually responds to treatment within a week or two. The presence of infected lanugo hairs will retard recovery. The eczematous type requires a longer time for cure, but the final result is usually satisfac- tory. In the manifestations of A. schoenleini the prognosis is good provided treatment is continued for a long period. The infections due to T. pur- pureum are similarly resistant and should always invite inspection of other likely sites of the infection. (f) Treatment.— Applications twice daily of an ointment containing 3 per cent salicylic acid and 5 per cent ammoniated mercury usually cause a lesion of tinea circinata to disappear within a week or two. Tincture of iodine (1 per cent) may be painted on the affected skin once daily, but not when ammoniated mercury is being used. Anthralin ointment (0.25 per cent) is useful but is irritating to a sensitive skin. For the eczematoid form, soothing treatment such as application of calamine lotion or, if exudation is pronounced, of dressings wet with a solution of boric acid or with dilute Burow's solution is the correct initial procedure. Roentgen therapy is useful in cases witli exudative processes. Infected lanugo hairs should be manually epilated. It is known that the) often break off and for this reason repetition of hand epilating may be necessary. In the manifestations due to A. schoenleini or T. purpureum, fungicides similar to those mentioned for ordinary tinea circinata may be used, but concentrations should be stronger. Compound ointment of benzoic acid is another useful preparation. The main point is to continue treatment, even Fig. 27. Tinea glabrosa. A, granuloma majocchi— an example of a vigorous response to the infecting micro-organism ( T. gypseum). B, disseminated erythematous crusted lesions due to A. schoenleini. 91 Fig. 28. Nonmycotic disorders often contused with fungous eruptions. A, disseminated neurodermatitis in a child with an allergic family history. When only the hands are affected, diagnosis is often difficult. B, lichen spinulosis, which is sometimes secondary to a fungous infection. C, erythema annulare centrifugum simulating the gyrate lesions caused by T. pur- pureum. D, psoriasis simulating tinea circinata. E, inframammary lesions of psoriasis resembling moniliasis. F, intergluteal patch of psoriasis. 92 The Superficial Mycoses 93 after all vestige ol the disease has gone, until cultures inoculated with ma- terial from the sites ol the former lesions are sterile. It should also be a rule to examine the patient carefully for other evidences ol the disease, since the body lesions are rarely the primary manifestations. In favus, the scalp is usually the initial site of infection; with T. purpureum the feet, groin or nails are usually concomitantly infected. In ease of a deep infec- tion (Majoeehis granuloma) filtered roentgen therapy should be adminis- tered, wet dressings applied and the iodides prescribed lor internal use. Salves seldom help. We do not now use or recommend the use of ultraviolet rays or injections of trichophytin in the treatment of tinea glabrosa. In rare instances there is a complete absence of resistance to infection on the part of the patient. This may rarely occur in cases of infection with fungi that ordinarily cause acute inflammatory responses in the patient's skin. Hazel and Lamb recorded the case of a girl, 23, who had gastrointes- tinal moniliasis and coincidentally a cutaneous rash due to M. lanosum. The latter eruption was widespread on the face and body; the fingernails and toenails were involved. The M. albicans infection was of 14 years' duration; the manifestations of M. lanosum had been present for seven years. Every possible form of therapy was administered without any con- sistent effect. We have observed several instances of resistance to treatment when cultural studies revealed a fungus which ordinarily responds satis- factorily within a short while. Fortunately, instances of stationary infections, such as that of the patient of Hazel and Lamb, are rare. BIBLIOGRAPHY Hazel, O. G., and Lamb, J. H.: Generalized skin eruption with gastrointestinal involvement due to two different species of fungi, J. Oklahoma M. A. 27:395, 1934. Molttch, M.: Dihvdroxv-anthranol in treatment of ringworm of face, neck and arms (tinea circinata), J. A. M. A. 106:1563, 1936. Paul, N.: Favus of glabrous skin, Brit. J. Dermat. 48:247, 1936. 4. TINEA CRURIS This is a superficial fungous infection usually confined to the inner sur- face of the upper parts of the thighs. There may be contiguous spreading, or other parts of the skin may become affected. In India the ailment is known as dhobie itch. It is sometimes still referred to as eczema mar- ginatum, under which term it was first described by Hebra in I860. (a) Etiology.— The classic form of the disease- is caused by E. inguinale (floccosum). It may be spread by infected articles of clothing or by an athletic suspensory, but at times the exact method of dissemination is un- 94 An Introduction to Medical Mycology known. There have been epidemics, such as that reported by Mercer and Farber. The localization is in part explained by the affinity of the fungus for intertriginous areas. The crural region may also be the site of mycotic in- fections due to T. gypseum and T. purpureum. (b) Immunologic reactions.— Epidermophyton inguinale usually does not initiate sensitization to trichophytin. A test with trichophytin usually elicits a negative or a mildly positive reaction. With T. gypseum, a positive reaction is usual, but when T. purpureum is the causative fungus, a nega- tive reaction is common. (c) Clinical data.— The rash is well marginated, the surface is scaly, and the border shows minute vesicopustules. There is little or no tendency to central clearing. The color of the lesions is brownish, with some redness due to inflammation. The eruption is usually bilateral and symmetrical; it favors the upper inner portions of the thighs but may extend up to the pubis and as far back as the sacrum. The genitalia may share the infection. According to Hopkins, the scrotum was commonly affected in patients he studied at Fort Benning. The axillas, the umbilicus, the inframammary areas and the interdigital webs of the feet are occasional sites of the infection. Vesicopustules are sometimes seen on the soles. With the friction of cloth- ing, especially during the heat of summer, varying degrees of secondary eczematization occur. Follicular involvement is unknown. We have never found E. inguinale in nail tissue. In cases of infection with T. gypseum, the feet are usually previously involved, and inflammation is more marked, as evidenced by vesiculation and exudative patches. The localization to the strictlv intertriginous parts is more pronounced. With infections due to T. purpureum, dull red, scaly, thickened plaques may be found in the crural region as part of a wide- spread eruption. Itching is more marked than when the infection is due to E. inguinale or to T. gypseum. The distribution is usually unilateral, in contradistinction to the type caused by E. inguinale. (d) Differential diagnosis.— There i mix be some confusion with ery- thrasma and moniliasis, particularly when areas other than the groins arc affected. The red border of the former disorder and the moist character ol the latter are distinguishing features. Psoriasis and seborrheic eczema may also be simulated, but these diseases are rarely confined to this lo- cation. (e) Prognosis.— The ordinary form of the disease usually responds read- ily to medicinal applications. Relapse is common; it is probably due to ill-timed stopping of the treatment or to reinfection from untreated parts or from clothing. The lesions caused by T. gypseum arc likewise readily cured, but those due to T. purpureum are extremely obstinate to all Fig. 29. Tinea cruris. The bilateral rash with well defined elevated edge and scaly surface is characteristic. Culture yielded E. inguinale. 95 Fig. 30. Tinea cruris. The classic cause is E. inguinale. However, in not all cases is tinea cruris caused by this species of fungus. Epidermophyton inguinale may also cause lesions in adjacent or remote parts of the skin. A, B and C, lesions caused by T. purpureum; cure is difficult. D, rash on the inner part of the thigh caused by E. inguinale. E and F, superficial circulate vesicular lesions in the axilla and on the dorsum of the foot (of the same patient); E. inguinale was isolated from both lesions. 96 The Superficial Mycoses 97 forms ol treatment and may soon recur il preventive therapy is abandoned. (f) Treatment.— Against the ordinary Form ol the disease (due to E. inguinale ), one ol the following topical applications may be used. 1. Salicylic acid, 3 per cent and precipitated sulfur 6" per cent in equal parts ot lanolin (hydrous wool fat) and petrolatum. It is advisable to begin with this concentration, but if on the next visit there is no evidence of irritation, the strength of both drugs may be doubled. With nightly applications of this ointment the patient is usually cured in about three weeks. 2. Resorcinol, 3 to 12 per cent in lotion of zinc oxide, is advocated by Wise. The peeling effect of the resorcinol is tolerated better in this medium than in a grease. .3. Compound ointment of benzoic aeid (Whitfield's ointment) may be used, with 3 per cent salicylic aeid and 6 per cent benzoic aeid. If there is no cutaneous reaction, the strength of the ingredients may be cautiously increased. It is inadvisable to use chrysarbbin or thymol in this location unless pre- vious medication is unavailing. When there is marked inflammatory reac- tion, soothing applications should first be applied. A 1 per cent aqueous solution of gentian violet (methylrosanilin) may be painted on the affected skin. If the infection is still present after the inflammatory reaction has subsided, one of the aforementioned prescriptions may be used. There is no indication for the use of roentgen or ultraviolet rays. We have never seen any benefit from the therapeutic use of trichophytin. The treatment of an infection due to T. gvpseum or to T. purpureum has been considered in the following section on dermatophytosis. Intertrigo of the groin due to M. albicans may also be confused; its treatment is discussed under moniliasis. BIBLIOGRAPHY Mehcer, S. T., and Fahbeh, G. J.: Epidemic of ringworm due to Epidermophyton floccosum (inguinale'. Arch. Dermat. & Syph. 32:62. 1935. Win i wis. C. M.: Dermatophytid complicating tinea cruris. Arch. Dermat. l\ Syph. 22:b37. 1930. 5. DERMATOPHYTOSIS (DERMATOMYCOSIS, INCLUDING ONYCHOMYCOSIS) The term dermatophytosis is commonly used in this country to refer to a superficial fungous infection of intertriginous or Hat areas ol skin. We here include under this heading tinea pedis, secondary lesions acquired by contact with lesions elsewhere on the body, particularly on the hands 98 An Introduction to Medical Mycology (tinea manuum), and allergic manifestations, or dermatophytids. Fun- gous infection of the nails (tinea unguium, or onychomycosis), which is caused by the same species of fungi, is usually described as a separate en- tity. The involvement of nails is linked so intimately with that of the feet that we believe it should be included as part of the syndrome. The usual varieties of infection of the nails are discussed in this section. Un- gual and paronychial infections due to M. albicans are described in the section on moniliasis, pp. 145 ff. We agree with Weidman that dermatophy- tosis of the type caused by T. gypseum is essentially an intertriginous con- dition and usually begins as such. Associated, however, are sensitization or the lack of it, secondary infection, acuteness or chronicity and a number of important incidentals. The terms epidermophytosis, epidermomycosis and trichophytosis are also used by some as synonyms for dermatophytosis but would better be reserved for instances of specific infection (as epi- dermophytosis: due to E. inguinale). (a) Incidence.— It has been variously estimated that from 50 to 90 per cent of the population of the United States are affected at some time dur- ing their lives. Hulsey and Jordan recorded a clinical incidence for tinea pedis of 67 per cent and a microscopic incidence of 63 per cent in a series of 100 university students. Gilman noted that of 390 new patients with diseases of the skin seen during six months in the Student Health Service of the University of Pennsylvania, 145 (37 per cent) had a mycotic infec- tion. The average age of these patients was 19/2 years. Gilman examined 500 students; 297 (60 per cent) had gross evidence of ringworm. Legge, Bonar and Templeton found that 53.3 per cent of the men and 15.3 per cent of the women of the 3,100 freshmen in a university were infected and that at the end of the spring semester 78.6 per cent of the men and 17.3 per cent of the women had tinea pedis. Muskatblit examined 112 medical stu- dents and 100 dispensary patients. Evidence of dermatophytosis was pre- sented by 89 per cent. Andrews and Birkman in a clinical studv of 520 public school students between the ages of 14 and 20 noted that 65 (12/2 per cent) showed clinical signs of fungous disease. We can substantiate the relative infrequency of Trichophyton infection in adolescents and in children. Prehn found that 88 per cent of 1,500 men examined on 11 ships of the United States Navy showed clinical evidence of ringworm of the feet. In a survey of over 300 patients in a home for the aged we found evidence of residual infection in the skin and nails of over 90 per cent; only a few of the patients complained of the condition. Ajello, Keeney and Broyles stated that 40 per cent of young men entering military life had normal feet, whereas for the troops at Fort Benning, Hopkins and his co- workers reported normal findings in only 20 per cent when the feet were The Superficial Mycoses 99 examined painstakingly In clinical, microscopic and cultural methods. (b) Historical survey.— According to Ormsby, ringworm ol the hands was noted by Tilbury Fox in INTO and by Pellizari in 1888. The first detailed study of ringworm as it affects the hands and feet was that ot Djelaleddin- Monkhtar in L892, and credit should be given him for timely and accurate" observations. Whitfield, Sabouraud and Kaufmann-Wolfl made early reports. In this country, Ormsby and Mitchell were the first to report a compre- hensive series of cases of ringworm of the hands and feet. Many investiga- tors have since reported their findings. A selection will be found in the bib- liography. YYeidman's article (1927) was, and still is, the most important published on this subject in the American literature. The literature on this subject has been enriched by the exhaustive researches and careful, pains- taking observations and deductions of J. Gardner Hopkins and his group. The studies were carried out from 1942 to 1945 at an infantry post, Fort Benning, Georgia. Allergic secondary lesions (dermatophytids) were described by Jadas- sohn and others of his school as emanating from a deep focus such as an infection of hair follicles. C. M. Williams first showed that similar lesions can be present on a localized part of the body (usually the fingers and palms ) when the primary focus is on the interdigital webs of the feet. This observation has been substantiated by Peck, Walthard and many others. Hodges' report in 1921 focused attention on the disease as it affects nails. (c) Etiology.— Two organisms, T. gypseum and T. purpureum, cause the bulk of the infections (Table 16). Whereas in civilian life, E. inguinale TABLE 16.— Results of Culture of Material from the Feet over a Five Year Period (1942-46 Inclusive) Organism No. OF Cases Percentage of Cases Percentage of Organisms T. gvpseum 247 217 35 22 292 813 30.4 26.7 4.3 2.7 35.9 100 47.4 T. purpureum 41.7 E. inguinale 6.7 \I. albicans 4.2 No growth Total 100 is relatively uncommon as the cause, Hopkins and his co-workers reported an incidence of 17 per cent in soldiers; the}' found T. gypseum in 47 per cent and T. purpureum in 36 per cent of positive cultures. M. albicans may also cause intertrigo of the toes, and in rare instances M. lanosum and sev- eral other dermatophytes have been cultured. Occasionally lack of results from culture when a condition was clinically thought to be dermatophy- tosis has led some observers, including ourselves, to believe that strepto- 100 An Introduction to Medical Mycology cocci (which are occasionally present) and perhaps some of the ordinary saprophytes of the skin may cause the condition. This is purely speculative. We have reported 23 cases of multiple fungous infections with 12 different combinations of pathogenic fungi. Although some difficulty was encountered in deciding the role of the pathogenic species isolated from diseased tissue, in nine cases it was decided that the fungi present were in symbiosis. Mul- tiple fungous disease is probably not uncommon. In the majority of cases infection of the nail is also caused by T. gypseum or T. purpureum. Achorion schoenleini and several other fungi are occasionally found. Cases of infection due to M. albicans are discussed in the section on moniliasis ( pp. 145 ff . ) . While the toenails are usually infected secondarily to an interdigital infection of the feet, the fingernails may or may not be in- volved after infection in another site. In some instances the evidence points to a primary infection of the fingernails due to poor hygiene during a manicure. In many instances the method of infection is unknown. Hodges estimated that in the Southern states the prevalence of tinea unguium is 1 to 500 of the population. Incidence is at least as great in New York. The disorder is rarely seen in children. The most vulnerable age period seems to be from the sixteenth to the twenty-fifth year. Primarv infections usually appear during these most active years. The manifestations of the disease in later years, while common, may usually be placed in the category of flare-up, or exacerbation. The disorder is seen much more in males than in females. This may be due in part to more particular hygiene on the part of women or to the greater chance of contamination of men due to their greater interest in athletics and to their congregating in camps, clubs and gymnasiums, with the common use of locker rooms, shower baths and other facilities. There must be still another reason why many wives who were exposed prior to the knowledge of the contagiousness of the condition failed to become infected. It seems that men are more vulnerable. There was an apparent increase in the incidence of disabling dermatophytosis among the members of the armed forces in World War II over incidence in the same age group in civilian life. This is not unexpected, despite improved meth- ods of therapy, for the troops walk in bare feet over floors bound to be infected, there is common use of bathrooms, hygiene is poor during combat service and trauma and sweating after long marches are conducive. The disease is more prevalent in the summer. We observe fewer cases in New York in the winter than in the summer, and the character of the disease varies considerably with the season. In summer, exceedingly acute involvement occurs more often, and there is generally more in- flammation. The Superficial Mycoses 101 Hyperhidrosis is a common finding in patients with dermatophytosis. Just how much the sweat has to do with the furtherance of the infection has been the subject ol study of a number of investigators. Levin and Silvers showed that fungi will grow in sweat. Peck has found that true sweat has fungistatic power not possessed by insensible perspiration. The latter, when present to excess, produces maceration of the skin, which accordingly is more vulnerable to the invasion of fungi. The alkalinity or acidity of the sweat may play a part in the predisposition toward infection. The diet, the amount of sweat secreted and the amount of evaporation are factors in the pH of the sweat. Lowering of a patients vitality during a debilitating illness may be reflected in a predisposition to the disease. A quiescent interdigital in- fection may become inflammatory and spread to adjacent and remote cutaneous areas. In main instances, predisposing factors may not be manifest, and we are forced to conclude that infection may often take place when normal persons come in contact with pathogenic fungi. An abrasion may pro- vide a portal of entry, but even that is apparently unnecessary in most cases. The main factor in ascertaining the etiology and consequently the prophylaxis of the condition is determination of the reservoirs in order that they may be eliminated. The chief foci are to be found on the feet of carriers, w 7 ho are unaware of the disease or are careless in treating it. That pathogenic fungi may remain viable for some time in a dry state has been proved by Farley, Weidman, Mitchell and others. Weidman calculates that many pathogenic fungi may survive in the dry state from approximately six months to a year. Fungi of pathogenic titer have been yielded by cultures of material from floors, mats and gymnasium apparatus (Williams), shoes (Jamieson and McCrea), cotton, linen, silk (Hruszeck- Kadisch), wool and silk and many different woods and in the presence of moisture (Bonar and Drever). Goldman mentioned that spores of fungi have been carried nearly 14 miles (22 kilometers) up into the stratosphere and have survived cold, solar radiations and other extreme conditions. Fortunately, however, the spores of fungi are not as resistant as those of bacteria. Moreover, they are readily destroyed by heat. Weidman found that most species of fungi in culture and in scrapings were killed by ex- posure to a temperature of 48 C. for 10 minutes. (d) Immunologic reactions.— This topic is discussed at length in Chap- ter VI, "Immunity and Cutaneous Sensitization." The practical importance of the routine use of the trichophytin test in connection with other studies is well recognized. Initiation of sensitivity 48 hours after the test occurs in about 70 per cent of patients infected with T. gypseum, while only 30 102 Ajj Introduction to Medical Mycology per cent of those infected with T. purpureum have a positive reaction after 48 hours. With the latter infection an immediate wheal reaction to trichoph- ytin may be expected in about 40 per cent of patients. With the acute form of ungual involvement due to T. gvpseum, there may be initiation of cutaneous sensitivity, as evidenced by the development of a reaction to trichophytin. The superficial type (leukonychia trichophytica ) and the in- fections due to T. purpureum seldom have the ability to sensitize. The same is true of ungual infections due to A. schoenleini. (e) Clinical characteristics.— There are two chief forms of the dis- order, namely, (1) the inflammatory type, due to T. gypseum, and (2) the chronic type, due to T. purpureum. Since there is a wide difference in the appearance, behavior and response to treatment of each, they will be taken up separately. (1) Inflammatory type {Trichophyton gypseum). a. Involvement of the skin. The disease commonly makes its appearance on the feet in the form of vesicles on an interdigital web, on the sole or on both. In the first-mentioned location the vesicles, or bullae, rupture readily, and the skin at the site of the lesion becomes macerated and soggy. The process is usually associated with a certain degree of erythema, but this may be lacking. The condition may remain in this stage for weeks, months or years. On examination some maceration and peeling may be noted. The development of fissures or cracks is common. For some reason not yet known the web between the fourth and the fifth toe is particularly vulner- able. In this stage the inflammatory form may be indistinguishable from the chronic type ( due to T. purpureum ) . With favorable conditions the disease may assume a more inflammatory character. This usually occurs during the summer season, although not exclusively. The first indication may be pruritus of the toes accompanied by some swelling (edema) and followed by appearance of vesicles. The soles may be the chief areas affected, but if the inflammation is violent, vesicles may appear on the sides of the toes and feet. Owing to scratching and trauma from local applications (self-medication being exceedingly common) there is an increase in the inflammatory reaction, and secondary pyogenic infection may appear. Coincidentally with the increase in the lo- cal inflammation on the feet and frequently with the development of lesions on the soles, vesicles may appear at a site or sites remote from the original infection. The hands (particularly the palms and sides of the fingers) are chiefly affected. This type of eruption is due to the dissemination of products of fungi through the blood stream, and the lesions are known as der- matophytids. This Subject is considered in more detail on pages 116 to 119. Fig. 31. Dermatophytosis of the acute type affecting the hands and Feet. Trichophyton gypseum was repeatedly isolated from both sites. 103 Fig. 32. Acute dermatophytosis. Culture yielded T. gypseum in each ease. A, acute vesico- pustular rash of two weeks' duration. B, severe pustulobullous infection somewhat improved after wet soaks in potassium permanganate solution. C shows that after the subsidence of inflammatory tinea pedis there are scaling of the sole and interdigital maceration. Treatment should be continued in order to eradicate the disease. /), superficial infection of the nail (leukonychia trichophytica ) and vesicopustules, with fungi in both sites. /•,', interdigital macera- tion and scaling and superficial involvement of several toenails. 101 Fig. 33, Acute dermatophytosis (T. gypseum). A, maceration on the interdigital webs ol the feet and vesicular rash on the sole and hands (no fungi discovered), considered a good example of dermatophytid. B, C and D, erythematous squamous eruptions suggestive of psori- asis. E, vesicular and exudative areas on the under surface of the toes, with sterile vesicles on the sole. F, secondary dermatitis following use of a strong ointment. In G the toes are swollen, red, vesicular and scaly. (Courtesy of Royal Montgomery.) 105 106 A/j Introduction to Medical Mycology Because of mismanagement, a low state of resistance or a virulent strain of organism, the condition may spread from the feet to involve contiguous areas, which are sometimes of wide extent. The eruption is erythematous and vesicular in patches and is fairly well demarcated from normal skin. The folds and intertriginous areas are most vulnerable, and the infection may spread to any or all of the following sites: the upper parts of the thighs, the perianal region, the umbilicus, the axillae and the inframam- mary regions. There are a few instances of primary involvement of the hands and of other parts of the body. In instances of acute inflammation, secondary pyogenic invasion of the tissues is common. At times the pyo- genic element overshadows the characteristics of fungous disease. If the process becomes frankly pyogenic and spreads, the disease may have changed to infectious eczematoid dermatitis. Many clinicians believe that eczematous eruptions on the hands or elsewhere may be originally of fungous origin but persist owing to coincidental sensitizations or secondary pyogenic involvement. It is our opinion that fungous disease predisposes to contact sensitivity, so that a patient who ordinarily is not reactive to soap, dyes, salicylic acid, etc., may develop an inflammatory response to these or to many other drugs or chemicals, and that this superadded insult to the skin is often important in accounting for the lack of response of the disorder to therapy. b. Involvement of the nails. As part of the process, the nails, particularly of the toes, are not uncommonly affected. In fact nail tissue may be the first to be involved. The infection with T. gypseum may be superficial, merely causing a white patch on the surface or in the substance of the affected nail (leukonychia trichophytica ) . At other times there may be a more inflammatory and destructive involvement, in which case the nail becomes yellowish, opaque, lusterless and finally friable. The nail bed may become slightly erythematous, and separation of the nail from its bed may occur, this process usually beginning distally. Subungual hyperkeratosis and uneven dystrophic changes in the nail are frequent. Paronychia is rare. When destruction occurs, the process is fairly rapid, although there are rarely more 1 than three nails affected. Subjective symptoms are usually mild, but pain may be severe. (2) Chronic type (Trichophyton purpureum) .—In this form there is prac- tically never vesiculation or acute reaction. The interdigital webs alone may harbor the organism, in which case the appearance does not differ no- ticeably from that of the latent form described in the section on the inflam- matory type, although the duration is often considerably longer. Further characteristics of the infection may be described from the stand- point of the sites of involvement. Fig. 34. Acute dermatophytosis of the hands. There may be a focus on the webs of the feet, on the soles or elsewhere, or the infection may be primary. With secondary infection, dissemination may take place externally or through the medium of the blood stream. A, acute vesicular rash secondary to lesions on the feet. While this might be classed as dermatophytid, T. gypseum was isolated from the lesions. B, primary erythematous vesicular infection of short duration from which T. gypseum was isolated. There were no lesions on the feet. C, well defined subacute rash of the hand, with part of an eruption also on the feet, elbow and face, of one year's duration. D, early involvement of nails, showing destruction and separation at the base The violence of the process produced a spontaneous cure, and new nails were normal. 107 108 An Introduction to Medical Mycology \. Involvement of the hands and feet. The appearance of the eruption on the feet and on the hands appears to be peculiar to T. pnrpurenm. Le- sions of the feet may occur on the soles, the sides, the dorsa, the toes or the nails. The plantar surface is a common site. When the hands are in- \ ol\ ed, the palms, the dorsa, the fingers or the nails may be affected. Itching is frequent. The entire sole is frequently involved, but the infection may be localized to a small area around the heel or on the ball of the foot. When the sole is involved, the infection usually extends to the sides of the foot and about TABLE 17.— Location- of Infection Caused by T. Purpureum in 240 Patients Skin Feet 180 Hands 44 Trunk, arms and legs 27 Inguinal region 35 Trunk ( gyrate ) | 5 Face 3 Skin Total and Infec- Nails Nails ^I/LICLES tions 99 72 207 62 21 90 1 27 35 5 2 3 the heel. The infected skin is dull red and slightly thickened or indurated. The scaling, which is constant, is usually fine and thin (branny), in contrast to the large flaky scale found in psoriasis or in some types of dermatophy- tosis. The absence of visible vesiculation in the infected area is a per- sistent feature. Hopkins and his group reported that in many of the patients with T. purpureum infections studied at Fort Benning, 1942-45, the erup- tion was acute, severe and extensively vesicular. This is at variance with our (civilian) experience and may be explained partially by the climate and conditions under which the soldiers were living and the probability that these young men were experiencing their initial attack. There is usu- ally a sharply marginated border along the outside of the foot, between the infected skin and the normal skin on the dorsum. Small irregular infiltrated erythematous and scaly patches may be found on the dorsum of the foot and on the toes. The degree of erythema may vary within a single patch. There is no tendency to central clearing. The infection of the under surface of the toes and of the interdigital webs is clinically similar to the infection of the sole, sometimes with the addition of a certain amount of maceration. When the entire area about the toe is infected, the skin appears thickened and dry. Painful fissuring may occur about the joints. The eruption on the hands is similar to that on the feet. The entire palm may exhibit the characteristic dull red color, with thickening and scaling. Fig. 35. Chronic dermatophytosis of the feet (T. purpureum). In A and B, the affected skin on the dorsa and insteps of the feet shows a dull red, scaly, slightly edematous, well defined rash. C, scaling on the interdigital webs. D, marked hyperkeratosis in an untreated condition of long duration. In E the skin is diffusely thickened and scaly. UK) Fig. 36. Ringworm infection due to T. purpureum, showing multiple foci. A, follicular lesions on the upper lip. In B the soles are dull red, thickened and scaly. C, dystrophic fingernails. D, ill-defined scaly lesions across the buttocks. The organism was demonstrated by culture of material from all the sites. 1 10 Fig. 37. Infection due to T. purpureum. A, thickened, dry, scaly plaque on back of neck. B, solidly invoked area over fingers and back of hand, with sharply marginated border; the ring finger nail is yellow, opaque, thickened and spooned. Ill Fig. 38. Trichophyton purpureum infection involving the foot, hand, buttocks and thigh. Fungi could be isolated from all lesions without difficulty. 112 The Superficial Mycoses 1 L3 Friction and frequent washing in all probability make the scaling less ap- parent than that on the soles. The erythema may be slight and the condition thus be considered a callus. Isolated irregular patches may he present about the dorsum of the hand and on the fingers, as is the case with the feet. Frequent!) the skin of an entire finger is involved. Redness of the skin with or without sealing may he 1 noted oxer the joints ol the hands. Fissuring in affected patches about the joints is a fairly constant feature. The absence of vesiculation, except in rare instances, and the presence of severe itching are again notable. On several occasions, when the palm was involved, we observed a marked decrease 1 in the amount of sweat. b. Involvement of the nails. Nails infected with any pathogenic fungus except M. albicans are usually opaque, lusterless, friable and yellowish. Varying degrees of dystrophy, as evidenced by irregularities of the nail plate, separation of the nail and subungual hyperkeratosis, are frequently present. Nails infected with T. purpureum sometimes have certain features pecu- liar to this organism and not always shared by nails infected by other fungi. Unlike ungual infections caused by T. gypseum, the condition due to T. purpureum does not often concomitantly involve the interdigital webs of the toes. Furthermore, a superficial location of the infection on the surface of the nail is frequent with T. gypseum but practically un- known with T. purpureum. The duration of the infection is shorter and the progress of the infection is faster with T. gypseum. The onset and progress of the ungual infection due to T. purpureum is slow 7 and insidious. When the condition is first observed, one or more nails may be involved. Frequently the patient who has applied for treat- ment of infected fingernails may unknowingly have involvement of the toe- nails and even of the feet. There is little reaction in the subungual and paronychial tissues. We have not observed paronychia in our eases. (Com- pare infections due to T. gypseum or to M. albicans.) The infection usually begins under the free border or along the lateral margins of the nail plate. We have observed a single ease in which the infection started in the proximal portion of the nail. Yellow or white ver- tical streaks may appear in the nail, seeming to result from separation of the nail plate from its bed. These streaks gradually widen; the nail sepa- rates more and more and debris accumulates. There may be gradual in- volvement of the distal end of the nail, without the usual formation ot streaks. Meanwhile the nail itself becomes thinned, owing to gradual in- vasion of the fungus. The nail becomes brittle, and the 1 distal portion may be broken or worn of], leaving only the proximal part. Sometimes the entire nail plate is lost, leaving the nail bed covered with scales and debris. Fig. 39. Chronic dermatophytosis of the hands and fingernails (T. purpureum). A, con- dition which involved all the fingernails and toenails. Dull red, scaly and infiltrated lesions may be seen on the backs of the fingers and hands. B, fingernails showing different degrees of destruction. The infection usually progresses slowly. {Courtesy of Royal Montgomery.) C, dry intertrigo of the finger webs. D, advanced and early manifestations. The nails of the ring and little fingers show friable opaque yellow areas at the proximal portions, where the infection was introduced by a nail file. E and F show fingers and fingernails of a school teacher who had had the infection for 17 years. The moth-eaten appearance of the nails and the thickened scaly skin arc well shown. 114 Fig. 40. Chronic derrhatophytosis (onychomycosis) due to T. purpureum. A, involvemenl of all the toenails. In B the left great toenail has been pared down to show the depth of in- volvement. The right great toenail is yellowish, opaque and friable. C, marked crumbling of the toenails with neglected involvement. 115 116 An Introduction to Medical Mycology Only once have we been able to isolate T. purpureum from the surface of a nail obviously infected by fungi and never from a nail with no clinical evidence of fungous involvement. In connection with these observations we wish to point out that scrapings from the surface of an infected nail frequently contained the ordinary saprophytes but that when scrapings from the deeper portions of the nail were planted on agar slants, T. pur- pureum in pure culture resulted. For this reason cultures of infected nails should be taken from different depths in the nail substance. Unless the deeper portions are examined (and even when they are) a number of scrapings may be required before the organism can be cultured. Infection of a fingernail should always invite examination of the toenails, since the two sites are frequently simultaneously affected. In onychomycosis caused by T. gypseum and also when T. purpureum is the pathogen the toenails are involved more frequently than the fingernails in the ratio of 11:1. c. Involvement of other regions. It should be noted that lesions attrib- utable to T. purpureum may appear on the glabrous skin, on the upper parts of the thighs and in the inguinal and perianal regions, and occa- sionally the organism produces infection of the hair follicles. Peculiarities of the infection in these locations have been considered in the sections on tinea sycosis (pp. 75 ff. ), tinea glabrosa (pp. 78 ff. ) and tinea cruris (pp. 93 ff. ). Thompson and others have offered experimental proof that thromboangiitis obliterans is caused by infection spreading from the feet and due to T. purpureum. Reiss and Graham failed to reproduce the disease in animals and at this time the question of causal relationship must be considered not settled. (f ) Dermatophytid.— This subject was briefly considered in the section on tinea capitis (pp. 47 ff. ). The term dermatophytid is probably better than trichophytid, since allergic rashes due to Microsporum may be clin- ically indistinguishable from those due to Trichophyton. Guth, Bloch, W. Jadassohn, Peck and others have contributed to our knowledge of these rashes. It has been stressed by Bloch, Jadassohn and their school that allergy or an acquired specific sensitization is an invariable accompani- ment of the rash. The eruption was at first thought to follow deep infec- tion only, being considered due to dissemination of the products of fungi through the blood stream. Williams was the first to show that secondary eruptions may follow infection of the interdigital webs, and he later also found that macerated tissue in the groin max act in a similar way as the focus for a secondary rash at a remote point. The suggestion that nails may act in like manner as a focus for direct dissemination of the products of fungi through the blood stream lias not been confirmed. It is notable Fig. 41. Dermatophytid, secondary to tinea pedis. Trichophyton gypseum was cultured from the feet of all four patients. A, typical appearance, with severe vesicopustular lesions. The palms and sides of the fingers are the sites of election. No fungi were demonstrated in these lesions. B, acute vesicopustules with beginning eczematization. C, keratolysis exfoliativa, showing fine branny scaling. D, chronic edema of the ankle and leg of a patient who had re- peated attacks of acute lymphangitis; both fungi and streptococci were isolated from the interdigital webs. 117 ] 18 An Introduction to Medical Mycology also that with the dermatophytid described by Williams there was a ten- dency to a localized rash, the sides of the fingers and the palms usually being the sites. The reason for this localization is not known. The terminal circulation of the hands, traumatic factors, contact with fungi producing local sensitization and sensitization to light have been considered. It is not by any means a unique experience in dermatology to be unable to explain localization of a disease process. No one has satisfactorily explained the frequent involvement of the knees and elbows in psoriasis. In the classic dermatophytid following a deep infection of hair follicles, the trunk was usually involved. In this latter instance the character of the rash varied considerably. Follicular localization of lichenoid papules was common, but eruptions simulating erythema toxicum were also observed. In the type described by Williams, the lesions are essentially vesicular, being similar in appearance to dyshidrosis, although the contents frequently become purulent. Constitutional symptoms, often associated with der- matophytids secondary to kerion, are not commonly part of the syndrome which includes a rash secondary to tinea pedis. The term dermatophytid (or trichophytid ) appears to have been con- siderably overworked in this country. It is used by many without any tan- gible evidence of proof to account for the erythematous, vesicular and eczematous eruptions which so commonly affect the hands. We believe that a diagnosis of dermatophytid should be arrived at only after careful observation and study. There are definite criteria which must be fulfilled before this diagnosis is acceptable. Peck has laid down theoretically sound rules. His dictum that a positive blood culture is essential is perhaps too drastic. The following conditions for the diagnosis of dermatophytid, how- ever, are minimal and also obligatory. 1. There must be a demonstrable focus, and this focus must contain pathogenic fungi. On the feet, in the majority of instances, the causative fungus is T. gypseum. We have never observed dermatophytid with T. purpureum. 2. The secondary rash may be due to irritation of the primary focus by treatment or to a spontaneous inflammatory change. 3. The intracutaneous test with trichophytin reveals a positive reaction at the test site. 4. Fungi are usually not found in the lesions of dermatophytid. 5. The rash disappears spontaneously when the focus has been eradi- cated. The only exceptions occur when there are secondary eczematous changes and the rash continues because of sensitivity to other substances or because of the action of primary irritants. In all cases, even if the appearance of the rash and the results of the The Superficial Mycoses 119 investigation point to dermatophytid, possible sensitization from external contacts should be considered, and patch testing with suspected sub- stances is always in order. The same type ot vesicular dermatophytid which appears on the hands may also be found on the feet, particularly on the soles. Here, as on the hands, examination for fungi may yield negative findings. The condition known as keratolysis exfoliativa was studied by MacKee and Lewis, who considered that it is often a form of dermatophytid. They found that it frequently occurred in patients who had an active mycosis of the feet and that vesicular dermatophytids were commonly present. In keratolysis exfoliativa the lesions consist of superficial scaly macules, which may coalesce and are localized to the palms and/or soles. The lesions at first are unruptured empty vesicles. The scale is as thin as cigaret paper. When it is broken, collarets are formed at the edges. Only a few lesions may develop, or most of the skin on the palms and soles may be affected. The almost constant presence of the mosaic fungus is considered significant. Another type of dermatophytid occurring on the legs has been described as erysipelas-like. It appears to be proved that in some of the reported cases secondary allergic lesions arose from a focus on the interdigital webs of the feet. In other cases, little proof was offered that the lesions were not in reality of streptococcic origin. In several instances of eruptions of this character, with localized erythema and swelling and sometimes with fever and prostration, fungi were demonstrated in scrapings from the feet. The trichophytin test, however, did not elicit a positive reaction in every case, even when a site near the lesion was tested. Furthermore, in a number of instances bacteriologic studies revealed the presence of streptococci. Fur- ther study appears to be necessary to prove beyond doubt that in all or in most of these cases the condition is entirely due to the dissemination of fungi from the focus on the feet. •"Moreover, it must not be forgotten that many lesions at points remote from the initial infection are due to external dissemination of fungi. These lesions are not dermatophytids and certainly should not be classed as such. (g) Histology.— The findings vary according to the infecting micro- organism. (I) Acute injection— The changes in acute dermatophytosis are similar to those observed in acute eczematous eruptions. The stratum corneum shows some parakeratosis. Small vesicles are to be seen below this layer. The intensity of the process determines the degree and extent of vascular dilatation, of edema and of round cell infiltration in the upper cutis. In other words, there is a superficial exudative inflammatory process with some epidermal (eczematous) changes. 120 An Introduction to Medical Mycology (2) Chronic infection— li\ the chronic form there is a simple inflamma- tory process in the upper part of the cutis. The vessels arc slightly dilated; cellular elements are of the small round type and are sparse. There is mod- crate interstitial edema. The epidermis is slightly acanthotic. At times there is marked hyperkeratosis. The basal cell margin is intact. There is no inter- cellular edema, spongiosis or vesicle formation; occasional areas of para- keratosis are noted. ( h ) Differential diagnosis.— As in the diagnosis of other forms of mycotic infection, laboratory methods should be employed for every pa- tient suspected of having this fungous disease. The information to be ob- tained by such studies is frequently the only means of definitely establish- ing the diagnosis. (1) Interdigital lesions.— If the infection is present on the interdigital webs of the feet alone, it may be impossible to determine the species of infecting micro-organism by clinical observation. If all the webs are affected, infection with M. albicans is probable. The bright red base and overhanging collaret of skin suggest moniliasis. Intertrigo caused by T. purpureum or by T, gypseum may be indistinguishable. There are a number of instances of failure to demonstrate a pathogenic fungus. In some of these cases certain bacteria, especially strains of hemolytic streptococci, have come under suspicion without decision. Scaling between the toes due to the injudicious use of strong chemicals may lead the physician astray. Several instances of this character have come under our observation. The lack of laboratory confirmation and healing under bland applications tend to rule out tinea pedis. Maceration of the interdigital webs without evidence of inflammation may be caused by in- creased perspiration or by lack of drying after the bath. Such tissue is vul- nerable to pathogenic fungi and to bacteria. Syphilis may produce lesions difficult to distinguish from those of acute tinea pedis. The bright red, fleshy, exudative character should make one suspicious, and examination for condylomas or other evidence of the infec- tion will be fruitful. Soft corns are not uncommon and may be found in association with a fungous infection. They are, however, caused not by a fungus but by pres- sure of ill-fitting shoes. When they are present at the base of the web they may on superficial examination suggest tinea pedis. (2) Acute inflammatory tinea pedis.— Acute tinea of the feet, caused most commonly by T. gypseum, is usually accompanied by interdigital maceration. It should be remembered, however', that inflammation of the foot and tinea of the webs may be unrelated disorders. In most cases of inflammatory tinea the 4 reaction to the trichophytin test is positive. The Superficial M if coses L21 At limes patients arc seen who present SOggy, thickened, Iioim \ -combed solos, most involved over points ol pressure. The odor is that ol dirty feet. Although this condition is almost invariabl) attributed to fungous infection, the results ol culture are usually negative. It is our opinion that hyper- hidrosis plus bacterial invasion is responsible. Dermatitis venenata due to sensitivity to shoe leather, to the dye in stockings, to loot powder and to corn cures and the like should be con- sidered when the inflammatory disorder is first limited to the region ol the contacted substance. Once this dermatitis is established, secondary eczem- atous changes may quickly occur, further confusing the picture. The lack of other evidence of fungous disease, the negative findings on myco- logic examination, the results of patch testing and cine when the offending article is eliminated from the environment of the patient aid in establishing the correct diagnosis. When part of a widespread eczematous condition, whether due to con- tact or to some other cause, the involvement of the feet or ankles may mis- lead the unwary physician. He may consider the whole eruption mycotic because the feet are involved. In these cases, if the trichophytin reaction is negative, the diagnosis of tinea may be excluded. The disease known as pustular psoriasis frequently presents a confusing picture. The lesions appear in groups of small, thick-walled pustules. The arch and the heel are the commonest locations on the foot, but lesions may develop elsewhere. Frequently the hands are concomitantly involved. The lesions are usually sterile. Barber, Andrews, Hopkins and others have ob- served that in such cases cure has resulted from the removal of foci of infection. The resemblance to tinea pedis may be striking, but lack of interdigital infection, localization, resistance to therapy and lack of myco- logic confirmation should be sufficient to indicate the correct diagnosis. With acrodermatitis perstans or dermatitis repens, which are similar, if not identical, disorders, the initial lesion is usually paronychia. From this arises an undermining pustular eruption, which spreads on one digit and may finally involve large sheets of skin. If the condition is untreated, an exudative eczematous process ultimately develops. Streptococcic infections have been credited by Mitchell with causing lesions on the feet which resemble those due to fungi. Orbicular eczema is superficial, does not show a tendency to central clearing and does not respond to the usual fungicides. Results of all labo- ratory examinations are negative. (■3) Chronic types of infection. a. Psoriasis. So-called aberrant types of psoriasis are usually due to T. purpnremn. While the diagnosis can be made with certainty only from Fig. 42. Nonmycotic diseases simulating dermatophytosis. A, pitting of fingernails of a patient with psoriasis. B, congenital defect. C, onycholysis. D, severe dystrophic onychia with bulbous terminal phalanges. Typical psoriatic lesions were present elsewhere. E and F, acro- dermatitis perstans (Hallopeau). G, pustular psoriasis. 122 Fig. 43. Nonmycotic diseases to be differentiated from dermatophytosis. A, dermatitis venenata due to shoe leather. B, dyshidrosis, or pompholyx. C, D, E and F, psoriasis. G, pustu- lar psoriasis. H, syphilis with maculopapular lesions on the soles and moist, eroded lesions on the webs and under surfaces of the toes. (C to H, courtesy of Royal Montgomery.) 123 124 An I nl induction to Medical Mycology mycologic examinations (usually repeated several times), the laek of in- volvement of the scalp and the localization to areas not commonly the sites of psoriasis, such as the palms, the soles or the inner surfaces of the thighs, should make one suspicious. The presence of bleeding points after removal of the scale is not usual with the mycotic disorder. The histologic picture usually observed with psoriasis is absent in case of fungous infection. Pru- ritus, if severe, favors the diagnosis of dermatophytosis. b. Neurodermatitis (atopic eczema). On close inspection the affected patch will be seen to be lichenified, with exaggerated cutaneous markings. Scratch marks may be noted, as with the fungous disease. Careful investiga- tion of the history will elicit the fact that pruritus and scratching by the patient preceded the rash. There may be a history of allergy to foods or to inhalants or a tendencv to another allergic disorder, such as hay fever or asthma. ( 4 ) Onychomycosis. a. Infection with Monilia albicans. Chronic paronychia is practically constant. The edges of the nail become yellow and eroded or develop a dark stripe, but the nail substance is frequently firm and translucent. Un- even ridges and grooves are probably due to interference with nutrition. Most of these signs are not seen in nails infected with T. gypseum or T. purpureum. b. Psoriasis. Pitting of the nails is frequent. Ridges and grooves sometimes develop. Rarely a lesion of psoriasis develops in the nail bed. In this case the lesion is well demarcated, and there may be redness, which fades on pressure over the nail. The color of psoriatic nails usually remains unal- tered, although a yellow tinge may appear. The nail tends to remain firm and translucent. c. Pyogenic involvement of the paronychial tissues. This produces an acute, painful, bright red swelling. There may be a hangnail or some evidence of injury. The disease is of a few days' duration. Dystrophy of the nail, as evidenced by ridges and grooves, may result from interference with nutrition. d. Syphilis. This disease may affect the nail or the paronychial tissues. A chancre may appear, and considerable destruction of tissue with painful swelling of the parts is common. Another form of syphilitic involvement of the ungual tissues, usually seen in association with a late cutaneous or other manifestation, results in atrophy ol the nail. e. Other diseases. Tuberculosis and leprosy also affect nails and the sur- rounding tissues, dystrophies of varying degrees being present. f. Other fungous infections. In the clinical diagnosis of fungous infection of the nails, one should remember that chronic paronychia with secondary Fig. 44. Non mycotic rashes simulating dermatophytosis. A, dyshidrosis, or pompholyx. B, erythema toxicum. C, contact eczema. D, so-called parasitic, or nummular, eczema. 12". 126 An Introduction to Medical Mycology changes in the substance of the nail is usually due to M. albicans. In the invasive type of filamentous infection, the cardinal symptoms of yellowness, friability and opacity of the nail and the negative sign of lack of paronychia will usually point to the correct diagnosis. The white specks or patches fre- quently seen on the edges of toenails are due to the presence of T. gypseum. (5) Dermatophytid-like eruptions.— Toxic eruptions simulating derma- tophytid may result from sensitivity to certain drugs. The absence of signs of a focus of tinea, the lack of an inflammatory focus on the feet and the history of ingestion of a drug point to the correct diagnosis. When a vesicu- lar eruption is present on the hands, particularly on the fingers and palms, the diagnosis of dermatophytid is commonly given even without corrobora- tion. In the majority of cases, however, such a condition is not of fungous origin. The criteria for the diagnosis of dermatophytid have already been detailed; it is at least necessary to find an active fungous focus and to ob- serve a positive reaction to the trichophytin test. The diagnosis of dyshi- drosis or pompholyx is made by excluding dermatophytid and dermatitis venenata. The former disorder has been discussed; in diagnosing the latter, one is helped by the absence of an active fungous focus and of a reaction to trichophytin, but their presence does not exclude the condition. An accurate history of contact with a possible sensitizing agent, particularly if the initial exposure was fairly recent, may point to the correct diagnosis. When sec- ondary eczematous changes result from trauma or misdirected therapy, an additional factor or factors may make a definite diagnosis impossible. At present, unfortunately, a large number of patients with such lesions present themselves for treatment; they constitute a rather unsatisfactory group, in regard to both accurate diagnosis and therapeutic results. We believe that it is a mistake to classify all eczematous changes in the hands as derrna- tophytids. Another disorder previously mentioned, namely, pustular psori- asis, shows groups of deep-seated pustules. The sides of the fingers are rarely involved, the lesions are not evanescent, and response to therapy is poor. (i) Prognosis.— This varies for involvement both of the skin and of the nails according to the infecting micro-organism, the allergic response in the patient, the factors predisposing to the infection and the duration and extent of the involvement. When T. gypseum is the causative fungus, the prognosis is hopeful. The infection may be severe, but cure may be expected. If T. purpureum is the offending micro-organism, cure is difficult and will probably take several months or even years. A vigorous reaction to the trichophytin test is a hopeful sign. As For the factors which predispose toward the disease, hyperhidrosis, unless it is controlled, may hinder a rapid response to therapy. If an underlying factor of ill health is uncor- The Superficial Mi /coses 12, rected, the results oi treatment maj be disappointing. Everything else being equal, tin* longer the duration and the more numerous the areas <>1 skin actuall) involved, the more difficult it is to eradicate the disease. (j) TREATMENT OF SKIN.— Few dernuUologic diseases have reeeived more attention and space in scientific journals than deriuatoph\ tosis. The ma- jority ol the articles are clinical, and most are concerned with therapy or prophylaxis. It is unnecessar) to mention the long list of proprietary drugs extensivel) advertised and sold to the public. In most textbooks as well, a long list of drugs and formulas is given. All this has led to confusion, and, as Osier has pointed out, the very multiplicity of remedies lor a disease means that no one remedy has much value. We agree with .Mitchell that in an approach based on scientific logic- one should first make an accurate- diagnosis. Suppose that the disorder is localized to an interdigital web. We have mentioned that from the clinical signs one may not be able to differentiate between T. gypseum and T. purpureum as the causative fungus. A cultural diagnosis will assist one to determine the prognosis and the importance of treatment. Thus if T. pur- pureum is cultured, the interdigital maceration may be hard to eradicate, but treatment is essential if other areas are not to be subsequently infected. With T. gypseum, on the other hand, therapy is usually effective, but one need not be seriously disturbed if the treatment is not carried out faithfully. The type of treatment should be indicated by the type of fungus present, cutaneous sensitization or lack of it and the clinical signs. Our methods of treatment and their results leave much to be desired. Bechet stated an obvious truth when he declared that "the more experience one gains in the treatment of this obstinate dermatosis, the less faith one has in our present methods of treatment." The various forms of therapy will be discussed according to the follow- ing subdivisions: (1) topical applications ( keratolyses, fungicides and soothing agents); (2) physical agents (such as roentgen rays), and (3) biologic methods (injections of trichophytin, implantation of harmless sap- rophytes). Therapy of infections of the glabrous skin is discussed sepa- rately ( see the section on tinea glabrosa, pp. 78 ff. ) . The treatment of der- matophvtosis of the skin is taken up first; that of the nails next. (1) Topical applicat ions. —Some form of topical treatment is essential in all types of the disease. If involvement is localized to the interdigital webs of the feet or if it is widely distributed and T. purpureum is the infecting micro-organism, no other form of therapy need be considered. The various medicaments to be applied to the surface of the skin include soothing agents, keratol) tics and fungicides. A. Soothing agents. These are required when acute inflammation is pres- 128 An Introduction to Medical Mycology ent, whether on the hands, the feet or other parts. One should forget for the time being that the primary disease is mycotic. The safest application is a continuous wet dressing or soak, with use of Burow's solution (solution of aluminum acetate, 1:15); solution of boric acid (3 to 4 per cent) or solution of silver nitrate (0.125 to 0.25 per cent), particularly if there is an exuding surface, which indicates eczematization. Even when there are numerous unbroken vesicular lesions, wet dressings or soaks are best. Large pustules and blebs may be incised and all loose tissue clipped away. The same solutions or a solution of potassium permanganate (1:3,000) or of tannic acid (2 per cent) will be useful. If no secondary eczematization is present and if it is inconvenient or impossible to use wet dressings, the application of paints, lotions and powders may be considered. A 1 per cent aqueous solution of gentian violet (methylrosanilin) is soothing and, as Sut- ton pointed out, is not known to be a sensitizer. Damage to clothing may be controlled by careful handling. As substitutes, a 2 per cent solution of mercurochrome or an aqueous 1 per cent solution of brilliant green (mala- chite green) may be employed. The calamine shake lotion commonly used in the treatment of eczema and other cutaneous disorders may be used on the hands or body when an acute inflammatory disease is present. Purified talc to which 10 per cent each of zinc oxide and boric acid have been added is often gratefully accepted by swollen and acutely inflamed feet. When the acute vesicular character of the rash has passed, zinc oxide (20 per cent) in petrolatum may be followed by the sparse application of a tar (3 per cent juniper tar or 5 per cent solution of coal tar) in zinc oxide paste ( 10 to 20 per cent ) or incorporated in boric acid ointment. If no irritation results, the use of stimulating remedies is in order. b. Keratolytics. These are useful in peeling off the stratum corneum, which contains many fungi. By doing away with extraneous material they also prepare the way for the fungicides to act more effectively. The two drugs most commonly employed are salicylic acid and resorcinol. Most skins tolerate salicylic acid better. The strength of either drug depends on the site in which it is to be used and the character of the infection. Treat- ment between the toes is usually begun with a strength of 6 per cent. The same strength may be used on the soles. On the dorsa of the feet and on the hands a 2 per cent solution of salicylic acid should not be ex- ceeded at first. If this is well tolerated, stronger concentrations may be used to promote more vigorous exfoliation. Satenstein stated that he used an alcoholic solution ol salicylic acid in a strength of from 20 to 30 per cent. These drugs arc commonly employed with fungicides, although they may be used singly. The vehicle also may vary. According to some observers, drugs are more active in alcoholic or aqueous solutions than in grease. In The Superficial Mycoses 129 general, an alcoholic solution is probably superior to a salve when used on the webs ol the toes or on the palms or soles. On other locations it is best to use a grease, Since there is less irritation. Francis stated that he obtained satisfactory results with a mixture ol camphor and phenol. He gave the following directions lor making and using the preparation : Melt U.S.P. phenol and measure out 3 CC. into a mortar; weigh 3 Gm. of U.S. P. camphor, break into small pieces and add to tlu 1 melted phenol. Huh until the entire mass is liquefied. Transfer into a vial with a stopper suitable tor use as a dauber. Keep stoppered when not in use. Experiments indicate that the ingredients may be mixed in the proportion ol 3 parts phenol and 1 part camphor. The mixture is nonirritating to the skin and may he painted between the toes sev- eral times a day, the small rubber stopper ol the vial being used as a dauber. The sock may he replaced immediately without danger of corrosion. There is no discoloration ot the clothing. Relief from itching is immediate. It should he pointed out, however, that the phenol-camphor preparation should not he applied to the wet skin, since water causes a breakdown ot the preparation, with the result that it heeomes caustic. Confirmation is lacking that the combination of drugs is both safe and effective. Glenn and Hailey reported indifferent results in a series of 85 pa- tients. We have seen the preparation misused and believe that unfortunate publicity through a lay periodical has resulted in considerable self-treatment with poor general results. Danger from local necrosis or from absorption makes the use of camphor-phenol undesirable. In treatment of chronic infection of the feet due to T. purpureum, the use of the following paste was advocated by Glaze and by King: Salicylic acid 3 oz. Starch 3 dr. Petrolatum 3 oz. Only two applications, made on successive nights, are advised. A layer /s in. (0.32 cm.) thick is placed on the entire affected area, covered with a bandage, left overnight and wiped off in the morning. No washing, however, is permitted. The result is the separation of the superficial cutaneous layers from the deeper parts, usually in a cast. There may be an acute inflammatory reaction. In several instances we have been impressed with the rapidity of response 1 in patients who have used various other remedies without any improvement. C. Fungicides. The exact mechanism of the lethal action ot drugs on fungi is not fullx explained. Some drugs apparently act as reducing agents. There is usually a certain degree of stimulation to the vascular supply. The degree of direct poisonous effect on the fungus is difficult to determine. In choosing a fungicide, one may determine its activity in vitro and note its power to irritate human tissues and its effect after clinical trial. There have been several thorough investigations of various drugs. The 130 An Introduction to Medical Mycology results of the work of Gould and Carter, Schamberg and Kolmer, Scham- berg, Brown and Harkins, Kingery and Adkisson, and Emmons indicate that the fungicides to be discussed are active in the approximate concen- trations named. Since these and other investigators based their results on the use of varied technics and different species of fungi, there are many discrepancies in the reports of the concentrations of drugs necessary to ob- tain the desired effect. There are, however, few actual differences of opinion. 1. Salicylic and benzoic acids were found to be only feebly fungistatic when tested separately by Schamberg and Kolmer, but Gould and Carter found that by combining and adding to culture mediums salicylic acid in the strength of 1:10,000 and benzoic acid 1:5,000, no growth resulted when the culture mediums were inoculated with six strains of common patho- genic fungi. 2. Iodine is strongly fungistatic (1:10,000) but not as strongly fungicidal (1:500). Schamberg, Brown and Harkins found iodine to be a powerful fungicide. Emmons, too, found it the most efficient fungicide, on the basis of its phenol coefficient. Others have confirmed these results. 3. Gentian violet, crystal violet and brilliant green restrained growth of fungi but were found to be less active as fungicides than as bactericides. Loos found brilliant green to be a most effective substance. 4. Mercurial products were effective both as fungistatic and as fungicidal agents. 5. Thymol, oil of cinnamon and oil of cloves were active in vitro. 6. Chlorine ( sodium hypochlorite ) was found by Emmons to be almost as effective a fungicide as iodine. That complete reliance cannot be placed on laboratory tests is indicated by the poor results recorded for sulfur and chrysarobin. It is well known from clinical experience that both these drugs are valuable fungicides. So- dium hydroxide proved to be a poor fungicide in vitro. When the various drugs just enumerated ( and many others ) are applied to skin it is at once apparent that there is marked variance in cutaneous tolerance to them. Thus, thymol must be used in high dilutions, and while its performance is excellent in vitro it is not quite so effective in clinical trial. The prescriptions which we shall present may be found useful. It must be reiterated that the patient should be treated as an individual, the strength of the drug and the choice of vehicle depending greatly on the personal requirements. It is customary to apply the medicament to the affected parts before retiring for the night. While this is usually the most convenient time, in many cases morning may be better. It is essential that the product be applied with pressure or massage, to insure the optimal effect. A smear or The Superficial Mycoses 131 a hast) application is almost useless. In many cases the preparation may be kept on the part day and night, being reapplied two Or three times during the 21 hours. 1. A clean, efficient application tor localized scaly noninflammatory inter- trigo consists ol 1 per cent tincture ol iodine. The majority of persons ma) use this daily without its causing irritation. 2. Compound ointment of benzoic acid (Whitfield's ointment) is made as follows: Benzoic acid 5 per cent Salicylic acid 3 per cent Soft paraffin 25 per rent Coconut nil ad. 100 per tent In hot climates 2 to 4 per cent hard paraffin may be added. This is the ointment as originally advised by Whitfield. In this country the salve is often compounded in the following manner: Salicylic acid 3 per cent Benzoic acid 6 per cent Hydrous wool fat, and , Petrolatum aa p.e. This is referred to as "full strength." If there is considerable inflammation (but no vesicles) it may be used half-strength or even quarter-strength. If one desires a strong keratolytic effect it may be prescribed in double or triple strength. In general, this prescription, or a modification (to be men- tioned ), should be used only on the interdigital webs, the palms or the soles. On the dorsa of the feet, on the glabrous skin or on the backs of the hands it too frequently produces secondary inflammatory changes (which often be- come eczematous ) to allow of its indiscriminate use on these parts. Various other drugs may be added to modify the formula, the most commonly employed being iodine and chrysarobin. Both increase the irri- tability of the skin. It is advisable to begin with 1 per cent iodine or 0.25 per cent chrysarobin, later increasing the strength of either or both. The vehicle also may be changed. White wax (2 to 10 per cent) may be added to diminish softening, particularly in hot weather. If alcohol is used, the strength of the active drugs should be decreased by one-third or more; a strength of 2 per cent salicylic acid and 3 per cent benzoic acid will be found potent. Aqueous solutions are not possible, owing to insolubility ol the drugs. 3. A modification of Dreuw's ointment according to the following formula is sometimes very effective. Rectified oil ol birch tar per cent Chrysarobin 1 per cent Salicylic acid per cent Soil soap, and Wool fa1 aa 12 per cent 132 An Introduction to Medical Mycology Because it is apt to produce secondary dermatitis, its use is somewhat restricted. When considerable inflammation is present, only a limited por- tion of the skin should be treated, so that if the condition is made worse, little harm is done. 4. The following prescription is usually well tolerated on the glabrous skin : Sulfur 6 per cent Salicylic acid 3 per cent Hydrous wool fat, and , Petrolatum aa p.e. The strength of both active ingredients may also be modified. 5. Mercurial products are mentioned because in vitro they show good restraining and fungicidal powers, although in clinical use they are rather disappointing. Phenyl mercuric nitrate provides an exception and at times is a useful fungicide. Levine found that it is best used in an oint- ment base in dilution of 1:1,500, when it is not a primary irritant. 6. Applied and allowed to dry on the affected skin, the following prep- aration has the advantage of being clean, and on the fortunate patient in whom pruritus is not induced it usually has a good clinical effect. It may be tried on vesicular lesions with caution. Thymol 1 per cent Salicylic acid 3 per cent Alcohol (90 per cent) q.s. 7. An aqueous solution of gentian violet ( 1 per cent ) has been mentioned as valuable when there is marked inflammation. It may also be painted on chronic soggy intertrigos (some of which are due to M. albicans). There is little penetrating power, and it is not suitable for the treatment of areas of hyperkeratosis. 8. Another paint, first described by and named after Castellani, is some- what irritating and must not be used on an acutely inflamed surface. It is effective as a fungicide and also possesses some keratolytic action. Saturated solution of basic fuchsin 10 Aqueous solution of phenol ( 5 per cent ) 100 Boric acid 1 Acetone 5 Resorcinol 10 Add the basic fuchsin to the solution of phenol and filter. Add the boric- acid, after two hours the acetone and after two more hours the resorcinol. The solution should be kept in a dark bottle. 9. In many instances, particularly if the patient is working, it is im- possible or inadvisable to have an ointment on the skin during the day. In this case a bath may be taken in the morning, followed by a liberal application of this powder. The Superficial Mycoses L33 Thymol I pei cent Boric arid 10 per cent Zinc oxide 20 pei cent Purified talc q.s. Its beneficial eflFect may be attributed « both to the active ingredients and to the value of any powder in combating perspiration. 10. A 10 per cent aqueous solution of silver nitrate is often effective if painted daily on localized macerated, fissured or exudative skin areas. Manx other drugs and prescriptions might be mentioned. Most of them, however, have little advantage except in providing a change, which is sometimes essential when the infection is long drawn out. The use of iontophoresis to introduce copper salts or other chemicals deep into the skin has been advocated. Greenwood and Rockwood found the method ineffective, a finding with which we concur. The use of soap and water is usually permissible. In most instances, the patient should be encouraged to bathe. However, when an acute inflam- matory condition exists, suspension of bathing, particularly with soap, may be best (see the section on prophylaxis for instructions on the care of the bathtub, p. 139). During the past few years many investigators have evaluated the action of tatty acids, known to be protective against bacteria, as therapeutic anti- fungal agents. Laboratory tests indicate a favorable effect, although clin- ical trial is somewhat disappointing. Most of the acids in the concentration advocated (5 to 15 per cent) are relatively nonirritating in ointments or powders, an advantage in the treatment of a highly sensitized skin. At this time, undecylenic acid appears to be somewhat more potent than pro- pionic acid and others of the fatty acid series. Hopkins and co-workers found undecylenic acid (5 per cent in carbowax, pH 6.8) to be the best local preparation in their extensive investigation. Muskatblit confirmed the lack of irritation from commercial preparations of undecylenic acid and salts. He thought this agent had some use in the therapy of tinea, al- though it was far from a superior fungicide. (2) Physical agents— There appears to be little if any advantage in the use of ultraviolet radiation. If the disease is of the inflammatory type, an induced reaction to ultraviolet rays may cause it to spread and to assume an eczematous character. Roentgen rays, while not in themselves fungicidal, are frequently of great help in cases of severe inflammatory involvement. They are impo- tent in instances of infection due to T. purpureum, and little if any favor- able effect will be obtained by directing them toward the interdigital webs. When there is an exudative inflammatory change the rays may be helpful either by aiding absorption of the exudate or by temporarily increasing the 134 An Introduction to Medical Mycology acidity of the tissues. It should be reiterated that roentgen rays are danger- ous unless employed with care and judgment and after study of the proper technic (see MacKee and Cipollaro, X-Rays and Radium in the Treatment of Diseases of the Skin). (3) Biologic methods.— The use of biologic products ( trichophytin ) in the treatment of fungous eruptions (particularly dermatophytids ) has been the subject of much investigation and subsequent discussion. Early reports (such as those of Van Dyck and others) were extremely optimistic. Sulz- berger and Wise expressed their enthusiastic belief that a new and useful method of curing recalcitrant lesions had been brought forward. They reported cases in which cutaneous allergy to species of Trichophyton had been relieved by desensitization. Subsequent investigation has produced sharply divided opinions, ranging from that of Traub and Tolmach, who expressed doubt that trichophytin is of any therapeutic value, to that of Robinson and Grauer, who have obtained spectacular results with autog- enous vaccines. Sulzberger later expressed his belief in the soundness of the conception of the principle of desensitization but admitted that the clinical response to treatment was poor. Combes and some others have held that the principle of desensitization is wrong, as a reduction in the immune forces may follow reduction in sensitivity. From our research, it seems that in most of the cases of actual fungous infection, an increase in sensitivity is desirable (provided this is linked up with acceleration of the immune forces). Thus, in the infections due to T. purpureum, the lack of reaction at the site of the trichophytin test after 48 hours is too frequent to be ig- nored as an explanation for the chronicity of this type of fungous disease. In dermatophytid, the condition should respond when the residual focus is eliminated. We believe that the diagnosis of dermatophytid is made much too often and that this reaction is relatively infrequent. The vesic- ular eruptions on the hands can be proved to be of mycotic origin in not more than one case in 10. In the cases in which theoretically trichophytin should be of service, it is unnecessary. In general, we do not at the present time advocate its use in treating either a definite fungous disease or an allergic manifestation (dermatophytid). This statement holds true for fungous infections due to any dermatophyte and in any site, including the scalp. Considering our results, we are unable to agree that the extravagant claims for one extensively advertised (South American) brand of trichophy- tin are justified. A rational therapeutic attack in another direction has been attempted. Weidman and Chambers noted that some interdigital webs were free from fungous disease, and were often able to isolate Bacillus subtilis from this site. Subsequent implantation of the cultural growth of B. subtilis on The Superficial Mycoses 135 the sites of interdigital fungous infection was followed l>\ clinical improve- ment. In studies along the same direction we were further influenced by the rapid overgrowth of many culture tubes by some of the common molds. Since 1941 we have had under observation in the laboratory a bacterial filtrate with a potent fungistatic capacity. This filtrate of Bacillus (subtilis) XG has shown promise of clinical value in the treatment of the superficial mycoses. From the reports of Tolmach and Lowenthal and of Hopkins and his co-workers, clavacin and some other antibiotics are also promising fungicides, although by no means superior to many of the standard rem- edies. It is of interest that Belisario some years ago found lemon juice to be an effective fungicide. The work of Peck indicates that ascorbic acid has definite fungicidal and fungistatic properties. (k) Treatment of nails.— In the main, the indications for treatment and the principles underlying it are the same for the nails as for the skin. Because there are minor differences and additional therapeutic procedures, the treatment of the nails is considered separately. If a fingernail is the site of an infection due to T. purpureum, it is prob- able that the feet and the toenails are also infected. Infection due to T. gypseum may usually be cured by a combination treatment consisting of scraping the nail and applying fungicides. Roentgen therapy is sometimes useful. Evulsion of one or two fingernails may be carried out provided there is no other evidence of infection. If the infection is due to T. purpureum, one is faced with a difficult ther- apeutic problem. The condition has probably been present for several months or even years, and infection of at least several nails is likely. There is probably also concomitant infection of the feet or of other regions. Com- plete evulsion of nails is not usually recommended here, as recurrence will almost invariably follow. Reliance must be placed on topical measures, after the nail has been scraped or as much nail substance as possible has been removed. If a sharp scalpel is available and the procedure is carried out with care, a surprising amount of nail can be removed without pain. Although there are important disadvantages to the office use of a burr powered by a small motor, its use has been gratifying in selected cases when patients purchased their own equipment and used it regularly to remove the infected nail material. One need not fear that the patient will destroy normal structures since pain will indicate when to stop. Newspapers should be spread over the floor to collect the material and a surgical mask should be worn. The topical application may be changed from time to time, and various medicaments may be used. (I) Complete surgical evulsion.— Evulsion of a fingernail is not difficult, 136 An Introduction to Medical Mycology but the proper technic should be carried out to the letter. We do not advise the evulsion of more than two or three fingernails. We almost never advise the evulsion of toenails because reinfection nearly always takes place and the procedure usually leaves the tissues so painful that the patient is kept from walking. Complete evulsion should not be considered when infection is due to M. albicans. After sterilization of the overlying and surrounding skin with tincture of iodine, the paronychial tissue is infiltrated with procaine hydrochloride. The free border of the nail is grasped with a pair of forceps, and by blunt dissection the nail is progressively separated from its bed. Care should be taken not to break up the friable nail or, when the lunula is reached, not to destroy or injure the nail bed, since this would prevent or interfere with the return of a normal nail. The last attachment of the nail should be sepa- rated by tearing it gently across. Sterile gauze is applied with pressure until all bleeding is arrested. This usually takes from 10 to 15 minutes. The region is then painted with a 1 per cent aqueous solution of gentian violet, and a loose dry gauze dressing is applied. Since exudation may be expected, the dressing should be changed in two hours. After this a daily change of dressings is usually sufficient. Gentian violet should be applied each time the dressing is changed and daily for five or six days, after which the dressing is usually omitted. We do not advise the use of an ointment after the evulsion, particularly while exudation is still to be noted. (2) Roentgen therapy.— When indicated, unfiltered roentgen radiation in fractional doses (90 roentgens) may be administered once weekly for six weeks. Further treatment is only given if cure is imminent. (3) Mechanical removal of infected nail tissue.— A great deal of diseased nail tissue may be removed by the physician or technician by successive peeling with a Bard-Parker knife. (If care is used, a sharp blade will do no harm and does save time.) It has become our practice to use this method more often than formerly, repeating the procedure every two or three weeks. We have become more confident of ultimate success and are rarely disappointed, even in infections due to T. purpureum. As mentioned previously, the use of a revolving burr is of value for the same purpose. How- ever it is difficult to sterilize and the infective material is widely dis- seminated. The patient should always be instructed to scrape the nail until the part becomes sensitive before any application. He may use a file or a piece of glass (the broken edge), and all removed nail should be collected on paper and burned. (4) Useful applications.— 1. Chrysarobin is probably the best single drug. It may be used in the strength of 20 per cent in collodion or 1 per cent in chloroform. There are other ways of using the drug, but these Fig. 45. Treatment of nails infected with fungi should include at least partial evulsion. \\ itli care, anesthesia is unnecessary. As much of the invaded nail as possible is cut away with a sharp scalpel. Medicinal agents then have more chance of direct action. The two top pic- tures show nails infected with M. albicans before and after partial evulsion. The two lower pictures arc oi nails infected with T. purpureum before and after the same procedure. 137 138 An Introduction to Medical Mycology are the cleanest and probably the most efficacious. It should be remem- bered that chrysarobin is a cutaneous irritant and should be confined to the nail. Unless care is exercised that none comes in contact with the eyes, conjunctivitis may occur. As with all applications, the old medica- ment must be scraped away before any more is applied. 2. Salicylic acid is combined with benzoic acid in a salve (double- strength Whitfield's ointment), the proportions usually being 6 per cent of the former to 12 per cent of the latter. The obvious disadvantage of any ointment is that a great part of it is rubbed off; its use therefore is not only wasteful and unpleasant but somewhat ineffective. In order that these objections may be overcome, the surrounding skin should be covered with petrolatum and an adhesive finger cot should be applied to cover the entire end of the finger. Another useful application is a 40 per cent salicylic acid plaster cut out to fit the nail and changed daily. We can attest to its efficiency and cleanliness. 3. Resorcinol alone is not of much value, but it is useful in combination with other drugs. 4. Thymol is a strong fungicide. Its use on the skin may be attended with considerable reaction, but one need not worry over that effect in the treatment of nails. Thymol (2 to 5 per cent) may be combined with resorcinol (10 per cent) in an ointment and applied under adhesive covering, as mentioned previously. 5. Gentian violet and other dyes are not particularly efficacious in treat- ing most cases of onychomycosis due to a species of Trichophyton. 6. We do not advise the use of copper sulfate as a soak to soften the nail. It has been recorded that in some instances gangrene has resulted from this treatment. In general we do not approve of the use of medicinal wet applications under an occlusive dressing for long periods, such as overnight. Softening of the nail may be partially secured by the careful application of potassium hydroxide ( 10 to 20 per cent ) . This may precede by half an hour or more the application of one of the remedies mentioned. Finally, the patient should be made to realize at the outset that cure will require his faithful co-operation. Several months' therapy is usually necessary before all the fungi are destroyed. (1) Prophylaxis.— The problem of prevention of infection with a patho- genic dermatophyte is difficult to solve. Many dermatologists believe that attempts to prevent infection are useless. It is their opinion that all the measures to be described and discussed here are of no avail and may even be harmful as tending to shift the emphasis to procedures which are time- consuming and of dubious benefit. The majority of uninfected persons are unwilling to be discommoded in any way when they have little conception The Superficial Mycoses L39 ol the serious consequences which sometimes occur. At times one en- counters persons who apparently have natural immunity, which may per- sist through life. Even those' with interdigital maceration ol the feet are frequently unconcerned or ignorant . regarding the actual or potential presence ol infection. Because ol the ignorance or carelessness of the majority of uninfected persons or ol those with latent involvement, certain measures to enhance protection to the public have been promulgated. It ma\ again he mentioned that the chronic type of deniiatophvtosis (T. purpureum) may he overlooked. The measures to he discussed are perhaps more generally necessary for patients who are in a state ol remission (the largest percentage) and for those who have been cured of an attack of dermatophytosis. Apparent immunity sometimes follows a severe attack, hot more frequently no im- munity is conferred. We believe that cure of the chronic form of dermato- phytosis is rarely accomplished and that relapse after an apparent cure is more common than reinfection. Certain hygienic rules should be applied in the treatment of every patient with dermatophytosis. He should be made conscious of his re- sponsibility to other members of his family and to those who use the same locker room, shower bath or gymnasium, whether at college, at a social club or at the less personal Turkish bath or sandy beach. The following discussion covers a few oi the many points. (1) Patients apparently cured.— These patients should receive the bene- fit of cultural studies. If results are negative, a prophylactic powder should be dusted on the skin after a daily bath, the skin having been carefully wiped dry. This treatment should be continued indefinitely. Thymol 1 per cent Salicylic acid 2 per cent Boric acid 3 per cent Purified talc q.s. (2) Patients under treatment.— 1. The shoes, slippers and other footwear should be sponged out every few weeks with a 10 per cent solution of formalin. They should not be worn for 24 hours after an application in order that contact dermatitis may be avoided. Henderson and also Ayres, Anderson and Youngblood have found formaldehyde vapor an effective means of fumigation. 2. Cotton socks worn by patients with tinea pedis should be boiled for 10 minutes or immersed for half an hour in a 1:1,000 solution of bichloride of mercury. They may then be washed with soap and water or sent to the laundry. Woolen and silk stockings may be ruined by boiling, but the use of formaldehyde vapor in a box will he found effective. 3. The bathtub used by a patient with dermatophytosis should be washed 140 An Introduction to Medical Mycology out with a 1:1,000 solution of bichloride of mercury or a 2:100 solution of cresol. A 5 per cent solution of formalin is also satisfactory. 4. The bath mat should be used only by the infected person. Once weekly it should be placed to soak in a 2 per cent solution of cresol and afterward washed. A newspaper spread over the bath mat should later be picked up and burned. 5. A patient may advantageously use paper slippers in walking to and from the bath. These may then be burned. Walking over rugs, carpets or bare floors may leave the infection for others to pick up. Pathogenic fungi may remain viable for several months. 6. It is unwise ever to scratch, pick or scrape an area of dermatophytosis with the fingernails. Most infections of the fingernails are thought to be derived directly from the feet. (.3) Uninfected persons. a. Individual measures. Although, as previously mentioned, some people appear to have natural immunity, the fact that one does not have an infec- tion is usually solely due to lack of contact with a pathogenic fungus. In order to remain free from dermatophytosis, one should observe the follow- ing precautions. 1. One should have a daily bath. The feet should be carefully dried, and purified talc, or better still a talc containing 1 per cent thymol, may be dusted liberally under and between the toes. If other members of the household are infected and use the tub, chlorine may be added to the bath water. 2. Loose and dead skin should be removed, and nails should be kept trimmed. Callosities should be treated. Fungi grow in horny material. 3. Attention should be given to flatfoot or other orthopedic conditions. These predispose to hyperhidrosis, which in turn favors invasion of a pathogenic fungus. 4. Hyperhidrosis may be relieved by roentgen therapy or by soaking the feet for two to 10 minutes daily in a 25 per cent solution of formalin. Only sufficient solution is placed in a basin to cover the sole and reach part way up the sides of the foot. The solution is too strong for the dorsum of the foot. 5. As a rule one should avoid public bathing places and Turkish baths. If possible, one should refrain from walking on carpets, rugs or bare floors. If in a hotel, one should walk to the bathroom in slippers and place newspaper on the bathroom floor to stand on. The tub or shower should be washed out with hot water if no antiseptic is available for this purpose. 6. If one visits a public beach or bathing resort or other place where exposure is likely, the feet should be painted as soon afterward as possible The Superficial Mycoses 141 with a 1 per cent aqueous solution ol gentian violet or 1 per cent tincture of iodine, particular attention being given to the inner and under surfaces of the toes. 7. One should avoid persons known, to have the disease. II a member of the family is infected, one 1 should sec* that he is under treatment, that he uses his own bath mat and towel, that he does not walk around in his bare feet and that the 1 tul) is washed out with an antiseptic after he uses it. b. Public health measures. Since one cannot depend entirely on individual responsibility and initiative, a number of attempts have been made to protect the uninfected by measures carried out by those in authority in various institutions. A commonly used method is to plaee a solution in a eonvenient place so that persons using a swimming pool will have to walk through it in passing to and from the pool. According to Claassen, sodium thiosulfate (10 per cent), which has been advocated, will support the growth of fungi in culture. Osborne has drawn attention to the fact that sodium thiosulfate if used near swimming pools is carried into the water and neutralizes the sodium hypochlorite, thus exposing the persons in the pool to bacterial con- tamination. Sodium hypochlorite (1 per cent), first advocated by Osborne and Hitchcock, seems to have more adherents. The solution must be changed frequently (every 48 hours). Sodium hypochlorite may be pur- chased from man\ r chemical houses in a 20 per cent solution and diluted with water in the ratio of 20:1 for use in the pans. Tile floors should be washed with a cresol solution once daily. Prophylaxis may be easily attained with a mild fungicidal powder, such as has been mentioned. It should be placed conveniently for use after the bath. Such a simple procedure as the daily application of a powder was advo- cated for general use to prevent dermatophytosis among the armed forces. Under conditions of active combat, a powder is more easily carried than ointment or liquid. A preparation containing 1 per cent thymol (fungicide), 2 per cent salicylic acid (keratolytic) and 3 per cent boric acid (to alter the pH) in talc is theoretically sound and has been found effective in practice. In many modern schools and colleges, students found harboring an active or latent fungous infection are excluded from the recreational facilities of the institution until the disease has been cured. BIBLIOGRAPHY Vjello, L.; Keeney, E. L., and Bhoyles, E. N.: Observation on incidence ol tinea pedis in group <)t men entering military life, Bull. Johns Hopkins Hosp. 77: HO. L945. Alexander, \.: Die Trichophytie der Hande und Fiisse, Mid. Klin. 18:1550, H)22. 142 An Introduction to Medical Mycology Andrews, G. C, and Machacek, G. F.: Pustular bacterids of hands and feet, Arch. Dennat. & Syph. 32:837, 1935. , and Birkman, F. W. : Fungous infections of feet: Observation of their incidence in a school in New York City, New York State J. Med. 31:1029, 1931. Ayres, S., Jr.; Anderson, N. P., and Youngrlood, E. M.: Fumigation as aid in control of superficial fungous infections, Arch. Dermat. & Syph. 24:283, 1937. Bang, H.: Sur une trichophytie cutanee a grands cercles causee par un dermatophyte nouveau, Trichophyton purpureum Bang, Ann. de dermat. et syph. 1:225, 1910. Bechet, P. E.: Treatment of dermatophytosis, New York State J. Med. 31:1456, 1931. Belisario, J. C: Mycotic infections and their treatment, Brit. M. J. 1:404, 1936. Berberian, D. A.: Dermatophytosis of feet: Sources and methods of prevention of reinfection, Arch. Dermat. & Syph. 38:367, 1938. Bloch, B.: Zur Lehre von den Dermatomykosen (klinisch-epidemiologische und experimen- tell-biologische Beitrage), Arch. f. Dermat. u. Syph. 93:157, 1908; Die Trichophytide, in Jadassohn, J.: Handbuch der Haut- und GeschlccJrtskrankheiten (Berlin: Julius Springer, 1928), vol. 11, pp. 564-606. Bonar, L., and Dreyer, D.: Studies on ringworm funguses with reference to public health problems, Am. J. Pub. Health 22:909, 1932. Brandt, T. : Beport on an epidemic of trichophytosis, Acta dermat. -venereol. 13:443, 1932. Caro, M. B.: Fungous infections of foot, J. A. M. A. 124:751, 1944. Carrion, A. L.: Observations on dermatomycosis in Porto Bico, Arch. Dermat. & Syph. 7:773, 1923; Observations on dermatomycosis in Puerto Bico: Beport on fungus commonly associated with foot dyshidrosis, Puerto Bico J. Pub. Health & Trop. Med. 5:278, 1930. Castellani, A.: Observations on new species of Epidermophyton found in tinea cruris, Brit. J. Dermat. 22:147, 1910; Carbol-fuchsin paints in treatment of certain cases of epidermo- phytosis, Am. Med. 23:351, 1928. Cleveland, D. E. H.: Ringworm of hands and feet, Canad. M. A. J. 17:68, 1927. Cremer, G. : Untersuchungen iiber die Epidermophytie der Fiisse und Hande in Amsterdam, Arch. f. Dermat. u. Syph. 169:244, 1933. Darier, J.: Dysidrosis: Its parasitic nature, Lancet 2:578, 1919. Djelaleddin-Moukhtar: De la trichophytie des regions palmair.es et plantaires, Ann. de "dermat. et syph. 3:885, 1892. Ellis, F. A.: Pustular psoriasis: Its relation to acrodermatitis continua vel perstans, Arch. Dermat. & Syph. 33:963, 1936. Emmons, C. W.: Pleomorphism and variation in dermatophytes, Arch. Dermat. & Syph. 25:987, 1932; Fungicidal action of some common disinfectants on two dermatophytes, ibid. 28:15, 1933. Epstein, E.; Lewis, G. M.; Loveman, A. B.; Pillsbury, D. M.; Schoch, A. G; Shelmire, B.; Smith, D. C; Swartz, J. H., and Wieder, L. M.: Symposium on practical management of eczematous ringworm of hands and feet ("athlete's foot"— dermatophytosis and dermatophy- tids), J. Invest. Dermat. 3:523, 1940. Fernet, P., and Boyer, P.: Le traitement externe des epidermomvcoses, Progres med., p. 2088, 1933. Foster, M.: Favus and ringworm of nails, J. A. M. A. 63:640, 1914. Francis, E.: Phenol-camphor for "athlete's foot," J. A. M. A. 117:1973, 1941. Gilman, B. L.: Incidence of ringworm of feet in university group: Control and treatment, J. A. M. A. 100:715, 1933; Practical points in treatment of ringworm, M. J. & Bee. 137:369, 1933. Glaze, A.: Treatment of epidermomvcoses of feet and hands. South. M. J. 17:643, 1924. Glenn, W. R., and Hailey, H. E.: Fungous infections of feet treated with camphor-phenol mixture, Arch. Dermat. & Syph. 47:239, 1943. Goij>man, L.: Prevention ol infection and relapse in fungus disease ol feet, Ohio State M. J. 34:405, 1938. Gonzalez, U. J.: Ringworm of the soles in Mexico: Clinical study, Arch. Dermat. & Syph. 21:909, 1930. Gould, A. G, and Garter, E. K.: Fungistasis in ringworm of toes and feel: I. Salicylic and benzoic acids. Arch. Dennat. & Syph. 22:225, 1930; II. Two per cent mercurochrome-220 soluble and liquor hexylresorcinolis 1:1.000 (ST 37), ibid. 25:348, 1932. Con. i). \Y. J. : Ringworm of feet, J. A. M. A. 96:1300, 1031. The Superficial Mycoses 143 Greenwood, a. \1.: Epidermophytosis, Boston M. & S, J. L87:178, \ i )22. , a\i> lux kwood, E. M.: tontophoresis ol copper sulfate in cases "I proved mycotic infec tions, Arch. DniH.it. & Syph. 1 1:800, L941. Guy, \\. II., ami Jacob, F. M.: Epidermophytosis: Sequel to vaccination, Arch. Dermat. & Syph. 12:233, L925; Differential diagnosis "I parasitic infections "I hands and Feet, Pennsyl- vania M. J. 26:384, L923. Hartzell, M. B.: Eczematoid ringworm, particularl) ol hands ami Feet, Am. J. M. Sc. L49:96, 1915. Henderson, V: Fungus infection of feet: Fumigation of shoes with Formaldehyde as means of treatment, Arch. Dermat. & Syph. 20:710, 1932. Highman, W. J.: Epidermophytosis and epidermophytids ol hands, |. A. \l. A. 95:1158, 1930. Hodges, R. S.: Ringworm of nails. Arch. Dermat. & Syph. 4:1, 1921. Hopkins, J. G.: Ringworm and moniliasis: Their differential diagnosis, Pennsylvania \I. |. 11: 155, 1938. ; Fisher, J. K.; Hillegas, A. B.; Ledin, B.; Rebell, G. C., and Camp, E.: Fungistatic agents lor treatment of dermatophytosis, J. Invest. Dermat. 7:239, 1946. . ; I In ii (.as, A. B.; Ledin, R. B.; Rebell, G. C., and Camp, E.: Dermatophytosis at an infantry post: Incidence and characteristics of infections bv three species of fungi, J. Invest. Dermat. 8:291, 1947. Hulsey, S. II., and Jordan, F. M.i Ringworm of toes as found in university students, Am. J. M. Se. 169:267, 1925. Hutchtns. M. B.: Contribution to treatment of phytosis of feet, Arch. Dermat. c\ Syph. 6:761, 1922. Jadassohn. W., and Peck, S. M.: Epidermophytide der Hande, Arch. f. Dermat. u. Syph. 158:16, 1929. Jamieson, R. C, and McCrea, A.: Recurrence or reinfection in ringworm of hands and of feet, Arch. Dermat. & Syph. 25:321, 1932; Shoes: Source of reinfection in ringworm of feet, ibid. 35:203, 1937; Ringworm of feet: Shoes and slippers as source of reinfection: Final report, ibid. 44:837, 1941. Karrenberg, C. L.: Present state of epidermophytosis in Europe, Arch. Dermat. 6c Syph. 17:519, 1928. Kaufman-Wolf, M.: Ueber Pilzerkranknngen der Hande und Fiisse, Dermat. Ztschr. 21:385, 1914. Kegel, A. H.: Fungi of "ringworm" group isolated from handles of clubs used on miniature golf courses, Bull. Chicago School San. Instr. 25:1, 1931. Kesten, B. M.; Ashford, B. K.; Benham, R. W.; Emmons, C. W., and Moss, M. C: Fungus infections of skin and its appendages occurring in Porto Rico: Clinical and myco- logic study, Arch. Dermat. & Syph. 25:1046, 1932. Kingery, L. B., and Adkisson, A.: Certain volatile oils and stearoptens as fungicides, Arch. Dermat. & Syph. 17:499, 1928. ; Williams, R., and Woodward, G.: Further studies in fungicides: Comparative evalua- tion of phenol derivatives by modified laboratory procedure, ibid. 31:452, 1935. Kirby-Smith, J. L.: Trichophytosis: Dermatological problem in Southern states, South. M. J. 20:606, 1927. Kittredge, H. E.: Trichophytosis including onychomycosis universalis simulating tinea im- bricata, Arch. Dermat. & Syph. 27:607, 1933; Onychomycosis universalis tiichophytina et epidermophyta: Report of seventh case thus far recorded in English, ibid. 34:398, 1936. Kurotchkin, T. J., and Chen, F. K.: Study of etiology of Hongkong loot, Nat. M. |. China 16:556, 1930. Lane, J. E.: Ringworm of hands and feet, Boston M. & S. J. 174:271, 1916. Legge, R. T.; Bonar, L., and Templeton, H. J.: Ringworm of feet, J. A. M. A. 92:1507, 1929; Incidence of foot ringworm among college students, ibid. 93:170, 1929; Epidermo- mycosis at University of California, Arch. Dermat. & Syph. 27:12. 1933 and 29:521, 1934. Lf.hmann, C. F.: Acute vesicular eruptions of hands and feet, Arch. Dermat. & Syph. 21:449, 1930. Levin, O. L., and Silvers, S. II.: Possible explanation for localization ol ringworm infection between toes, Arch. Dermat. & Syph. 26:466, 1932. Levine, B.: Use of phenvlmercuric nitrate in tinea and yeast infections ol skin, J. A. M. A. 101:2109, 1933. 144 An Introduction to Medical Mycology Lewis, G. M., and Hopper, M. E.: Concurrent, combined and consecutive fungous infections of skin, Arch. Dermat. & Syph. 47:27, 1943. ; Hopper, M. E., and Schultz, S.: In vitro fungistasis by a Bacterium (Bacillus subtilis var. XG and XV), Arch. Dermat. & Syph. 54:300, 1946. -; Montgomery, R. M., and Hopper, M. E.: Cutaneous manifestations of Trichophyton purpureum (Bang), Arch. Dermat. & Syph. 37:823, 1938. Lieberthal, D., and Lieberthal, E. P.: Epidermomycosis and flatfoot, Arch. Dermat. & Syph. 29:356, 1934. Loos, H. O.: Zur Bekampfung der Epidermophytie der Fiisse und Hande, Arch. f. Dermat. u. Syph. 170:602, 1934; abstracted in J. A. M. A. 104:264, 1935. Low, R. C: Fungus infection of finger nails, Edinburgh M. J. 6:121, 1911. McCrea, A.: Parasitic fungi of skin, J. Trop. Med. 34:204, 1931. MacKee, G. M., and Lewis, G. M.: Keratolysis exfoliativa and mosaic fungus, Arch. Dermat. & Syph. 23:445, 1931. Miescher, G.: Trichophytien und Epidermophytien, in Jadassohn, J.: Handbuch der Haut- und Geschlechtskrankheiten (Berlin: Julius Springer, 1928), vol. 11, pp. 378-563. Mitchell, J. H.: Further studies on ringworm of hands and feet, Arch. Dermat. & Syph. 5.174, 1922; Need for research in treatment of epidermophytosis, J. A. M. A. 89:421, 1927; Streptococcic infection simulating ringworm of hands and feet, ibid. 104:1220, 1935. Muskatblit, E.: Ringworm of toes in students and dispensary patients, New York State J. Med. 33:632, 1933; Observations on Epidermophyton rubrum or Trichophyton purpureum, Mycologia 25:109, 1933. •: Clinical evaluation of undecylenic acid as fungicide, Arch. Dermat. & Syph. 56:256, 1947. Ohmsby, O. S., and Mitchell, J. H.: Ringworm of hands and feet, J. A. M. A. 67:711, 1916. Osborne, E. D., and Hitchcock, B. S.: Prophylaxis of ringworm of feet, J. A. M. A. 97:453, 1931. Pardo-Castello, V.: Diseases of the Nails (2d ed.; Springfield, 111.: Charles C Thomas, Publisher, 1941). Peck, S. M.: Epidermophytosis of feet and epidermophytids of hands, Arch. Dermat. & Syph. 22:40, 1930. ■ , and Rosenfeld, H.: Effects of hydrogen ion concentration, fatty acids and vitamin C on growth of fungi, J. Invest. Dermat. 1:237, 1938. -; Rosenfeld, H.; Leifer, W., and Bierman, W.: Role of sweat as fungicide, with special reference to use of constituents of sweat in therapy of fungous infection, Arch. Dermat. & Syph. 39:126, 1939. Pollitzer, S.: Recurrent eczematoid affection of the hands, J. Cutan. Dis. 30:716, 1912. Priestley, H.: Ringworm and allied parasitic skin diseases in Australia, M. J. Australia 2:471, 1917. Rajka, E.: Zur Aetiologie der Dyshidrose, Arch. f. Dermat. u. Syph. 143:204, 1923. Reiss, F., and Graham, J. B.: Absence of thromboangiitis obliterans in experimental der- matophytosis, J. Invest. Dermat. 7:127, 1946. Rucgi.es, E. W.: Therapeutic suggestions regarding treatment of affections of hands and feet, Arch. Dermat. & Syph. 5:462, 1922. Schamberg, J. F., and Kolmer, J. A.: Studies in chemotherapy of fungous infections, Arch. Dermat. & Syph. 6:746, 1922. ; Brown, H., and Harkins, M. J.: Chemotherapy of ringworm infections, Arch. Dermat. & Syph. 24:1033, 1931. ScHOLTZ, M.: Epidermophytids as a clinical conception, Arch. Dermat. & Syph. 25:812, 1932. Semon, II. C: Tinea unguium, Brit. J. Dermat. 34:397, 1922. Sharp, W. B., and Taylor, E. K.: Interdigital ringworm control among students, J. Prev. Med. 2:485, 1928. Spring, D.: Morphologic variations within same species of dermatophyte, as observed in hanging drop cultures, Arch. Dermat. & Syph. 23:1076, 1931; Heterothallism among der- matophytes, ibid. 24:22, 1931. Sthickeer, A.: Fungicidal properties of certain clinically recognized fungicides, Arch. Dermat. & Syph. 28:836, 1933. — •, and Friedman, R.: Symptomatic and asymptomatic ringworm <>l feet. Arch. Dermal. & Syph. 24:430, 1931. The Superficial Mycoses 145 . wi> McKekveb, W. ll.: Recurrence ol infection oi Feet due to ringworm Fungus, Vrch. Dermat & Syph. 29:526, L934 : Ozeixers, 1'.. \. \m> Zaj i n i .. H. I'.: Modern interpretation oi mycotic infections oi feet and hands, Arch. Dermat. & Syph. 25:1028, 1932. s. i i,.N, R, L., Jr.: Gentian violet as therapeutic agent, J. A. \l. V 110:1733, L938. Takahamii. S.: Contribution to knowledge <>l dysidrosis, |ap. |. Dermat. & Urol. 25:38, 1925. 1i;\ih. !•'.. \\, and Tolmach, |. A.: Erysipelas-like eruption comphcating dermatophytosis, J. A. \l. \. 108:2187, L937. Weedman, F. 1).: Laboratory aspects "I epidermophytosis, \rch. Dermat. c\ Syph. L5:415, I927j Dermatophytosis, the newer ringworm, J. A. \1. A. 90:499, L928. . wi> CiivMiu-Hs, S. 1).: Fungistatic strain of Bacillus subtilis isolated Froi rmal toes, \u li. Dermat. & Syph. 18:568, 1928. Emmons, C. W.; Hopkins, J. G., \m> Lewis, G. M.: The war and dermatophytosis, J. A. M. A. 128:805, l l )T>. \\m ik, C: Studies in mycotic dermatitis: II. Mycotic inguinal lymphadenitis associated with superficial fungus dermatitis ..) Feet, Arch. Dermat. & Syph. 18:271, 1928; Dermatophytosis of extremities associated with peripheral occlusive endocarditis, f. A. M. A. 90:1865, 1928; \ntoinoeulation dermatophytosis from toe cultures: Clinical, laboratory, experimental and therapeutic studies in superficial mycotic dermatitis, Arch. Dermat. & Syph. 20:315, 1929. White, C. J.: Question ol Epidermophyton infection, problem in dermatological diagnosis; J. Cutan. Dis. 37:501, 1919; Fungous diseases of skin: Clinical aspects and treatment, Arch. Dermat. & Syph. 15:387, 1927. — -, and Greenwood, A. M.: Epidermophytosis, J. A. M. A. 77:1297, 1921. \\ hi i field, A., and Sabouraud, R.: Eczematoid ringworm of extremities and groin (with dis- cussion), Brit. J. Dermat. 23:375, 1911. Wieder, L. M.: Fungistatic and fungicidal effects of two wood-preserving chemicals on human dermatophytes, Arch. Dermat. & Syph. 31:644, 1935. Williams, G. M.: Diagnosis of some eruptions on hands and feet, Arch. Dermat. & Syph. 5:161, 1922; Dermatophytid complicating dermatophytosis of glabrous skin, ibid. 13:661, 192fi; Enlarging conception of dermatophytosis, ibid. 15:451, 1927. — ■, and Barthel, E. A.: Tinea of toenails as source of reinfection in tinea of feet, J: A. M. A. 93:907, 1929. Williams, ]. W.: Incidence of dermatophytosis at Boston City Hospital, Arch. Dermat. & Syph. 33:335, 1936. \\ ii son, D. J.: Dermatomycosis and the soldier, Arch. Dermat. & Syph. 30:841, 1934. Wise, F., \m> Wolf, Jy: Dermatophytosis and dermatophytids, Arch. Dermat. & Syph. 34:1, 1936. 6. MONILIASIS This disease syndrome embraces a number of manifestations which until recently were considered to be unrelated. Although the skin is the most common site, the infection may invade the lungs and, rarely, other organs. The causative fungus is a yeastlike organism, Monilia ( Candida) albicans. (a) Historical survey.— In 1839 Langcnbeck demonstrated fungi in material taken from a patient with thrush. Robin published a description of the micro-organism in 1843 and named it Oidium albicans. The vari- ous manifestations of the disease were recognized and studied by different investigators, and an involved nomenclature came into use. Through the work of Kaufman-Wolf, Fabry, Kumer, Ravaut, Hopkins. Benham and others, the relationships of the various rashes and conditions have been better understood. Schambcrg, in 1915, was one ol the first in the 146 An Introduction to Medical Mycology United States to report a case of generalized cutaneous thrush. Engman in 1920 described a case of moniliasis localized to the upper parts of the thighs, the vulva and the inframammary regions. The article by Shelmire and that by Beeson and Church were also early contributions. (b) Etiology.— The causative micro-organism, M. albicans, is seldom if ever found on the normal skin. Other yeastlike fungi should not be confused. The organism is a common inhabitant of the gastrointestinal tract, where it may produce no symptoms. While it was formerly consid- ered, mainly through the investigations of Ashford, to be of etiologic significance in sprue, later research does not appear to bear out such a relationship. The incidence of infection increases with age. There is a more or less corresponding increase with age in the involvement of the gastrointestinal tract. Relapse of cutaneous lesions may take place when a systemic or de- bilitating illness is experienced. The resistance of the patient to M. albi- cans is decreased by diabetes, probably because the storing of sugar favors the growth of the organism. We have noted that a large percentage oi the patients with different types of cutaneous moniliasis are obese. The organism is more apt to find suitable soil in persons whose skin is macer- ated by frequent or prolonged immersion in water. Profuse sweating may be followed by moniliasis. Housewives, bartenders, waiters and bakers appear to be more prone to the condition because of their occupations. The organism is probably of weak pathogenicity, but once the disease state is established, through a letdown in the natural immune forces, the condition is apt to persist indefinitely. The organism multiplies rapidly; it may be isolated from such diseased tissues as those of carcinoma, and it may be found in the sputum of a patient approaching death. In such instances, one must be careful to differentiate between the saprophytic and the pathogenic significance. It is probable that the virulence of M. albicans may so increase that the fungus is capable of causing an infection without any apparent predisposing factor. The series of cases of perleche of children in an orphanage, as reported by Finnerud, mav be cited as a possible example. (c) The clinical syndrome.— The manifestations of M. albicans may be grouped as (1) localized, (2) of moniliid type, (3) generalized cu- taneous and (4) systemic. (1) Localized forms. a. Onychia and paronychia. It is chiefly the fingers which are affected, although we have observed instances of infection of the toenails. There mav be involvement oi only owe digit, but multiple infections are more frequently seen. The paronychia] tissues are usually the first to be involved, Fig. 16. Moniliasis of the Feet and hands. A. acute exudative soggy vesiculobullous in- fection. B. chronic thickened scaly rash with moist intertriginous involvement of all the webs. C, eruption spreading to sides and dorsa of feet. D and E, onychia and paronychia. The changes ol the nail maj be ^\\u- to nutritional conditions. Invasion of the nail at the sides is lather typical of M. albicans. F, erosio interdigitalis blastomycetica or intertrigo <>f a finger web. i \ and C, courtesy of Royal Montgomery. I 1 1; 148 An Introduction to Medical Mycology and the condition may appear not unlike a pyogenic infection. There is usually little or no pain except on pressure, but sometimes the parts throb. No pus will be found if the tissues are incised; a thin purulent discharge may appear under the nail fold. In the nail, transverse ridges are noticed. The nail remains hard but gradually becomes thickened and distorted, particularly at the edges. The color may not change or it may become brownish. Usually the shine is unaffected. The proximal portions or the edges of the nail sometimes become eroded. It is at once apparent that the cardinal signs of tinea unguium, namely, crumbling, yellow color and loss of luster together with lack of paronychia, readily distinguish the two conditions. b. Intertrigo. Well defined, bright red, exuding patches with scalloped borders give a fairly characteristic picture of monilial intertrigo. Outside the zone of intertrigo, small flaccid vesicopustules may be noted. There is usually a bright red border of skin around the satellite lesions. According to Hopkins, these represent the primary lesions from which intertrigos develop. The common sites of monilial intertrigo are the axillae, the infra- mammary folds, the groins, the umbilicus, the interdigital webs of the feet and the intergluteal fold. The process may extend from a primarily intertriginous location to the flat skin, and large sheets of skin of a suscep- tible person may be affected. It may be pointed out that interdigital in- volvement of the toes may be mistaken for dermatophytosis caused by filamentous fungi. In case M. albicans is the cause, all the webs of the toes are usually involved. A bright red color and soreness with satellite vesicopustules also favor a diagnosis of moniliasis. Lesions of a similar na- ture on the hands and at the angles of the mouth have distinct names. c. Erosio interdigitalis blastomycetica. This form of intertrigo affects the interdigital webs of the hands (usually the third or fourth). The lesion has a bright red base with a moist surface and a peeling border. The lesions are tender rather than itching. d. Perleche. This type of intertrigo affects the angles of the mouth. The base is bright red, the surface may show a pellicle of skin, and fissures commonly develop. Some cases of perleche are said to be due to infection with streptococci. Avitaminosis may be a predisposing factor. e. Asymptomatic gastrointestinal form. The presence of M. albicans in the saliva or in the stools of patients with no symptoms referable to this and with no concomitant involvement of the skin suggests that many persons are carriers. With many forms of moniliasis of the skin, organisms can also be located in the gastrointestinal excreta. In the treatment of perleche, cure is often difficult unless the mouth is treated at the same time. f. Intraoral thrush. Thrush is most commonly seen in infants and some- I Hit m it Fig. 47. Moniliasis, showing types of involvement of the skin. A and B, perleche. C, beefy-red, smooth tongue. D and E, inframammary intertrigo; note the outlying satellite lesions. F, intertrigo in the inguinal region. G and H, intertrigo of the axilla. 149 150 An Introduction to Medical Mycology times ill babies only a few days old. A whitish, loosely adherent membrane is attached to the inner surface of the cheeks or to the palate and sometimes to other portions of the oral mucosa. g. Superficial glossitis. This is manifested by a beefy-red, smooth, some- times mottled or enlarged, tongue. Stomatitis is often associated. h. Water bed dermatitis. Kumer and others noted that many patients acquired an eruption when kept in continuous baths, when wet applications of bland nature were applied over long periods or occasionally when occlu- sive dressings were left on a part for a considerable time. The affected skin is macerated and peels off, a red base may be noted, and satellite vesicopus- tules may be present. It is to be noted that other yeastlike micro-organisms may be present, and, as with M. albicans, they may be living a solely sapro- phytic existence. i. Eczema. White and others have noted the occurrence of yeastlike organisms in cases of typical infantile eczema. There is some doubt as to whether M. albicans is able to cause this type of response. Many instances of secondary cutaneous thrush (in children) or of moniliids may be mis- takenly considered to be eczema. j. Vaginitis. The finding of M. albicans in the vagina does not neces- sarily denote more than an asymptomatic involvement. There is little doubt, however, that the organism may produce vaginitis with a low grade inflammatory response accompanied by a thin discharge. Pregnancy and diabetes are considered to be important conditioning states. Pruritus may be a troublesome symptom. Rubbing and scratching often lead to sec- ondary pyogenic infection and eczematization, either or both of which may become sufficiently severe to mask the original infection. It is believed that thrush in newborn infants may be secondary to infection of the vagina. k. Pruritus ani. In cases of severe itching, when one notes considerable maceration around the anal orifice, M. albicans may be the cause. More than one of the localized types of infection may be present in the same patient. (2) Moniliids, or levu rides. —Sterile vesicular lesions on the hands and localized or widespread erythematous vesicular exudative patches caused by dissemination through the blood stream of products of M. albicans have been described by Ravaut and others. According to Hopkins, certain cases of miliaria are due to M. albicans. The condition is probably a moniliid, although Hopkins found the organism in some of the lesions. A focus may be found elsewhere on the skin, but according to Hopkins the gastrointes- tinal tract is a frequent site. The diagnosis of moniliid of the hands is similar to that of trichophytid. Sometimes the absence of a fungous focus on the feet will make one suspicious of moniliid (rather than trichophytid). FlG. 48. Moniliasis of generalized type, showing discrete Hat pustules, exudative inflam- matory patches (suggestive of seborrheic eczema), perleche, beefy tongue with membranous plaques and diffuse loss oi hair on the scalp and eyebrows. The fingers, toes and other parts ol the bod) were also affected. {Courtesy of Wilbert Sachs.) \~\ 152 An Introduction to Medical Mycology (3) Generalized cutaneous forms.— A fortunately uncommon manifesta- tion seen in children is the type in which the hair of the scalp is sparse and the scalp partially inflamed, with perleche and glossitis present as well as other types of localized infection. The patient also may exhibit widespread eruptions of the glabrous skin. Characteristic flat pustules may be observed in some part of the eruption. The infection may last for many years and be extremely resistant to therapy, and in some instances the outcome may be fatal. (4) Systemic forms.— Greenwood and Rockwood and others have re- ported instances of fatal systemic infection. This may be superimposed on the type just discussed. Involvement of the meninges has been de- scribed. In some instances bronchitis has also been considered to have a monilial source. The finding of Monilia in the sputum in cases of suspected bronchial moniliasis is not sufficient to establish a definite diagnosis, since the organism is often present in the mouth and in the gastrointestinal tract. In a patient with symptoms referable to the lungs, when repeated tests for the tubercle bacillus have been fruitless, a mycotic disorder may be sus- pected. The roentgenogram showing a mycotic disease of the lungs may reveal shadows and densities of varying degree, often confined to the base. Since the exact diagnosis is not a purely theoretic problem, in case of doubt specimens should be obtained after bronchoscope study. It should also be remembered that yeastlike fungi are notorious secondary invaders; their presence in diseased tissue does not always mean that they are responsible for the disease. The presence of M. albicans in diseased tissue is not always sufficient evidence of its pathogenicity, and in some cases the cause of the condition is difficult to ascertain. It is often necessary to study a patient for some time before a definite diagnosis can be made. Castellani de- scribed monilial bronchitis affecting tea-tasters of Ceylon. This is a rela- tively banal infection with periodic flare-ups of a productive cough lasting for years but finally disappearing spontaneously. More severe infections of bronchopneumonic type are uncommon. A presumptive diagnosis is in order after repeated examinations (including gastric washings) have been negative for tubercle bacilli if massive amounts of the fungus are observed in the sputum on several occasions. Joachim and Polayes reported the case of a white man, 48, who had been addicted to the use of morphine and heroin for 20 years. For 18 months he injected the drug intravenously. Systemic manifestations developed and he finally died of subacute endo- carditis. A species of Monilia was obtained in blood cultures and from vegetations on the heart valves. Wikler and his associates also reported the case of a drug addict who died of mycotic endocarditis, the organism being M. parapsilosis. The Superficial Mycoses 153 (d) Histology.— It is advisable to scrape the biopsy material For cult inc. Mycelium is sometimes demonstrable in section but a diagnosis on tin's alone is impossible. The findings arc usually those of a chronic inflammation with round cells and occasional giant, cells. (e) Differentia] diagnosis.— Usually, little difficulty is encountered in recognizing tlic localized forms of moniliasis and distinguishing them from similar disorders. Intertrigo of the feet may occasionally be puzzling, and areas ol widespread involvement, especially if they have been overtreated, ina\ be difficult to recognize at first. Pyodennic infection and tinea due to Trichophyton are easily' distinguished by the acute painful paronychia associated with the former and by the lack of paronychia and the presence of a yellow triable nail with the latter. The moniliids are not as definite an entity as one would desire, and the diagnosis must frequently be ascer- tained by the exclusion of other diseases. Severe generalized involvement should not be confused with any other disorder, although in some instances it is mistaken for seborrheic eczema, and there may be slight resemblance to disseminated neurodermatitis (atopic eczema). The greasy scales of the former and the hchenification present in some areas of the latter, together with the lack of flaccid vesicopustules and negative results of cultural studies should be sufficient to distinguish these diseases. The oidiomycin test is of no value in differential diagnosis. Demonstration of the organ- isms in culture from lesions of moniliasis is usually readily accomplished. As mentioned previously, tuberculosis must be distinguished from mondial bronchomycosis. (f) Prognosis.— Patients with any form of moniliasis should be con- sidered potentially diabetic. The infection may be the first manifestation of diabetes. The local varieties usually respond to treatment, but relapse may occur. It is difficult to eradicate the micro-organism from the gastro- intestinal tract. Generalized involvement and moniliids are resistant to therapy, and cure may require months or years. When infection is general- ized, the prognosis should be reserved; in cases of systemic involvement the outcome is often fatal. (g) Treatment. (I) General instructions.— If it is to be comprehensive and permanently effective, therapy should be directed toward the eradication of all foci, both in the skin and in the gastrointestinal tract. Unfortunately, treatment of the latter is not highly effective. Infection caused by M. albicans calls for urinalysis, to determine whether an otherwise asymptomatic glycosuria is present. The treatment of infections of the skin caused by M. albicans depends partly on the site of the disorder and partly on the individual patient. 154 An Introduction to Medical Mycology When the hands are affected, it is important to keep them from frequent immersion in water. The use of cotton and rubber gloves may protect them to some degree. Improvement in hygiene may be helpful in preventing the development of lesions. Multivitamin supplement to the diet is indi- cated. We have not had much success with low caloric diets. Most of our patients did not wish to reduce their weight. Hopkins noted that a patient with generalized cutaneous moniliasis and with involvement of the gastrointestinal tract improved while on a diet free from bread, cereals, potatoes and other starchy vegetables and with the use of dextrose instead of cane sugar. Magnesium carbonate and calcium carbonate were given in large doses. (2) Local treatment with gentian violet.— Churchman first introduced this substance as effective in the treatment of infections caused by gram- positive organisms. Gomez-Vega noted that the growth of organisms of the genera Monilia and Torula, when tested in vitro, was inhibited in dilutions of 1:1,000,000 of gentian and methyl violet. Cornbleet found gentian violet more effective when followed by an application of Gram's solution of iodine. W 7 e subscribe to the opinion of many observers that a 1 per cent aqueous solution of gentian violet is probably the best single topical remedy against Monilia infections of the skin. It may also be used in the treatment of oral thrush. We have used it with success in supposi- tories (2 gr. |0.13 Gm.] to each) in the treatment of monilial vaginitis and pruritus ani due to M. albicans. The chemical may also be incorporated in zinc paste. Sutton has written a comprehensive article on the uses of gentian violet in dermatology. (S) Local treatment with other applications.— Many other advocated local remedies are useful in certain instances. Wet dressings are almost always well tolerated and are often an acceptable means of beginning treatment. A solution of 1:2,000 potassium permanganate or a 1:5,000 solution of perchloride of mercury applied for a few days in continuous wet dressings to areas of local infection often brings about considerable clinical improvement. Sodium perborate as a mouthwash and a 1 per cent solution of silver nitrate in nitrous ether have proved of value in many instances of monilial intertrigo. Ormsby recommended chrysarobin in strengths of 5 to 10 per cent, tincture of iodine or an ointment con- taining salicylic and benzoic acids. Mercurial preparations, such as am- moniated mercury ointment (3 to 10 per cent), are more effective against moniliasis than against ringworm infections. Soothing applications, such as zinc oxide lotion or wet compresses of boric acid, are sometimes neces- sary when acute inflammation is present. (4) Roentgen therapy.— Roentgen raws are useful in the treatment of The Superficial Mycoses 155 paronychia and onychia and arc also sometimes effective in the treatment ol perleche. The usual dose is 90 roentgens administered without filtration once weekly for four to six treatments. (5) Treatment with iodides.— We have had limited experience in the administration of potassium iodide by mouth in the treatment of the local- ized forms of moniliasis. In some instances we have given the medication to the point of evidence of intolerance. Our results, however, have not been conclusive, and we have not observed any ernes. Lugol's solution diluted one-hall with water is a nonirritating application which we have used suc- cessfully in the treatment ol oral thrush as well as in other types of monilia- sis. In an apparently hopeless ease of the systemic type of moniliasis ob- served b\ MacKee, M. albicans was isolated from the skin, gastrointestinal tract and sputum. Treatment by topical applications of gentian violet to- gether with daily inhalations of ethyl iodide according to the method of Swart/, resulted in marked clinical improvement. When last observed, the patient was in excellent condition. (6) Vaccine, therapy. —There are not many reports in the literature re- garding the efficacy of this form of therapy. Sulzberger and Wise and later Kerr, Pascher and Sulzberger reported successful quantitative intracu- taneous therapeutic desensitizations with Trichophyton and Monilia ex- tracts, alone and in combination. Olah tried autovaccine therapy without success in cases of onychia and paronychia. In a series of 48 patients, we used intracutaneous injections of oidio- mycin. The patients received from six to 44 injections, the average num- ber being 11. The vaccine was administered in dilutions of 1:1,000 to 1:500, 1:100 and 1:50, beginning with the more dilute and proceeding to the more concentrated doses. The patients were given a bland applica- tion for topical use, for the most part a colored petrolatum. No absolute cures were noted, but there was an apparent improvement in the condition of a few of the patients. In the great majority of cases no improvement was noted. In no case was there any harmful complication, such as an exacerbation of the eruption or a focal reaction. (7) Other measures.— When the infection is severe, attention to the gen- eral health and measures to build up bodily resistance, such as vitamin therapy, a nutritious diet and added rest, may be of primary importance. In the treatment of Monilia infection of the nail the patient should be told to avoid soaking the hands in water, particularly with soap, to avoid the peeling of unwashed vegetables and to dry the skin carefully after washing the hands. If possible, a housewife should arrange to do all the scrubbing or washing at one time of the day. Roentgen therapy may be used. A 1 per cent aqueous solution of gentian violet may be applied at 156 An Introduction to Medical Mycology the base of the nail and gently inserted under the nail fold with an orange- wood stiek. Chrysarobin in collodion (5 to 10 per cent) may be painted over the paronychial tissues once daily. Boric acid ointment and sodium perborate paste are other useful topical remedies. In the bronchopulmonary and pulmonary forms, potassium iodide should be administered in ascending doses over prolonged periods. In some cases there seems to be an advantage in employing ethyl iodide by inhalation. Gentian violet, intravenously, has been advocated by Stovall and Greeley. BIBLIOGRAPHY Beeson, B. B., and Church, J. G.: Superficial yeast infections of skin and its appendages, Arch. Dermat. & Syph. 13:643, 1926. Benham, R. W.: Certain monilias parasitic on man, J. Infect. Dis. 49:183, 1931; Pathogenic Fungi, in Gay, F. P., et al.: Agents of Disease and Host Resistance (Springfield, 111.: Charles C Thomas, Publisher, 1935), p. 1109. • , and Hopkins, A. M.: Yeastlike fungi found on skin and in intestines of normal subjects, Arch. Dermat. & Syph. 28:532, 1933. Biberstein, H., and Epstein, S.: Immunreaktionen bei der menschlichen und tierexperimen- tellen Oidiomykose der Haut, Arch. f. Dermat. u. Syph. 165:716, 1932. Bland, P. B.; Rakoff, A. E., and Pincus, I. J.: Experimental vaginal and cutaneous moniliasis: Clinical and laboratory study of certain monilias associated with vaginal, oral and cutaneous thrush, Arch. Dermat. & Syph. 36:760, 1937. Churchman, J. W.: Selective bactericidal action of gentian violet, J. Exper. Med. 16:221, 1912. Cornbleet, T. : Use of gentian violet in erosio interdigitalis saccharomycetica, Arch. Dermat. & Syph. 20:184, 1929. Downing, J. G., and Hazard, J. B.: Cutaneous moniliasis associated with oral thrush: Unusual case, Arch. Dermat. & Syph. 31:636, 1935. Engman, M. F.: Peculiar fungus infection of skin (Soorpilze), Arch. Dermat. & Syph. 1:370, 1920. Fabry, ].: Ueber Erosio interdigitalis blastomycetica seu saccharomycetica, Miinchen. med. Wehnsehr. 64:1557, 1917. Finnerud, C. W.: Perleche: Clinical and etiologic study of 100 cases, Arch. Dermat. & Syph. 20:454, 1929. Gomez- Vega, P.: Mycostatic studies on certain Moniliae and related fungi, Arch. Dermat. & Syph. 32:49, 1935; Effect of irradiation and irradiation plus sensitization on yeastlike fungi and related organisms, ibid. 34:961, 1936. Hopkins, J. G.: Moniliasis and moniliids, Arch. Dermat. & Syph. 25:599, 1932. , and Benham, R. W.: Monilia infections of hands and feet, New York State J. Med. 29:793, 1929. Joachim, H, and Polayes, S. H.: Subacute endocarditis and systemic mycosis (Monilia), J. A. M. A. 115:205, 1940. Kaufman-Wolf, M.: Zur Klassifizierung einiger Dermatomykosen, Dermat. Ztschr. 22:441, 1915. Kingery, L. B., and Thienes, C. H.: Mycotic paronychia and dermatitis: Hitherto undescribed condition apparently peculiar to fruit canners, Arch. Dermat. & Syph. 11:186, 1925. Kumer, L.: Die Soormykose der Haut, Arch. f. Dermat. u. Syph. 140:105, 1922. Lewis, G. M.; Hopper, M. E., and Montgomery, R. M.: Infections of skin due to Monilia albicans: I. Diagnostic value of intradermal testing with commercial extract of Monilia albicans, New York State J. Med. 37:878, 1937; II. Immunologic, etiologic and therapeutic considerations, ibid. 38:859, 1938. Mitchell, f. H: Erosio interdigitalis blastomycetica, Arch. Dermat. & Syph. 6:675, 1922. Ravaut, P.: Les eczematides secondaires, d'origine allergique, survenant au cours des inter- trigos a levures (Levurides), Bull. Acad, de med., Paris, 101:680, 1929. Robinson, L. B., and Moss, M. C: Superficial glossitis and perleche due to Monilia albicans, Arch. Dermat. & Syph. 25:644, 1932. The Superficial Mycoses 157 Km kwood, E, M.. \\n Gri i nwood, A. \l.: Mondial infections "I ^k 1 1 1 . Arch, Dermat. & Syph. 29:574, L934. s< ii \miii iu.. |. 1'.: Case nl extensive fatal thrush, with involvement of skin and secondarj infection oi the mother's breasts, \ivli. Pediat. 32:617, L915. Sum Mini. B.: Thrush infections oi skin, \n h. Dermat. & Syph. 12:789, L925. Stokes, W. R.j Kiser, E. F., vnd Smith, W. H.\ Bronchomycosis, J. \. \l. \. 95:14, L930. Stovall, W. D., vnd Greeley, H. P. : Bronchomycosis: Report of 18 cases oi primarj infection of lungs, J. A. M. A. 91:1346, L928. Sutton, R. L., |u.: Ccntian violet as therapeutic agent, with notes on case of gentian violet tattoo, |. \. \l. \. L10:1733, 1938. \\ iki i r, V; Williams, E. G.; Douglass, E. D.; Emmons, C. \\ .. vnd Dunn, R. C.: Nfycotic endocarditis: Report oi case, J. A. M. A. 119:333, 1942. 7. TINEA VERSICOLOR This disorder, also known as pityriasis versicolor and chromophytosis, is a common superficial mycosis readily recognized and treated. The condition is chiefly of importance cosmetically. However, there are several interesting tacts about the disease and its management. (a) Etiology.— The micro-organism causing tinea versicolor is known as Malassezia furfur. The disease affects young adults (of both sexes) by preference, but we have observed instances of infection in children and in the aged. While social standing is not important, the lack of personal hygiene, more common in the dispensary patient, predisposes to infection. Some persons appear to be rather susceptible. Hyperhidrosis is said to pre- dispose. Several members of a family may be infected. Contrary to an old tradition, the disease is apparently not more common in patients with pul- monary tuberculosis. The usual physical examination of such persons prob- ably led to the discovery of the disease, and its equally frequent inhabita- tion of the skins of other persons was not realized. While the disease is probably not more common in the summer than in the winter, patients with the disorder are usually seen in the warm weather, when its presence is more evident. (b) Clinical data. (1) The usual symptoms.— The disease manifests itself by scaly macules and patches starting from barely visible lesions in single or multiple foci. The color varies from that of the skin to dark brown. It is said that the usual color is yellowish fawn, but the shade varies with the season. During the winter the color may be that of the skin or light brown. In the summer, particularly toward the end, the color becomes darker and may be of a chocolate shade. Usually no inflammation is evident. The surface of the affected skin is sometimes noticeably scab', but often a scratch is necessary to dislodge the scales. Cases of follicular involvement arc rarely observed. In such cases the lesions remain small and may become slightly elevated. Fig. 49. Tinea versicolor, or chromophytosis. A, typical brownish scaly patches, usually most marked on the torso. The color varies with the season, being darker in the summer and lighter during the winter. B, pseudo-achromia caused by the screening effect of the lesions during exposure to ultraviolet rays. Tin's may be mistaken for vitiligo. 1 58 Fig. 50. Tinea versicolor of the papular follicular variety, very rarely observed. (Courtesy o) ('■< orge M. MacKee. ) 159 160 An Introduction to Medical Mycology The sites of predilection are the chest, the abdomen and the back, but the condition may attack any part of the skin, including the scalp and the palms and soles. Baer noted an instance of involvement of the face and scalp. We have observed a number of instances of infection on the back of the neck, and the extensor surface of the arm above the elbow appears to be a common site. At times the eruption favors intertriginons locations, such as the axillae, the inframammary folds or the inguinal regions; adiposity may predispose to the involvement of these regions. The disease sometimes involves large sheets of skin, and the manifestations may be extreme. Mild itching may be present. There is little if any tendency to spontaneous cure. When lesions of tinea versicolor are examined under filtered ultraviolet rays, fluorescence is noted; this varies from golden yellow to dark brown (depending on the amount of pigment in the lesions). This fluorescent characteristic has proved of interest and value not only in establishing a diagnosis but in determining the extent of the eruption. Changes of the color of the skin may be invisible in ordinary light but will be readily de- tected when a thorough cutaneous inspection under filtered ultraviolet radiation is undertaken. (2) Psetido-achromia.— During the summer or autumn, a patient with tinea versicolor not uncommonly exhibits light-colored (apparently de- pigmented) areas on the surfaces of skin exposed to sunlight. These areas usually appear suddenly after sunburn followed by peeling, although a history of a visible reaction is not always obtained. The patches occupy the sites of lesions of tinea versicolor; thev are irregular and of various sizes and appear chiefly on the trunk. Their color is not the dead white of vitiligo, although because of their contrast to the surrounding skin, espe- cially in persons of dark complexion, they may be mistaken for that disease. Areas of skin on the covered parts of the body are usually found to match in color the achromic-appearing spots. There is no increase of pigment at the periphery of a lesion. A scarcely perceptible scaling may be noted. Sometimes the condition appears year after year, becoming less no- ticeable during the winter and reappearing during the summer. The light areas do not, as a rule, become tanned after further exposure to ultraviolet radiation; on the contrary, they become more and more noticeable, owing to the increase of pigment in the surrounding normal skin. Examination for fungi combined with observation of the patient under filtered ultraviolet rays reveals that organisms are frequently present in these light patches. Some writers have expressed the opinion that there is definite achromia. Our inquiry into the nature of the lightening of the skin favored the theory of mechanical screening of the sun's rays, suggest- ing that the skin was light by contrast to the surrounding, normally pig- Fig. 51. Hidden lesions of tinea versicolor. A indicates that clinical inspection does not shovi the infection. During the winter the color of the patches ma> he similar to that oi the skin. B, lesions outlined as they were revealed under filtered ultraviolet rays. J 61 162 An Introduction to Medical Mycology mented skin. A mechanical cause was indicated by the facts that ( 1 ) the dopa reaction revealed a normal amount of pigment in the skin; (2) the scales of tinea versicolor protected the skin from ultraviolet rays to a greater degree than the scales of psoriasis or of pityriasis rosea; (3) fluo- rescent material from cultures of other fungi possessed a screening effect against ultraviolet radiation, and (4) increase in pigment in a patch was possible only when the overlying micro-organism had previously been treated and destroyed. (c) Immune reaction.— There is no acquired sensitivity to trichophytin. Since the cultivation of M. furfur is still a matter of conjecture, specific sensitization to a vaccine remains to be proved. Since the process is super- ficial and no involvement of the cutis is to be observed, sensitization is unlikely. (d) Differential diagnosis.— The ordinary form of tinea versicolor can hardly be confused with any other disease. If of limited extent, it may simu- late chloasma. Since the organism can be readily demonstrated and since the appearance under the filtered ultraviolet rays is characteristic, there should be no mistake. With pseudo-achromia of tinea versicolor, however, certain other diseases may be considered. (1) Achromie parasitaire a recrudescence estivale— From the published description of Jeanselme it appears that this disease is pseudo-achromia of tinea versicolor. (2) Achromia parasitaria.— It is difficult to fit together the varied symp- toms in the syndrome which Pardo-Castello and Dominguez described. In some cases irregular, dirty-white macules and patches which are slightly inflamed, scaly and somewhat itchy are present on the face and neck. In other cases the eruption is generalized, no inflammatory symptoms are present, and the disorder simulates the pseudo-achromia of tinea versicolor. In one of the illustrations in the article by Pardo-Castello and Dominguez are shown lesions on the trunk which suggest the last-mentioned disease. In both disorders, the scaling in the early macules is white and furfuraceous and the older lesions are devoid of scales. There is no increase of pigment at the edges. The mucous membranes, hair and nails are not affected. In the series reported by Pardo-Castello and Dominguez there were four cases in which the disorder was generalized, the palms and soles being free. Aspergillus was cultured in six of 36 cases and was considered a pos- sible cause of the disease. No mention was made of examination of scales in potassium hydroxide for the presence of M. furfur. In a later communi- cation, Pardo-Castello expressed his belief that the same clinical picture may be found in patients of different races and in persons residing in differ- The Superficial Mycoses 163 cut countries, that it max affect different types <>l persons and that it ma) be caused In a variety <>t organisms, lie did not believe that the rays of the sun play any part in the cause. Further investigative work appears necessary to clarify the picture. (3) Tinea flava or tinea versicolor tropicalis.— Castellani stated that this condition is identical with achromia parasitaria (Pardo-Castello and Dom- inguez). The fungus responsible cannot be distinguished from M. furfur in potassium hydroxide preparations, and like that organism it is nonenl- turable. Castellani differentiated tinea flava from tinea versicolor as it occurs in the temperate /.ones by the following points. (1) Tinea flava begins in childhood and may persist during life. (2) It usually affects the exposed parts of the body. (3) Cure is difficult. (4) The fungus seems to have a marked depigmentary action. (4) Endemic vitiligo of Turkestan.— According to Kistiakovskv, who has observed the disease, there is no difference between this disorder and vitiligo. (5) Pinta. —When this condition is observed early, the characteristic hues of the affected skin in no way suggest tinea versicolor. Later, when vitiliginous areas are present, differentiation may be more difficult. The disease causes coarse scales, the affected skin is infiltrated, occasional Assuring is noted, and loss of hair is usual. When extensively involved, the skin presents an odd, piebald appearance. (6) Syphilitic leukoderma— This condition is seen almost exclusively in women. The lesions are commonly symmetrically located on the sides and back of the neck, are oval or irregularly shaped and vary from the size of a split pea to that of a dime. Concomitant hyperpigmentation is some- times noted. No scaling is present. Other evidence of syphilis, including a positive serologic reaction, may usually be detected. (7) Vitiligo.— The irregular, asymmetrical, snow-white patches, show- ing hyperpigmented edges and affecting by preference the face, hands, forearms and male genitalia, should not often prove difficult to differentiate. No scaling is present. Vitiliginous skin observed under filtered ultraviolet rays has a characteristic fluorescing, glistening white appearance. It must not be forgotten that patients with tinea versicolor may also have vitiligo. This unrelated association is the probable explanation for the absolute achromia reported by a few 7 observers and thought to be consecutive to the pigmented rash of tinea versicolor. (8) Posteruptional depigmentations.— Seemingly depigmented areas may be noted at the former sites of syphilitic, psoriatic and other cutaneous lesions. Without any history of a preceding eruption, differential diagnosis inav be difficult. 164 An Introduction to Medical Mycology As with the ordinary form of tinea versicolor, diagnosis requires micro- scopic studies re-enforced by studies with filtered ultraviolet rays. (e) Prognosis.— The outlook for complete cure is good if treatment is thorough. Reinfection will occur if the patient is re-exposed, since immu- nity is not produced by an attack. (f ) Treatment.— The extent of the eruption should be determined by a complete examination of the whole cutaneous surface under filtered ultra- violet rays, and the patient should be advised to treat all parts that show fluorescence. If all the affected areas are treated, improvement will be rapid. It is advisable that all family contacts be examined and, as in the treat- ment of scabies, that all members affected should concurrently receive therapy. It is important that clothing be cleaned, if possible by washing, although dry cleaning will suffice. The patient, on examination after two weeks and subsequently, should again be observed under filtered ultraviolet rays. Areas which have escaped medication will be revealed. Scrapings taken from suspected areas will yield either positive or negative information. We stress the method of treatment rather than the medicaments to be used. A 10 per cent solution of sodium hyposulfite sponged on once daily before the patient retires is a satisfactory application. However, almost any exfoliant or fungicide will prove effective. A hot bath previous to appli- cation of the remedy may be helpful. BIBLIOGRAPHY Biert, C. M. G.: Tinea versicolor of the face, J. Cutan. & Ven. Dis. 3:73, 1885. Castellani, A.: Tropical forms of pityriasis versicolor, J. Cutan. Dis. 26:393, 1908; Fungi and fungous diseases, Arch. Dermat. & Syph. 17:194, 1928; Case of pityriasis versicolor trop- iealis, Brit. J. Dermat. 47:484, 1935. Kistiakovsky, E. V.: Pityriasis versicolor and ultraviolet rays, Arch. Dermat. & Syph. 15:685, 1927. Lewis, G. M., and Hopper, M. E.: Pseudoachromia of tinea versicolor, Areh. Dermat. & Syph. 34:850, 1936. McEwen, E. L.: Unusual ease of tinea versicolor, |. Cutan. Dis. 29:19, 1911. Pardo-Castello, V.: Achromia parasitaria, Arch. Dermat. & Syph. 25:785, 1932. , and Dominguez, M. M.: Achromia parasitaria, Areh. Dermat. & Syph. 9:82, 1924. Sidlick, D. M., and Corson, E. F.: Tinea versicolor of the face, Areh. Dermat. & Syph. 5:604, 1922. Smith, E. O.: Rare ease of tinea versicolor, New York M. J. 64:583, 1896. 8. ERYTHRASMA This is a superficial mycosis resembling tinea versicolor but with more tendency to localization. Burckhardt first described the disease in 1859. (a) Etiology.— The causative fungus is a minute threadlike micro- organism, Actinomyces minutissimus (M. minutissimum ). Little is known Fig. 52. Erythrasma. The process is usually localized and well demarcated. .A. in and near (In axilla. H. region of umbilicus. C, upper inner thighs and inguinal region. 165 166 An Introduction to Medical Mycology concerning predisposing causes or methods of transmission of the infection. Lack of cleanliness may be a factor. The disease is less common in the United States than in Europe. It is seen much less frequently than tinea versicolor. (b) Symptoms.— The patients are usually young adults, men more com- monly than women. There is usually localization to the axillae, the groins, the intergluteal cleft or other intertriginous areas, with involvement of one or more regions. The disease begins as small scaly macules which gradually enlarge to form various sized patches. The lesions are well circumscribed, the margins being accentuated by a reddened border. The color varies through yellowish brown, orange and reddish brown, the exact shade de- pending on the amount of pigment in the skin of the subject, the age of the lesion ( the older the darker ) and the amount of solar radiation to which the lesions have been subjected. The surface of the lesions is scaly. Vesicles, papules and follicular lesions are not present. (c) Differential diagnosis.— In tinea versicolor, there is less tendency to localization in intertriginous areas and there is no erythematous border. When the inner surfaces of the thighs, the inguinal region or the pubic area is affected, tinea cruris may be simulated. The long duration, the lack of inflammation ( especially of a vesicular border ) and the absence of satel- lite lesions tend to rule out tinea cruris. The demonstration of the micro-organism may be difficult when one uses the usual technic in examining scales. The organism may sometimes be noted under the ordinary high power magnification, but use of the oil immersion objective is usually requisite in order that one may be certain of its presence. In all cases, a mycologic diagnosis should be made. (d) Prognosis.— Provided all areas are treated, relapse is uncommon. (e) Filtered ultraviolet radiation.— When examined under filtered ultraviolet rays, the eruption shows little change from its usual appear- ance except that the color is less distinct. (f ) Treatment.— All areas of infection as noted by a thorough inspection must be treated. All the affected members of the family should receive treatment at the same time. The daily application of a 10 per cent solution of sodium hyposulfite usually is sufficient. Daily bathing should be carried out to prevent reinfection. 9. TINEA IMBRICATA This superficial fungous disease is rarely seen except in the tropics or subtropics. It was first recognized and described by Alibert in 1832. (a) Etiology.— The causative fungus has been described by Castellani Fig. 53. Erythrasma. A, patient with lesions of both erythrasma and tinea versicolor. The lesions scattered over the chest are those of tinea versicolor. B, the patient shown in A, with lesions of erythrasma in the axilla. C, typical site and appearance of a patch <>f erythrasma. 167 168 An Introduction to Medical Mycology as belonging to the genus Endodermophyton. Tie lias found four species of Endodermophyta— concentricum, indicum, tropicale and mansoni— to be the pathogens responsible. Most workers believe that these are variants of a single species and classify it as Trichophyton. Yonng adults are especially likely to contract the disease, and men are more susceptible than women. Children are less prone to develop tinea imbricata. The condition is observed in places where the coconut tree grows. It is fairly common in many of the Pacific islands, in the Malay States and in central and southern China; cases have also been reported from North China. In recent years it has spread to Ceylon and Southern India. Cases have been reported from South Africa and from South and Central Amer- ica, but some doubt has been expressed as to their being tine instances of tinea imbricata (Castellani). (b) Clinical characteristics.— The condition begins as one or more brownish spots, which slowly increase in size. The central portion of the superficial epidermis finally becomes detached, the epidermis cracks, and there is an opening from the center toward the border. Around the lesion a brownish zone appears. In this latter site, rupture of the skin again occurs. This process is repeated until numerous rings are formed, more or less con- centrically arranged and imbricated. Other patches develop, and after several months a large portion of the cutaneous surface may be affected. There is little if any visible redness. Scaling may be profuse. Itching is usually intense. The face is often affected. The scalp also may be involved, but the hair follicles are usually spared. The nails may be infected. (c) Differential diagnosis.— The absence of redness and the typical concentric rings are evidence against the diagnosis of tinea glabrosa. In a case reported by Kittredge an eruption similar to tinea imbricata was caused by T. purpureum. Ichthyosis is usually present from birth, and the scaling lacks the concentric rings seen in tinea imbricata. (d) Prognosis.— Cure is said to be difficult, and relapse is common. (e) Treatment.— Castellani advised treatment either with 25 per cent resorcinol in tincture of benzoin or with 5 to 10 per cent ehrysarobin in an ointment base. BIBLIOGRAPHY Castellani, A.: Tinea imbricata (Tokelau), Brit. |. Dermat. 25:377, 1913; Fungi and fun- gous diseases. Arch. Dermat. c\- Syph. 17:359, 1928. 10. OTOMYCOSIS (MYRINGOMYCOSIS) This rash of the external ear and the aural canal has a mixed and dis- puted etiology; it is marked by an exudative inflammation and pruritus. Fig. 54. Tinea imbricate in a Chinese. Above, irregular gyrate patches on the legs. Below, the elevated border and tendency to concentric scaling shown with magnification. {Courtesy of Frederick Reiss. I 169 170 An Introduction to Medical Mycology (a) Etiology.— While a number of writers have described this dis- order as of fungous origin, few exact technical studies have been carried out. Whalen stated that species of Monilia, Aspergillus, Penicillium and Achorion may be found. He mentioned that in China and in the Americas the predominating organism is a species of Aspergillus. In the Canal Zone, however, Monilia is more often found. The question arises whether these fungi, which are for the most part common laboratory "tramps" and may be cultured from the surface of normal skin, can be incriminated as the cause of the disease in question. The evidence so far offered is not sufficient to prove beyond doubt that they can. It is possible that the spe- cial conditions present in the external aural canal, particularly with retained cerumen, also favor the proliferation of ordinary saprophytes, so that a path- ogenic propensity is established. In our studies, Aspergillus has been a common finding, but autoinoculation experiments on several occasions have not been successful. If a species of Aspergillus is to be considered patho- genic, it must be with the qualification that the site and the material present are predisposing factors. We have cultured few fungi of recognized patho- genic titer from this site. Streptococci have also been considered as possible causative agents, since they are sometimes obtained on culture. We have not noticed a common history of allergy in patients with otomycosis. No age is exempt, although the majority of patients are young adults. Season and climate have little effect on the course of the disorder. Swimming in infected pools has been suggested as the origin of some characteristic in- fections. (b) Symptoms.— The external ear around the meatus is swollen and red. A moist mass of debris is usually present and may completely fill the canal. When this is removed, the affected skin is seen to be exudative. If the con- dition is mild or just beginning, the debris may be scanty, and at times it is dry and flaky. While pruritus (worse at night) is present in almost every case, evidence of trauma is rare. The disorder may extend down the canal and affect the drum. It has been said that if the drum is perforated, the in- fection may extend to the tympanic cavity and even invade the mastoid cells. (c) Differential diagnosis.— Seborrheic eczema is rarely observed in this site alone, so evidence should be sought on the scalp, behind the ears and in other sites. The crusting has an oily character not present in otomy- cosis. We are unable to differentiate this disorder from the exudative inflam- matory disorder due to streptococci described by Mitchell as occurring on the infra-auricular fold. Localized atopic eczema is of frequent occurrence and in this location The Superficial Mycoses 171 max predispose l<> invasion l>\ micro-organisms. With this disorder there are usually an associated Family or personal history ol other allergic diseases and a discernible allergen to account for the exposure; change ol environ- ment or season should favorably affect the disease it uncomplicated by micro-organisms. Contact dermatitis from nail polish, hair lotion or dressing, or other skin sensitizing agents is usually seen in women, is very pruritic and often affects the eyelids. (d) Prognosis.— Treatment is usually successful, although recurrence is not uncommon. (e) TREATMENT.— The extent of the disease should be ascertained. If it is localized to the external ear and the aural canal (the usual sites), the following treatment may be given. 1. Irrigate with a warm dilute solution of sodium bicarbonate until all the debris is removed. 2. Paint the affected area with a I per cent aqueous solution of gentian violet. Other drugs which may be painted on include a 1 per cent aqueous solution of brilliant green, a 1 per cent solution of silver nitrate, 2 per cent salicylic acid in alcohol, 5 per cent phenol in glycerin and 1 per cent thymol in alcohol. 3. Roentgen rays in fractional dosage are often valuable, administered cither alone or in combination with one of the remedies just mentioned. 4. Acetvlsalicylic acid, given internally, is useful to relieve the pruritus. BIBLIOGRAPHY Amstutz, O. C: Otomycosis: Report of case, J. A. M. A. 102:1562, 1934. Cavii.i i.wi. A.: Fungi and fungous diseases, Arch. Dermat. & Syph. 17:93, 1928. Whauen, E. J.: Fungous infections of external ear, I. A. M. A. 111:502, 1938. 11. LEPOTHRIX (TRICHOMYCOSIS AXILLARIS) Tin's is a common silent disorder in which nodes develop on the axillary hair. (a) Etiology.— According to Castellani, Actinomyces tenuis is the causal micro-organism. Micrococci may be associated and are said to be responsible for the formation of red or black pigment if present. Huang isolated A. tenuis in 24 of 25 instances of the disorder. (b) Clinical characteristics.— The condition is noted in the axillae, where irregular concretions form and attach themselves to the hair. Occa- sionally the pubic hair is affected. The attachment is firm, and the nodes are difficult to dislodge. The entire circumference of the hair is ordinarily involved. The concretion is usually yellowish; red and black varieties are uncommon in New York but are seen with more frequency in the tropics. 172 An Introduction to Medical Mycology Hairs on which the nodosities form may become triable but are otherwise unchanged. Weidman cultured a species of Actinomyces from a hairy black tongue. When the fungus was fed to a monkey, lesions of trichomycosis developed on the hair of the face and of the axillae. (c) Diagnosis.— This is usually indicated by the clinical appearance. The concretions, or nodes, exhibit fluorescence under filtered ultraviolet rays. If a hair to which the concretions are attached is examined under a micro- scope, the mass is seen to be present along a portion of the hair and nits can be excluded from consideration. In our experience, microscopic and cultural examinations have been fruitless so far as the demonstration of fungi has been concerned. Special mediums are necessary, such as those used in isolating Actinomyces bovis. (d) Treatment.— The daily use of 10 per cent xylene in petrolatum sometimes dissolves the concretions. Shaving the part is the fastest and surest cure. Recurrence is common. Scrupulous cleanliness is essential to prevent recurrence. BIBLIOGRAPHY Castellani, A.: Fungi and fungous diseases, Arch. Dermat. & Syph. 16:383, 1927. , and Wilkinson, A. G. : Observations on trichomycosis axillaris rlava, rubra and nigra, Brit. J. Dermat. 34:255, 1922. Huang, P.: Untersuchung iiber die Erreger von Lepothrix Wilson (Trichomycosis palmcllina, Pick), Arch. f. Dermat. u. Syph. 168:235, 1933. Lane, J. E.: Lepothrix, ]. Cutan. Dis. 37:387, 1919. Sibley, W. K., and Muende, I.: Notes on case of trichomycosis axillaris rubra, Brit. J. Dermat. 43:88, 1931. Weidman, F. D.: Affinities between black tongue and trichomycosis, Arch. Dermat. & Syph. 18:647, 1928. 12. TINEA NODOSA (PIEDRA) According to McCarthy, two varieties of this disorder exist: (1) the Colombian (South American) type, and (2) the European and Asiatic variety. In both, the disease is manifested by small, hard nodes along the involved hair shaft. We have not observed this disease in New York. (a) Etiology.— The disease is said to develop in individuals who wash their hair in stagnant river water and then apply a sticky hair dressing. Two fungi, Trichosporum (Piedraia) hortai and Trichosporum giganteum, are causative. The first-named micro-organism may be isolated from black nodes, whereas the latter is credited as the etiologie agent in the so-called "white" variety in which the nodes are light brown. The infective agent may be demonstrated by mounting the hair with nodes attached in potash solution. The hair is said not to lie affected in any way. According to Mc- Carthy, the nodes are made up of a large number of closely packed cells. The Superficial Mycoses L73 (hi Clink \i characteristics.— The disease is confined to scalp hair of women in South America. The European and Asiatic variety affects onl) the male heard and mustache, never the scalp. The nodules of both varie- ties arc 1 stonx hard and light or dark .brown. In the Colombian variety the) may be so small that they can be felt but not readily seen; iii the other type, the nodules are usually large enough to be seen. From one to 25 may be present on one hair. (c) DIAGNOSIS.— The color and location of the nodes are different from those of lepothrix, which are yellow or red and confined to the axillae. Nits project out typicalh , are accompanied by pruritus, and pedicnli may usually be found. Monilethrix and trichorrhexis nodosa may be simulated, but these diseases are readily distinguished if the hair is examined microscopically. (d) Thkatmkxt.— Shaving is a certain cure. Vigorous shampooing and the application of 1:2,000 solution of bichloride of mercury are also advo- cated. BIBLIOGRAPHY McCarthy, L.: Diagnosis and Treatment of Diseases of the Hair (St. Louis: C. V. Mosby Company, 1940). 13. CHROMOBLASTOMYCOSIS (DERMATITIS VERRUCOSA) For the few cases that have been reported, there is a remarkably wide geographic range. In the United States, cases have been reported from Boston, Texas, North Carolina, Georgia, St. Louis, Philadelphia and Florida. The majority of cases have been recognized in South America, Puerto Rico and Cuba. An instance of an infection in the Dominican Republic was re- ported by Carrion and Pimentel-Imbert. According to Conant et ah, it has also been observed in Russia, Japan and South Africa. (a) Etiology.— According to Carrion, three fungi are recognized as causative. Both he and Emmons stated the belief that there is a generic relation between them. The fungi are Hormodendrnm pedrosoi, Hormo- dendrum compactum and Phialophora verrucosa. Conant and Martin also included Hormodendrnm langeroni as a proved cause. According to Weid- man. infection usually takes a direct route from the exterior following injury, particularly from wood. Most patients are mature males, predomi- nantly of the working class. (b) Immunologic reactions.— Conant and Martin noted that the serums of rabbits immunized with II. pedrosoi and II. compactum had a high titer of complement-fixing antibodies for their respective antigens and for each other. With P. verrucosa and II. langeroni. complement-fixing bodies were present only for the homologous fungus. Fig. 55. Chromoblastomycosis; superficial papillomatous lesions of several years' duration. [Courtesy of A. L. Carrion, San Juan, Puerto Rico.) IV I The Superficial Mycoses 175 (v) Symptoms.— There may be a superficial resemblance to tuberculosis verrucosa cutis or to blastomycosis. The lesions usually develop on the [eg; the condition may begin as a verrucous nodule or an ulcer. The nodule ii kin be reddish, purplish or brownish. After many months or years, ver- rucous masses may result from coalescence of two or more lesions and their subsequent growth. Pruritus may or may not be present. In Lane's ease there were two lesions, one an ulcer and the other a nodule, both on a buttock. Later, large cauliflower-like masses may be noted, with sec- ondary invasion of saprophytic micro-organisms, and a foul discharge may be present. No instance of metastasis to an internal organ has been re- corded; rarely, subcutaneous or intramuscular lesions occur at sites remote from the original focus of disease. Edema of the foot and ankle is frequent. Adenopathy is infrequent. In the case of chromoblastomycosis reported by ( larrion as due to H. compactum, the lesions were on the left arm and of 28 years' duration. There were no ulcers or large warty or cauliflower-like lesions. The eruption spread by extension rather than by satellite lesions, as is usual. The rash was dry, dull red or violaceous and scaly and was well demarcated. Scarring was present in healed areas. The disease resem- bled psoriasis, lupus erythematosus and tuberculosis. (d) Histology.— According to Weidman, the tissue reaction consists of granulomatous changes similar to those resulting from the presence of a foreign body; there are also interspersed small foci showing a tuberculoid reaction and still other areas in which there is some miliary abscess forma- tion. (e) Differential diagnosis.— Blastomycosis and tuberculosis verrucosa cutis may be confused with chromoblastomycosis. In blastomycosis the flat border studded with pustules and the budding of the organism in pus are two prominent differences, but with tuberculosis verrucosa cutis, only the results of mycologic study and the results of inoculation of guinea-pigs may serve as distinguishing features. (f) Prognosis.— While there is no tendency to spontaneous recovery, the prospect for cure is good. There is no need to fear internal involve- ment. (g) Treatment.— The administration of potassium iodide by mouth or sodium iodide by intravenous injection has proved curative in a number of instances. While we have had no experience in treating the disorder, roentgen therapy appears to be indicated, since it is effective in disorders of somewhat similar pathologic characteristics. Conant et ah treated one patient with copper sulfate administered by means of iontophoresis and obtained a good result after five months. If the condition is localized, elec- trodesiceation and curettage should be successful. 176 An Introduction to Medical Mycology BIBLIOGRAPHY Carrion, A. L. : Chromoblastomycosis, Mycologia 34:424, 1942. Emmons, C. W.; Hailey, Howard, and Hailey, Hugh: Chromoblastomycosis: Report of sixth case from continental United States, J. -A. M. A. 116:25, 1941. Lane, C. G.: Cutaneous disease caused by new fungus (Phialophora verrucosa), T. Cutan. Dis. 33:840, 1915. Martin, D. S.; Baker, R. D., and Conant, N. F.: Case of verrucous dermatitis caused by Hormodendrum pedrosoi (chromoblastomycosis) in North Carolina, Am. J. Trop. Med. 16:593, 1936. Moohe, M.; Cooper, Z. K., and Weiss, R. S.: Chromomycosis (chromoblastomycosis): Report of two cases, J. A. M. A. 122:1237, 1943. Pardo-Castello, V.; Rio Leon, E., and Trespalacios, F.: Chromoblastomycosis in Cuba, Arch. Dermat. & Syph. 45:19, 1942. Weidman, F. D., and Rosenthal, L. H.: Chromoblastomycosis: New and important blasto- mycosis in North America, Arch. Dermat. & Syph. 43:62, 1941. Wilson, S. ].; Hulsey, S., and Weidman, F. D.: Chromoblastomycosis in Texas, Arch. Dermat. & Syph. 27:107, 1933. CHAPTER X The Deep Myeoses (Essentially or Potentially Systemic DURING a lifetime of work in private and hospital practice, a physician may sec only a few patients with one of the deep fungous infections. However, the prompt recognition of the disease is vitally important, since delay in beginning treatment may result in a fatal outcome. Patients suffer- ing from these rare yet potentially dangerous diseases may consult the gen- eral practitioner, the internist, the surgeon, the gynecologist or some other specialist as well as the dermatologist; thus consideration of a few essential facts concerning the detection and management of these diseases appears of general interest. As a rule, diagnosis of the deep mycoses is not difficult, if they are kept in mind as possibilities. The following will be discussed: 1. Actinomycosis (streptothricosis) 2. Mycetoma (maduromycosis) 3. Nocardiosis (actinomycosis without granules) 4. Sporotrichosis 5. Blastomycosis 6. Histoplasmosis 7. Coccidioidomycosis 8. Granuloma Paracoccidioides 9. Torulosis 10. Rhinosporidiosis 1 1. Aspergillosis 12. Mycoses of the lungs 1. ACTINOMYCOSIS (STREPTOTHRICOSIS) Ol all the rare, deep mycoses, tliis is probabl) the most widely distrib- uted throughout the world. It may remain in a localized stage, in which 177 178 An Introduction to Medical Mycology vigorous treatment is curative, or become generalized in extent, when it may cause the death of its host. The disorder was described and named by Bol- linger, while in the same year ( 1877 ) Harz named the organism producing the disease, A. bovis. This organism was first cultured and carefully studied by Wolff and Israel. Bostroem found the fungus in diseased cattle. Murphy and Ruhrah first reported the disease in the United States. Blain estimated that about 1,000 cases of actinomycosis have been reported in this country and concluded that the actual number of cases in the population is many times as great. (a) Incubation period.— This is not definitely known, but it is probably only a few days or weeks. (b) Etiology.— Several fungi have been considered as the causative or- ganisms. It is generally agreed now that in many if not all cases actinomy- cosis proper is caused by A. bovis (Harz; Wolff, and Israel). The disease is more prevalent in farming country than in urban districts; nearly half the patients suffering from this disease are engaged in agricultural pur- suits. Wild and domestic animals (particularly cattle) are susceptible to the infection. However, inoculation of cultural material of A. bovis into animals never completely reproduces the disease. In half the cases no infec- tion results, and even when inoculation is successful only insignificant lesions appear. Adults are affected more commonly than children and males much more often than females ( approximately 2:1). Actinomycosis bovis has been isolated from the normal mouth and throat and is probablv frequently present in the mouth, throat and gastrointestinal tract of healthy human beings and animals. Emmons found granules containing Actinomyces in 47 per cent of the tonsillar crypts in a series of 100 consecutive tonsil- lectomies; in approximately half of these, a growth was obtained of a microaerophilic Actinomyces considered to be A. bovis. Trauma is un- doubtedly a frequent precipitating factor, and cases of infection following extraction of teeth and resulting from bites are not uncommon. There is a possibility that the saliva and the nasal discharges may also be responsible for its transmission. (c) Clinical characteristics.— According to Steinbach, the disease in human beings has four anatomic localizations: (1) head and neck, 50 per cent; (2) abdominal organs, 20 per cent; (3) thoracic organs, 15 per cent, and (4) other organs, including the skin, 15 per cent. Cope's statistics arc in virtual agreement. The infection may spread by continuity or by means of the blood stream to involve any part of the body. (/) Head and neck.— The primary lesion may often be detected in the buccal mucous membrane. The gums, the tonsillar crypts or other parts of the mouth mav be involved, the infection traveling to the subcutaneous Fig. 56. Actinomycosis. \, infection which, beginning in the region of the parotid gland burrowed under the skin to affect a large portion of the right click. Sum, ol the scars are the result of variola; this patient also had a laryngeal carcinoma, which was apparently cured by surgical excision. As seen in B, the openings of the sinus tracts exuded pus containing white Hecks. These on microscopic examination revealed the raj fungus. C, the patient seen in li. showing successful results Inun local use of roentgen rays and internal administrati 1 po- tassium iodide. /). solitarj lesion opening on the lower eyelid. 179 180 An Introduction to Medical Mycology tissue, where nodules develop. These nodules increase in size, suppuration takes place, and pus is discharged to the surface of the skin. Sinus tracts then develop. The infection may slowly progress subcutaneously, with the same, sequence of events, until considerable areas of skin are involved. A variable degree of edema may be noted. The tissues in the affected re- gions are usually bound down and often have a boardlike consistency. Pus usually may be expressed from the sinus openings. In the pus, the organism may be found in the form of granules (yellowish or white flakes). Sometimes these granules are not grossly noticeable unless the pus is spread out on a slide. The mandible and other bones, the parot- id gland, the nose, the eye and the tongue have all been found capable of being infected. (2) Abdominal organs.— The disease usually begins in the appendix or cecum; in women, the fallopian tubes may be primarily involved. The disease may also attack the gallbladder and the liver, producing abscesses. The symptoms of involvement in the abdomen usually result in operations, when the disease may or may not be suspected. The operation wound re- fuses to heal, and sinuses discharging pus remain. Spontaneous sinus forma- tion before operation is unusual. An instance of primary actinomycosis of the stomach with metastasis to the liver was reported by Blain. (3) Thoracic organs— The involvement may be primary, or it may be secondary to buccal actinomycosis. Tuberculosis with cavitation may be markedly simulated; chronic bronchitis and pneumonia, more rarely. Car- cinoma is occasionally difficult to differentiate. There is discharge of pus in the sputum. Pain because of pleuritis is a common symptom. The lower lobes of the lungs are usually involved. The infection almost always spreads to the chest wall, with the production of sinuses to the exterior. If un- treated, the patient develops a septic temperature, loses weight, and secondary infection often supervenes. (4) Other organs.— Primary cutaneous involvement is rare; when it does occur, ulcerations form, and the infection gradually becomes deeper. According to Jacobson, only 13 cases of primary actinomycosis of the kidney have been reported, involvement of the urinary tract being more often secondary to infection of other parts. Cerebrospinal involvement has been reported; it is probably always secondary. The symptoms are either those of an acute infection or those of a neoplasm. Besides the bones of the face, previously mentioned, the vertebral column is occasional!}' involved secondarily to an intestinal or pulmonary infection. (d) Histology.— The morbid picture is essentially the same no matter what tissue or organ is affected. At an early stage colonies of fungi are noted in the center of the lesion, together with polymorphonuclear leuko- EKL> Fig. 57. Actinomycosis. Sinus tracts leading to visceral lesions. A and B, patient from Afghanistan with intestinal fistulas, in pus from which granules were readily demonstrated. C and D, pleural and subcutaneous sinus tracts. Both patients responded well to therapy with penicillin and sulfonamides. LSI 182 An Introduction to Medical Mycology cytes, lymphocytes, plasma cells and eosinophils. Surrounding them is a variable amount of cellular detritus and granulation tissue. The ray fungus is described further on pages 320 and 323. As the lesion increases in size, the central purulent area becomes larger, and finally the pus pushes through normal tissue. Granulation tissue or, in later stages, scar tissue may be the only pathologic finding and granules may not be found. The final outcome is the development of sinus tracts leading to the surface of the skin or to a cavity within the body. (e) Immune reactions.— It was shown by Colebrook that serum taken from a patient with the disease will agglutinate the causal micro-organism. The diagnostic value of cutaneous tests with vaccines has been appraised by Conant et al. who reported that patients with actinomycosis are sensi- tive to both intracutaneous and subcutaneous injections of a vaccine made from the causative organism. (f ) Differential diagnosis.— While the absolute diagnosis rests on the demonstration of the ray fungus in the pus (see pp. 320 ff. ), the clinical picture is usually highly suggestive. The location, the development of sinus tracts and the presence of white or yellow granules in the pus are characteristics rarely noted with other infections. Sporotrichosis may be differentiated by the absence of granules in the discharge, by the devel- opment of successive lesions along a lymphatic chain and by breaking down of the lesions into ulcerations. Sporotrichum schencki is readily cultured but not demonstrated in pus. Granuloma coccidioides is characterized by the development of soft granulomatous lesions on various parts of the body, with symptoms of systemic infection. Coccidioides immitis is present in the pus, and guinea-pigs readily become infected. Tuberculosis may be simulated in lesions in the skin, in the lungs and in the vertebrae. Finding the ray fungus is necessary to determine the diagnosis; cultures of sputum which yield Actinomyces may be misleading, since the fungus is frequently saprophytic in the mouth. The roentgen picture of the lungs usually shows the disease affecting the lower lobes and rarely reveals cavity formation. When the vertebral column is affected, tuberculosis is simulated, but tuberculosis is usually limited to the anterior portion of the vertebral bodies. With involvement of the abdominal viscera, the diagnosis will be determined if actinomycosis is kept in mind as a possible cause for per- sistent sinuses following operation and if wet preparations of material from unusual pustular conditions found at operation are made routinely and examined for the ray fungus. When the tongue alone is involved, syphilis, carcinoma, tuberculosis or pyoderma may be suspected until the ray fungus is demonstrated. An elevated sedimentation rate and a moder- ate leukocytosis may occasionally be helpful laboratory findings. * J Fig. 58. Actinomycosis of the chest as shown by roentgenograms. A, infiltration in right lower lobe with associated pleural effusion; generalized cardiac enlargement. In the lateral view, the patchy infiltration was seen to occupy the right middle and lower lobes. B, sym- metrical thorax with smooth high diaphragm on the right. The diaphragm on the left is in average position but shows tenting. Both costophrenic angles are clear. Size and shape ol heart shadow are not unusual. The right lower lobe is reduced in volume and the lung mark- ings are prominent in this region. The dense shadow in the hilar region is probably due to an enlarged Lymph node. In the third left interspace, a uniform density is noted which gradually fades out toward the second anterior interspace. The first interspace is entirely clear. There is a veil-like density throughout the lower left lung field. In the lateral film, a dense round shadow, probably an enlarged lymph node, was seen in the hilar region. 183 184 An Introduction to Medical Mycology (g) Prognosis.— When localized, the disease usually responds well to treatment. In the systemic varieties, the issue is doubtful but not hopeless unless the brain and the spinal cord become affected. The period of involve- ment is important; infections of long duration are of graver portent than those of recent origin. The prognosis also depends on the nature of the treatment and on the efficiency with which it is carried out. The virulence of the infection may vary, and the natural immunity of the host also seems to be of importance in many cases. (h) Treatment.— This should be undertaken as soon as the ray fungus has been demonstrated in pus. Even when the outlook is favorable, prog- ress is slow and several months are required for cure. The following meas- ures are usually employed. (1) Preferred.— Combined therapy using penicillin, sulfadiazine and roentgen irradiation is advocated by Lamb and others and appears at this time to be superior to other schemes. It is recommended in all forms of the disease. A. Penicillin. This drug should be given intramuscularly, 40,000 units every three hours to a total dose of at least 6,000,000 units. r. Sulfadiazine. In 1938, Walker reported favorable results from the ad- ministration of sulfanilamide. There has since been ample evidence that the sulfonamides are useful agents. We prefer sulfadiazine because of its low toxicity. The dose at first should be from 4 to 6 Gm. daily, reduced to 2 Gm. daily after clinical improvement. Sodium bicarbonate should be prescribed to be taken coincidentally. It may be necessary to continue sulfonamide therapy for two to three months. The urine and blood should be examined regularly. c. Roentgen rays. This is usually administered to accessible lesions in semi-intensive dosage with some filtration. The treatment should be re- peated at intervals of three or four weeks. In cases of systemic infection, high voltage therapy usually results in symptomatic relief. (2) Other measures. a. Iodides. It is customary to use a saturated solution of potassium iodide, first giving 10 drops three times daily before meals in a glass of water. The dose may be increased 5 drops each day until symptoms of intolerance develop. Patients with actinomycosis appear to have more 1 than average tolerance for iodides, and large doses (up to 200 to 300 drops or more per day) are frequently well tolerated. Tincture of iodine may be given instead of potassium iodide, and other forms of iodide medication may be substi- tuted to provide a change for the patient during the long course of treat- ment. It is usually necessary to continue the administration of the iodides for several months. The Deep Mycoses (Essentially or Potentially Systemic) L85 b. Copper sulfate. This is <>l dubious value; \ ur. (0.016 Gm.) ma\ be given 1>\ inoiitli, or colloidal copper ma\ be administered intravenously. (. Local treatment. This should consist ol irrigation ol the sinuses with compound solution ol iodine (Lugol's solution), diluted, or with a 1 per cent aqueous solution ol gentian violet. Packing the sinus tracts with for- maldehyde gauze lias also been advocated. D. Surgical intervention. Accessible lesions may he completer) excised or incised to pro\ ide irrigation. e. Thymol. Preliminary experiments In Myers showed that a 1:1,000 aqueous solution of thymol possesses the power of destroying Actinomyces in 45 seconds. Myers treated five patients with thymol locally and sys- tenucallv, and all recovered. A patient who refused to take thymol inter- nally died of visceral involvement. For local use, Myers used a 10 to 20 per cent solution of thymol in olive oil. For internal use, thymol was ad- ministered 1>> mouth in crystal form in 1 or 2 Gm. capsules once daily or less frequently. It was given on an empty stomach. While the small number of patients who have been treated with thymol does not allow fair evalua- tion of its worth, we are of the opinion that it has merit and may be used for patients intolerant to the drugs advocated in the preferred schedule. BIBLIOGRAPHY Blatn, A. \\'.: Primary actinomycosis of the stomach, J. A. M. A. 100:168, 1933. Bollinger, O.: Ueber eine neue Pilzkrankeit beim Rinde, Centralbl. t. d. med. Wissensch. L5: 181, 1877. Bostroem, O.: Untersuchungen uber die Aktinonrykose des Menschen, Beitr. z. path. Anat. u. z. allg. Path. 9:1, 1891. Colebhook, L.: Mycelial and other micro-organisms associated with human actinomycosis, Brit. J. Exper. Path. 1:197, 1920. Cope, Z.: Actinomycosis (London: Oxford University Press, 1938). Emmons, C. W.: Actinomyces and actinomycosis, Puerto Rico J. Pub. Health & Trop. Med. 11:63, 1935: Strains of Actinomyces bovis isolated from tonsils, ibid. 11:720, 1936. Hall, W. E. B.: Sulfanilamide in actinomycosis, J. A. M. A. 112:2190, L939. Harz, C. O.: Actinomyces bovis, ein neuer Sehimmel in den Geweben des Rindes, Jahresb. d. k. Centralbl. -Tierarznei-Schule in Miinchen, 1879, p. 125. Lamb, (. II.: Lain. E. S., and Jones, P. E.: Actinomycosis of the face and Deck, |. A. M. A. 134:351, 1047. LORD, F. T.: Presence ol Actinomyces in contents of carious teeth and tonsillar crypts of pa- tients without actinomycosis, J. A. M. A. 55:1261, 1910. \ln i in, I-'.. \I.. wo Fell, E. H.: Sulfanilamide therapy in actinomycosis, J. A. M. A. 112:731, 1939. \li iu'iiv. J. 15.: Actinomycosis in the human subject, New York M. J. 41:17, 1885. Myers, II. B.: Thymol therapy in actinomycosis, |. A. M. A. 108:1875, 1937. Hi mi. mi |.: Actinomycosis in man, with special reference to eases which have been observed in \iin in a. \nii. Surg. 30:417, 1 III i \inoi.i). T. H.: Ntnanliosis cutis gangrenosa, \n h. Dermat. c\ Syph. 27:224, 1933. I. win. J, 11.: Personal communication. 4. SPOROTRICHOSIS While this disease was thought to be more prevalent in France and in the Mississippi Valley than elsewhere, the largest number of cases lias been reported from South Africa. Pijper and Pullinger in 1927 described an outbreak of sporotrichosis affecting 14 native miners working in one gold mine. In 1941, Dangerfield and Gear reported 74 cases occurring in workers in two Witwatersrand gold mines. A year later du Toit added 650 eases to the total for South Africa, when he reported an epidemic occurring in a shaft where about 2,500 native workers were emploved. Du Toit further mentioned that many other cases had not been recognized in other gold mines and have not been recorded. Schenck in 1898 first described the disease in this country. Smith classed the organism as a member of the genus Sporotrichum. A few more than 200 instances of the infection have been recorded in this country, and only five cases in which the diagnosis was proved have been reported from New York. The reports of de Beurmann, Ruediger, Meyer, Foerster and du Toit may be cited as particularly valuable for reference. (a) Period of incubation.— This is usually in the neighborhood of one week. It may vary from three days to three weeks (Dangerfield and Gear). (b) Etiology.— While several members of the genus Sporotrichum have been considered of pathogenic significance, S. schencki seems to be of predominant importance in this country. Numerous species of Sporotrichum are common saprophytes, being found on many types of vegetation in all parts of the world. They are also found in the excreta of human and animal carriers. Sporotrichum schencki has been inoculated successfully on carna- tions (Benhain and Kesten), and the work of Foerster indicated that the barberry shrub is of importance as an intermediary host. Sphagnum moss was thought to be the residual focus for the Sporotrichum in cases of six florists (Gastineau, Spolyar and Haynes). There is frequently a report of local injury or trauma with a thorn, cactus or briar. De Beurmann has shown that the organism may permeate the intact intestinal mucosa, and the infection thus may be contracted through the eating of contaminated 190 An Introduction to Medical Mycology raw fruits or vegetables. Sporotrichum schencki is pathogenic for the higher animals such as horses or mules, and some of the lower animals also may acquire lesions of sporotrichosis, the rat being particularly susceptible. In isolated instances the disease has been acquired from the bite of a rat, from patients with the disease and from cultures of the organism. In the majority of instances in the United States the disease in human beings is probably due to contact with infected vegetation at a site of local injury. The investigations of Dangerfield and Gear and of du Toit have focused attention on another means of dissemination of the disease. Dangerfield and Gear were certain that the infection in workers in gold mines in South Africa was contracted underground, but attempts to culture the fungus from rock, timber and underground water were unsuccessful. Rats caught in the mine were likewise not infected. Du Toit was more successful and isolated a Sporotrichum from dust floating about in the air and from timber, on which it was growing profusely. He was not certain that this fungus was the agent causing sporotrichosis since it was less virulent when rats were inoculated and the disease could not be pro- duced when the fungus was injected into human volunteers. (c) Clinical characteristics.— There are a number of clinical types of the disease. These may be summarized as follows. (1) Localized lymphangitic type.— Most of the reported cases in South Africa and in the United States are of this variety, in which a primary lesion, or chancre, appears on an exposed part of the body. The usual site is a finger or hand. In two recent cases, one of which was presented by John C. Graham, the initial lesion was on the face. The primary lesion is indu- rated; softening and abscess formation may take place; an indolent ulcer may develop, or the lesion may vegetate. Rarely the disease remains local- ized to this single lesion. Usually after a week or more a painless ascending inflammation develops in the regional lymphatics, along the course of which secondary nodules form and undergo changes similar to those noted in the chancre. Enlargement of regional lymph nodes is uncommon (an important diagnostic point in the clinical differentiation from tularemia, in which en- largement of lymph nodes is a constant finding). Systemic symptoms and generalized involvement are uncommon. There is little if any tendency to spontaneous recovery. Scarring of varying degrees of severity remains after involution of the lesions. (2) Disseminated subcutaneous type— In this variety, commonly ob- served in France, small hard painless subcutaneous nodules of varying number appear in scattered locations over the body. Within three to six weeks the skin becomes involved; the central part of the nodule softens and forms an abscess which may discharge if traumatized, becoming a cup- A ' fe ... • # Bb5.W»- Fig. 60. Sporotrichosis. A, the initial lesion, or chancre. B, secondary ulcerated lesions extending proximally along the course of the lymphatics. 191 192 An Introduction to Medical Mycology shaped ulcer with a firm indurated border. In the untreated patient, new lesions may continue to appear indefinitely. (3) Disseminated ulcerating type.— Although similar to the preceding type, this form is distinguished by a tendency to early spontaneous ulcer- ation of the lesions. The ulcerations vary greatly in size and character. At times large crateriform ulcers develop, simulating the lesions of tuberculosis or tertiary syphilis. There is little if any tendency to spontaneous cure. In the untreated patient the general health may become impaired, with the appearance of symptoms of toxemia. Moore and Kile reported an instance of generalized subcutaneous gummous ulcerating sporotrichosis with pos- sible involvement of the lungs. There was a favorable response to treatment. In a case of disseminated cutaneous and visceral infection reported by Collins, death occurred two months after onset. (4) Epidermal type— The primary lesion in sporotrichosis is nearly always subcutaneous. In some instances the epidermis at adjacent or remote sites becomes secondarily infected, with development of papules, pustules and small ulcers. Rare cases have been described in which the disease is limited to the skin, and in such instances tuberculosis is differ- entiated with difficulty. The mucous membranes may also become sec- ondarily infected in cases of the disseminated or ulcerating varieties. The organism is said to be capable of remaining as a saprophyte on mucous sur- faces after apparent cure, rendering the patient a possible carrier. (5) Verrucous dermatitis— Perhaps a variant of the preceding type has been described by Smith and Garrett. There was considerable resemblance in their case to blastomycosis with outlying satellite pustules. No lym- phangitis developed. (6) Systemic type.— At times S. schencki invades the deeper tissues and organs. In the majority of instances this occurs in the disseminated varieties of infection when treatment is not promptly instituted. The differential diagnosis must exclude cancer, syphilis, tuberculosis and other infections. The bones or joints may be affected, the tibia being the most common site of involvement. Invasion of the muscles and glandular structures may occur, and a number of instances of pulmonary involvement have been reported. Although a common site of involvement in laboratory animals, the epididymis is rarely affected in human beings. Gastrointestinal or cere- brospinal involvement is said to be extremely uncommon. In a case of meningitis studied by Hyslop, Neal, Kraus and Hillman, repeated attempts to culture spinal fluid were fruitless and iodide therapy was of no avail. The diagnosis rested on the observation of sporelike bodies ami mycelium in the centrifugated sediment of spinal fluid. There appears to be some doubt as to the exact diagnosis. Fig. 61. Sporotrichosis. Four cases of infection involving A, the upper eyelid; B, the lower eyelid; C, the base of the thumb and along the forearm, and D, the arm. 193 194 An Introduction to Medical Mycology (7) Allergic lesions.— Sporotrichids, comparable to trichophytids, have been described by de Beurmann. (d) Histology.— D. L. Satenstein's description of a section removed from the edge of an ulcerating lesion is fairly typical of the usual observa- tions: The epidermis is irregularly acanthotic The greater part of the cutis is filled with a dense cellular infiltrate. The blood vessels are markedly dilated, some approaching the size of sinuses. Scattered throughout the cellular infiltrate are many very small blood vessels. The cellular infiltrate is composed of a great many mast cells, some con- nective tissue cells and a few plasma cells, and in the central portion there is a large group of giant and epithelioid cells. There are also many polymorphonuclear cells scattered throughout the entire zone. There is no degeneration and no abscess forma- tion. The whole process is one of organizing granulomatous tissue with enormous numbers of mast cells. No fungous elements are noted in routine sections, in those stained by Gram's method or in those stained with polychrome methylene blue. The picture is not in itself diagnostic. One can determine that the process is granulomatous, but syphilis, tuberculosis and other deep mycoses may be difficult to differentiate. It should be remembered that S. schencki is seldom observed in tissue, in contrast to the readily demonstrated presence of most other pathogenic fungi. (e) Immune reactions.— An agglutination reaction may usually be dem- onstrated (de Beurmann; Moore and Davis). Du Toit found that serum of patients brought about agglutination in a titer of about 1:600. How- ever, the spores were similarly agglutinated by the serum of normal con- trols, thus nullifying the value of the test. The complement fixation test is unreliable. According to Bloch, the intracutaneous test with an extract of Sporotrichum is of value; de Beurmann expressed the opinion that a nega- tive reaction rules out the diagnosis of sporotrichosis; there may occasion- ally be a false positive reaction. Du Toit agrees that a positive skin reaction occurs with regularity in patients with sporotrichosis. In the experimental production of sporotrichosis in a volunteer, the response developed the fifth day following inoculation. (f ) Differential diagnosis.— A positive laboratory diagnosis may usually be made without difficulty from cultural studies. The micro-organism is difficult to demonstrate in fresh preparations. The initial lesion, or sporotrichotic chancre, usually develops on the fingers or hand. When lesions successively appear along the course of a lymphatic chain, the clinical diagnosis may be highly suggestive. Before secondary lesions have developed or if the initial lesion is in an atypical location, the correct diagnosis may not even be considered. The character of the lesions suggests a granuloma, and the differential diagnosis should The Deep Mycoses (Essentially or Potentially Systemic) L95 exclude another mycotic infection such as coccidioidomycosis, syphilis, tuberculosis, tularemia and pyoderma. The incidence <>l coccidioidomy- cosis is highest in California and ol sporotrichosis in the Middle West. The evolution of the lesions is usually Faster with sporotrichosis than with coccidioidomycosis, and the lesions tend to ulcerate more rapidly. In coc- cidioidomycosis, secondary lesions usually develop at a remote point. The lesion ot actinomycosis or of blastomycosis usually differs greatly from that of sporotrichosis, sinuses draining from deep lesions being present ill the former condition and verrucous lesions containing miliary abscesses in the latter. A syphilitic chancre or minima may be suggested when the initial lesion alone is present. Absence ol concomitant symptoms and signs ol syphilis may aid, but a cultural diagnosis should here be definitely estab- lished, particularly since it can usually be made without difficulty. Tuber- culosis develops more slowly, lesions of this character usually occurring in butchers or in patients with foci elsewhere; the pus is usually not so thick or profuse as in sporotrichosis, and the reaction to a high dilution of tuberculin is positive. Since culture is the only definite method or diagnosis and since' it is usually reliable, pus from any suspected lesion should be streaked on agar as described on page 324. If no growth results, agglutination and cutaneous tests may aid in diagnosis. The inoculation of pus into laboratory animals may help. Guinea-pigs are usually immune, but rats are usually susceptible. The absence of enlargement of lymph nodes and of fever is usualh sufficient to rule out tularemia. Pyoderma of granulomatous character is unlikely unless the blood sugar level is elevated. (g) Prognosis.— Most patients respond well to treatment, even if the disease has escaped diagnosis for several months. In rare instances, when the internal organs become involved, the outlook is more serious and ther- apy may not prove curative. As with the other deep mycoses, early diag- nosis is of paramount importance. (h) Treatment.— (I) Iodides.— -The usual procedure is to administer potassium iodide by mouth three times daily, beginning with 10 drops of the saturated solution. The dose is increased 5 drops daily until the limit of tolerance is reached. The medication should be sustained for several weeks at this point, until long after all signs or symptoms of the disease have disappeared. Sometimes tincture ot iodine, Lugol's solution, or colloidal iodine is used, but these forms have no demonstrated superiority except in isolated instances, when they may be better tolerated. The effect of iodides is probably indirect, although Shaffer and Zackheim cured a patient after 13 weeks of therapy with iontophoresis, using a strong solution ot iodine, U.S. P. According to Davis, fibroblastic elements arc stimulated, and the pro- 196 An Introduction to Medical Mycology liferation of this tissue produces the encapsulation and resultant cure. Some patients are unable to tolerate iodides. (2) Roentgen rays.— It is customary to administer roentgen rays in semi- intensive dosage with some filtration. While there is no direct fungicidal effect, the effect on granulomatous tissue and perhaps the blocking off of the lymphatics are of aid. (3) Surgery.— This is of no avail; but if fluctuation is present, a single incision may be made. It is better still to aspirate the pus without surgical incision. (4) Local medication.— Dressings of Burow's solution (1:15) or of potas- sium permanganate (1:3,000) may be applied for half an hour several times daily. Gentian violet (1 per cent aqueous solution) may be used to irri- gate the lesions, or Lugol's solution ( half -strength ) may be applied. (5) Thymol.— In case of intolerance to iodine, this may be given a thera- peutic trial. (6) Penicillin and streptomycin.— These are ineffectual. BIBLIOGRAPHY Benham, R. W., and Kesten, B.: Sporotrichosis: Its transmission to plants and animals, J. Infect. Dis. 50:437, 1932. De Beurmann, L.: On sporotrichosis, Brit. M. J. 2:289, 1912. Campbell, H. S.; Frost, K., and Plunkett, O. A.: Sporotrichotic chancre, Arch. Dermat. & Syph. 28:61, 1933. Collins, W. T.: Disseminated ulcerating sporotrichosis with widespread visceral involvement, Arch. Dermat. & Syph. 56:523, 1947. Crutchfield, E. D.: Sporotrichosis, Arch. Dermat. & Syph. 7:226, 1923. Dangerfield, L. F., and Gear, J.: Sporotrichosis among miners on Witwatersrand gold mines, South African M. J. 15:128, 1941. Du Toit, C. J.: Sporotrichosis on the Witwatersrand, Proc. Transvaal Mine M. Officers A., vol. 22, June, 1942. Foerster, H. R.: Sporotrichosis, Am. J. M. Sc. 167:54, 1924; Sporotrichosis: An occupational dermatosis, J. A. M. A. 87:1605, 1926. Gastineau, F. M.; Spolyar, L. W., and Haynes, E.: Sporotrichosis : Report of six cases among florists, J. A. M. A. 117:1074, 1941. Greenburg, W.: Sporotrichosis: Report of case in California, Arch. Dermat. & Syph. 36:355, 1937. Hektoen, L., and Perkins, C. F.: Refractory subcutaneous abscesses caused by Sporothrix schenckii: New pathogenic fungus, J. Exper. Med. 5:77, 1900. Hyslop, G. H.; Neal, T. B.; Kraus, W. M., and Hillman, O.: Case of sporotrichosis menin- gitis, Am. J. M. Sc. 172:726, 1926. Lawless, K. L.: Diagnosis of sporotrichosis, Arch. Dermat. & Syph. 22:381, 1930. Lewis, G. M., and Cudmore, J. H.: Sporotrichosis: Report of case originating in New York, Ann. Int. Med. 7:991, 1934. Meyer, K. : Relation of animal to human sporotrichosis, J. A. M. A. 65:579, 1915. Moore, J. T., and Davis, D. J.: Sporotrichosis following mouse bite with certain immunologic data, J. Infect. Dis. 23:252, 1918. Moore, M., and Kile, R. L.: Generalized, subcutaneous, gummatous, ulcerating sporotrichosis: Report of case, with study of etiologic agent, Arch. Dermal. & Syph. 31:672, 1935. Pijper, A., and Pullinger, B. D.: Outbreak of sporotrichosis among South African native miners, Lancet 2:914, 1927. Ruediger, G. F.: Sporotrichosis in the United States, J. Infect. Dis. 11:193, 1912. The Deep Mycoses (Essentially or Potentially Systemic) 197 Schenck, B. R.: On refractor) subcutaneous abscesses caused !>> ;i fungus possibly related to Sporotricha, Bull, fohns Hopkins Hosp. 9:286, L898. Shaffer, L \\ ., ind Zackheim, H. S.: Sporotrichosis, Arch. Dermat. & Syph. 56:244, 1947. Smith, L. M., ind Garrett, II. I).: Verrucous sporotrichosis, Vrch. Dermat. <.\ Syph. 56:532, 1947, Tempi i pon, H. | . uro Lunsford, C. [.: Sporotrichosis on tin Pacific ('nasi. Northwest Med. 80:132, L931. ' 5. BLASTOMYCOSIS The North American form of blastomycosis is chiefly seen in the Middle West, particularly in the region around Chicago, but the disease may appear sporadically in any section of the country. There are only three proved in- stances of the disease originating outside the United States, one each in Canada. England and France. The case reported by Brody occurred in an American soldier who was in France for 10 months before he showed clinical signs of the disease. The presence of budding cells in the diseased tissue was first demonstrated by Gilchrist, in 1896, and the organism causing the disorder was later described in detail by Gilchrist and Stokes. A number of articles and case reports have since appeared, and the nature of the disease is now well known. (a) Period of incubation.— Although unknown, it is probably one to two weeks. (b) Etiology.— Although Blastomyces dermatitidis is the organism caus- ing American blastomycosis, other organisms are capable of producing lesions which simulate this disorder. The European type of blastomycosis (torulosis) is a distinct entity (Benham). Most of the patients are adults, 50 per cent being over 40 years of age and about the same proportion being between 20 and 40. Most patients are men. The organism may have a saprophytic existence on plants, since numerous Blastomyces are wide- spread in nature. Two instances of spontaneous blastomycosis in dogs have been reported. Trauma is usually necessary for development of the infec- tion. Scratches, puncture wounds, bruises and the like have been reported as predisposing factors. (c) Clinical characteristics.— The disease may be local or systemic. In most cases the initial lesion appears on the skin. The chief sites are the face, hands, wrists and forearms, although any part of the body may be involved. In some instances the tongue and the lungs are the sites of the first manifestations. On the skin, the first lesion is a papulopustule, which soon becomes crusted. There is peripheral enlargement, and after several weeks a plaque elevated above the surrounding skin is present. Crusting may be of slight amount or may cover the entire lesion. Beneath the crust, the surface shows irregular papilliform elevations and is covered with a Fig. 62. Blastomycosis: infection of 15 years' duration with widespread involvement of the skin. There was no evidence of internal dissemination of the infection. A, B and C, active verrucous and (ungating lesions with extensive scarring after healing. The disease was present on the lace, including the eyelids. The scar tissue on the neck prevented free motion of the head. D and E, marked involution of the lesions six weeks alter beginning intensive internal therapy with potassium iodide and roentgen irradiation ol the lesions. HIS Fig. 63. Blastomycosis secondarily affecting the bones and subcutaneous tissues. The pri- mary focus was the skin. A, elbow. B, leg. C, ankle. 199 200 An Introduction to Medical Mycology seropurulent secretion, which may be increased by pressure of the affected tissues. According to Ormsby, the border of the patches is one of the most characteristic features. This edge is smooth and slopes down abruptly to normal skin. On its surface are minute abscesses, which may be super- ficial or deep seated; when the disease is actively spreading they are pres- ent in large numbers. The hand lens may be required to see these lesions. Puncture of the minute abscesses along the border of a lesion provides the best material for isolation of the organism. Healing occurs first in the central portions of the lesion and is followed by formation of scar tissue. The patches slowly enlarge, and in half the cases (Ormsby) one or more lesions develop in adjacent or remote parts of the skin. When systemic dissemination of the organism occurs, any organ or tissue in the body may be attacked. The lungs are the commonest site and often the primary focus; they are affected in over 90 per cent of the cases of systemic involvement. The symptoms at first may be those of an acute infection of the respiratory tract, and a characteristic feature is pain in the chest. Later a syndrome suggestive of tuberculosis is present. The skin may become secondarily infected from deep sites, the organism being carried by the blood stream, in which case subcutaneous abscesses develop. These finally rupture, and one may then note shallow ulcerations, showing granulations at the base, covered with purulent discharge and frequently crusted. When the kidneys become involved, symptoms of nephritis are evident. The bones, particularly the ribs and vertebrae, are frequently affected in the systemic types of the disease, and, according to Stober, the fungus may cause osteomyelitis, periostitis or arthritis. The central nervous system is occasionally involved, and any part of the brain, spinal cord or meninges may become affected. The tongue, the larynx and the intra- abdominal organs have all been reported as occasional sites of the disease but invasion of the intestinal tract is unusual. (d) Histology.— Sometimes the pathologic appearance of a visceral lesion suggests tuberculosis. The presence of central necrosis is charac- teristic, and the organism is usually associated with leukocytes, red blood cells and debris. Giant cells of the Langhans type may be noted at the periphery. Granulation tissue usually surrounds the nodule. In the skin, marked and irregular acanthosis is a feature. There are also epidermal abscesses, in which budding yeast cells are associated with the type of cells noted in the center of the visceral nodule just described. A cellular infiltrate and interstitial and parenchymatous edema of the underlying cutis are present. (e) Differential diagnosis.— With this, as with other fungous diseases, the causative organism must be demonstrated. Usually this is not difficult Fig. 64. Blastomycosis affecting the lungs and bones. In A, the right side of the dia- phragm is in the usual position. The costophrenic angle is clear. On the left, the diaphragm is indistinctly seen; the costophrenic angle appears shallow, and there is evidence of slight pleural thickening. The upper three-fourths of the right lung field shows a definite increased density with multiple interspersed translucent anas. A similar picture is seen in the upper portion of the left lung field. Extending outward from the cardiac shadow in the lower left lung field there is density of a sott character, poorly defined and irregularly mottled. B, large saucerized defects of the left fibula with periosteal reaction. Similar destructive defects are seen in the upper shaft of the tibia. C, higher magnification of B. D, left elbow involvement with cortical erosion of the medial epicondyle. E, similar destructive changes in the tarsal na\ icular bone and in the os calcis. 201 202 An Introduction to Medical Mycology if one examines the small abscesses at the periphery of a cutaneous lesion. Pus is expressed on a clean slide, and a cover slip is dropped on it. Bud- ding cells should be readily observed, but if they are not the preparation may be ringed and left for a few hours, after which budding will probably be noted. The organism is more difficult to isolate from sputum or from secondary ulcers on the skin. Tuberculosis verrucosa cutis lacks the peripheral miliary abscesses and is usually of firmer texture. Verrucous areas due to the ingestion of bromides develop more quickly and do not show minute abscesses. Prickle cell epi- thelioma, in contradistinction to the ulcerative variety of blastomycosis, shows a rolled border, more rapid development and usually absence of systemic symptoms; the histology is characteristic. According to jacobson, the systemic form of blastomycosis resembles granuloma coccidioides so closely that a differential diagnosis is made possible only by laboratory methods, i.e., examination of the organism and inoculation of guinea-pigs. (A guinea-pig is usually not infected with blastomycosis; the animal dies of invasion of C. immitis. ) The systemic forms of the disease may simulate tuberculosis. In lung tissue, however, there is less tendency to cavitation (Stober). Osseous involvement is multiple and occurs usually in small bones, with rapid spread and concomitant involvement of the lungs and the skin. Pain is commonly present. A positive reaction to vaccine or a fixation of complement denotes an infection when either is obtained; these reactions are not invariably present in patients with blastomycosis. Smith has pointed out the main features which differentiate true blastomvcosis from blastomycosis-like infections. In granuloma Paracoccidioides the in- testinal tract is commonly affected and the cutaneous lesions are usually in the region of the mouth. (f) Prognosis.— If the diagnosis is made promptly, before there is dis- semination to internal organs, the prognosis is usually favorable. Even after being neglected, the lesions may remain localized and respond to treat- ment. No one can determine whether or when the disease will become systemic; when this occurs, the outlook is not promising, and, according to Jacobson, 90 per cent of such cases terminate fatally. When the central nervous system becomes invaded, the disease is always fatal. (g) Treatment.— (i ) Surgery.— If the lesion is small and accessible, i.e., cutaneous, surgical excision is probably the surest way of eradicating the disease. Other destructive measures, such as surgical diathermy or actual cautery, may be substituted. (2) Roentgen rai/s.— Lesions not suitable for surgical excision should re- ceive filtered roentgen rays in semi-intensive or intensive dosage. (S) Iodides.— Saturated solution of potassium iodide is the usual ve- The Deep Mycoses \ Essentially or Potentially Systemic) 203 liicle. Therapy is begun with L5 drops, well diluted, given three times dail) before meals. The dose is increased 5 drops daily until there are symptoms of intolerance. The dosage just below that which produces symptoms should he maintained lor several weeks or months, according to the response <>l the patient. Tincture ol iodine is sometimes given for a change. Ethyl iodide In inhalation has also been used. (4) Specific vaccinotherapy.— -This was advocated by Stober, who has obtained clinical improvement with its use. Martin and his collaborators believe that desensitization should be practiced in all patients found sensi- tive to the fungus on testing, before any other therapy, such as administra- tion of iodides, is instituted. (5) Colloidal copper.— Jacobson recommended intramuscular injections. (6) Antiserum.— Martin reported favorably on the use of anti-Blastomyces rabbit serum kept for diagnostic purposes. (7) Supportive measures— Thev are of vital necessity, particularly in systemic involvement. Rest, sunshine and a nutritions diet may be helpful. BIBLIOGRAPHY Benham, R. W.: Fungi of blastomycosis and coccidioidal granuloma, Arch. Dermat. & Syph. 30:385, 1934. Bergstrom 3 Y. \\\; Nugent, C, and Snider, M. C: Blastomycosis: Report of case with involvement of skin and bones, Arch. Dermat. & Syph. 36:70, 1937. Brody, M.: Blastomycosis North American type: Proved case from European continent, Arch. Dermat. & Syph. 56:529, 1947. DeMonbreun, W. A.: Experimental chronic cutaneous blastomycosis in monkeys: Study of etiologic agent, Arch. Dermat. & Syph. 31:831, 1935. Foshay, L., and Madden, A. G.: The dog as natural host for Blastomyces dermatitidis. Am. J. Trop. Med. 22:565, 1942. Gilchkist, T. C.: Case of blastomycetic dermatitis in man, Johns Hopkins Hosp. Rep. 1:269, 1896. Martin, D. S.: Practical application of some immunologic principles to diagnosis and treat- ment of certain fungus infections, ]. Invest. Dermat. 4:471, 1941. Montgomery, F. H.: Brief summary of clinical, pathologic, and bacteriologic features of cutaneous blastomycosis (blastomycetic dermatitis of Gilchrist), from observations of James Nevins Hyde and the writer, with illustrations from 13 cases, J. A. M. A. 38:1486, 1902. , and Ormsby, O. S.: Systemic blastomycosis, Arch. Int. Med. 2:1, 1908. Ormsby, O. S., and Miller, H. M.: Systemic blastomycosis, J. Cutan. Dis. 21:121, 1903. Hixiohd, E.: Two cases of protozoan (coccidioidal) infection of skin and other organs, Johns Hopkins Hosp. Rep. 1:209, 1896. Smith, L. M.: Blastomycosis and blastoim cosis-like infections, J. A. M. A. 116:200, 1941. Spring, D.: Comparison of seven strains of organisms causing blastomycosis in man, J. Infect. Dis. 44:169, 1929. Stober, A. M.: Systemic blastomycosis, Arch. Int. Med. 13:510, 1914. 6. HISTOPLASMOSIS This is a rare disease essentially affecting the reticuloendothelial cells and when well developed is almost always fatal. This active type is rarely diagnosed ante mortem. 204 An Introduction to Medical Mycology (a) Historical survey.— The first case of this disorder was described in 1906 by Darling, who was searching for cases of leishmaniasis in the Panama Canal Zone. He considered the causative micro-organism to be a protozoan parasite and named it Histoplasma capsulatum. Rocha-Lima is given credit for first proving the causative micro-organism to be a fungus. DeMonbreun and later Conant as well as others verified this fact and worked out the life cycle of the fungus. Meleney reviewed the subject in a comprehensive monograph. In a later short discussion ( 1942 ) he stated that 47 human cases have so far been described. (b) Etiology.— The causative micro-organism, H. capsulatum, may be discovered by direct examination or culture of the circulating blood, sputum or feces, by spleen, liver or lymph node puncture, or may be recognized in a biopsy section. According to Meleney, the fungus probably exists sapro- phytically in nature. Cases have been reported from widely separated geographic sites. No age is exempt and infants and children seem particu- larly susceptible. A dog and a ferret have been found suffering from the disease. Human subjects with the disease have all come from small towns or farms. The portal of entry may be the lungs, the gastrointestinal tract or an abrasion of the skin ( Meleney ) . (c) Symptoms.— The classic manifestations are hepatosplenomegaly, sep- tic temperature, anemia, leukopenia and progressive loss of weight. Lymph node enlargement may be the predominant feature affecting these struc- tures in the palpable regions, mesentery, intestines and lungs. The bone marrow may be involved early in the course of the disease. In children the first evidence of the disorder may be related to the gastrointestinal tract with nausea and diarrhea. The other symptoms then gradually appear. In general, the disease runs a more rapid course in children than in adults. The chief lesion may be ulcerative enteritis, as in the case reported by Hender- son, Pinkerton and Moore. Pulmonary tuberculosis is frequently found as a concomitant infection. The lungs may be either primarily or secondarily affected and very occasionally are the only site of the disease. When the infection becomes generalized the lungs are almost always involved. Bone lesions and adrenal invasion have been reported. There may be ulcerative lesions of the skin, tongue, nasopharynx or larynx. Purpura has been de- scribed, as have papules, plaques, abscesses and patches of dermatitis. Pal- mer, Amolsch and Shaffer reported an unusual case in which there was mucocutaneous involvement resembling leishmaniasis. Palmer believes that a mild subclinical infection with H. capsulatum is prevalent in certain parts of the country. This explains the finding of pulmonary calcification in patients showing negative reactions to tuberculin and coccidioidin, par- ticularly since many of these patients react to histoplasmin. Christie and The Deep Mycoses (Essentially or Potentially Systemic) 205 Peterson agreed with this opinion. They found the histoplasmin test posi- tive in KS1 children From middle Tennessee who had pulmonary calcifi- cation. The) cited a possible example of a nonfatal infection with II. capsulatuni. (d) Pathology.— Gray or white nodules may be noted in the spleen, liver, lungs and intestines as well as other tissues and organs. The niesen- Fig. 65. Histoplasmosis. teric lymph nodes are usually involved. The lesions are necrotic, simulating tuberculosis. In the spleen and liver the fungus is found in the fixed reticulo- endothelial cells. In other parts of the body it may be found in various phagocytic cells. (e) Differential diagnosis.— In the classic cases, leishmaniasis may be simulated. When lymph node enlargement predominates, Hodgkin's dis- ease, leukemia or lymphosarcoma may be considered. Pulmonary tuber- culosis or a chronic ulcer of the skin may be difficult to rule out in other cases. In all instances, the diagnosis is made by demonstration of the caus- ative fungus in smear, culture or biopsy section. (f) Prognosis.— In the well advanced ease the outlook is hopeless, and no therapy has yet been developed which has influenced the fatal outcome. (g) Treatment.— Since the diagnosis is usually made after death or late in the course of the disease, no specific therapy has had a fair trial. Meleney 206 An Introduction to Medical Mycology believes that antimony in the trivalent form (fnadin) and the pentavalent form (neostam) should receive particular attention. BIBLIOGRAPHY Chhistie, A., and Peterson, J. C: Pulmonary calcification in negative reactors to tuberculin, Am. J. Pub. Health 35:1131, 1945. Conant, N. F.: Cultural study of the life-cycle of Histoplasma capsulatum Darling 1906, J. Bact. 41:563, 1941. Darling, S. T. : A protozoon general infection producing pseudi (tubercles and focal necrosis in liver, spleen and lymph nodes, J. A. M. A. 46:1283, 1906. DeMonbreun, W. A.: Cultivation and cultural characteristics of Darling's Histoplasma cap- sulatum, Am. J. Trop. Med. 14:93, 1934. Henderson, R. C; Pinkerton, H., and Moore, L. T.: Histoplasma capsulatum as cause of chronic ulcerative enteritis, J. A. M. A. 118:885, 1942. Meleney, H. E.: Histoplasmosis ( reticuloendothelial cytomycosis), Am. J. Trop. Med. 20:603, 1940; Histoplasmosis, New York State J. Med. 42:346, 1942. Miller, H. E.; Keddie, F. M.; Johnstone, H. C, and Bostick, W. L.: Histoplasmosis: Cutaneous and mucomembranous lesions; mycologic and pathologic observations, Arch. Dermat. & Syph. 56:715, 1947. Palmer, A. E.; Amolsch, A. L., and Shaffer, L. W.: Histoplasmosis with mucocutaneous manifestations: Report of case, Arch. Dermat. & Syph. 45:912, 1942. Palmer, C. E.: Nontuberculous pulmonary calcification and sensitivity to histoplasmin, Pub. Health Rep. 60:513, 1945. 7. COCCIDIOIDOMYCOSIS This appears as an acute infection or in the form of granuloma coc- cidioides. The majority of cases of this disorder originate in the San Joaquin Valley and Los Angeles County, California, and for this reason it is famil- iarlv known as the California disease. There have been scattered cases in the Middle and Southwestern States, but in most instances the patients had lived in California. Smith stated that in a number of cases the disease origi- nated near El Paso, Texas; Farness reported five cases of the disease from Arizona and the remarkable fact that 90 per cent of the Indians in the Pima Reservation gave positive reactions to the coccidioidin test. Reports from other sections make it apparent that the organism may be more widely dis- tributed than is ordinarily thought. Credit for the first description of the condition is usually given to Rixford, who reported his findings in 1894. Cases of a disease with similar features reported from South America are instances of a different disease (granuloma Paracoccidioides). (a) Period of incubation.— This is between one and two weeks. In an instance of laboratory infection reported by Dickson the period of incuba- tion was seven days. (1)) Etiology.— The causal micro-organism is C. immitis. This fungus has been isolated from soil, from vegetation and from the internal organs of slaughtered cattle and sheep. Ashburn and Emmons found fungi in 25 Fig. 66. Coccidioidomycosis, showing different types <>! granuloma coccidioides. .\. cutane- ous lesions on the back of the neck; the nephrectomy wound was secondarily infected with C. iimnitis. B, verrucous type of cutaneous lesions; note the similarity to blastomycosis. C, cuta- neous lesions ol a patient who acquired the disease in Texas. D, abscess resembling a gumma at the sternoclavicular junction. There was a similar lesion on the forehead. E, subcutaneous abscess. F, two large subcutaneous abscesses. (A, B, D, I', and /•' were kindly given />;/ Howard Morrow, II. E. Miller anil L. B. Taussig, San Francisco; C was supplied by Leslie Smith, El Paso. Texas, i 207 208 An Introduction to Medical Mycology of 105 rodents trapped in the desert around San Carlos, Arizona. Definite identification of C. immitis was made in two animals. No instance has been recorded of transmission of the disease from one human being to another. It is thought that most infections occur through inhalation of dust laden with organisms. In a laboratory worker, observed by us, the infection was acquired from the inhalation of spores from an old culture. An injury to the skin may sometimes provide a portal of entry for the fungus. Most of the patients are laboring men, usually engaged in farming, and a high per- centage are Mexicans. The epidemiology of acute coccidioidomycosis has been carefully studied by Smith. (c) Clinical characteristics.— The primary lesion may be situated on an exposed part of the skin, but the condition more commonly develops first in the lungs, resulting from inhalation of dust containing the fungus. So-called primary involvement of the pelvis, of the meninges or of the bones is probably the first manifestation of systemic dissemination. The primary invasion of the lungs may be accompanied by a febrile state simu- lating influenza or bronchopneumonia. According to Dickson most of these patients recover completely. In a scientific exhibit at the annual meeting of the American Medical Association in 1938 he showed roentgen views of chests in which the process had resolved, in patients whose sputum con- tained the fungus. The roentgenogram of the chest reveals dense shadows in the hilar regions and scattered densities throughout the lungs, indicating parenchymatous involvement. The pulmonary involvement may occur with- out much fever and with only slight cough. Headaches and backache may occur and blood-tinged sputum may be noted. Pleuritic involvement may cause pain to be a prominent symptom. In cases in which the course is un- favorable, evidences of a spreading infection such as loss of weight, night sweats and fever are observed, and signs of lesions in other locations become evident. The acute infection has been reported only from the San Joaquin Valley, where it is known as valley fever or desert fever. A person of any age and either sex may be affected. In 354 instances of the acute illness, there was only a single death, from coccidioidal meningitis (Dickson). Commonly, from eight to 15 days after the onset nodules of erythema no- dosum develop on the shins or in other areas, disappearing spontaneously in four or five days. Recovery from the acute infection usually occurs in three to six weeks. The manifestations of Coccidioides are various, and the course of the disease is unpredictable. Thus the patient with a systemic infection may succumb within a lew weeks, or a chronic locus may remain localized lor years. The primary cutaneous lesions develop as granulomas, which eventually The Deep Mycoses (Essentially or Potentially Systemic) 209 iik-cratc. Healing ma) occur, or papillomatous fungating lesions may result. The secondar) lesions ma) occur in the subcutaneous tissue, causing flaccid abscesses, some oi which reach a large size. Lesions resembling gummas and other granulomas, such as tuberculosis verrucosa cutis, are not unknown. Scrofuloderma may be simulated in the rare eventuality that the disease invades the superficial lymph nodes. The pus present in active lesions is 67, ( loccidioidorrn cosis. thick, yellowish gray and ropy. Temporary healing results from formation of sear tissue. Disfigurement and limitation of movement may be produced. When generalization occurs, almost any tissue or organ may become in- volved. The symptoms may be mild at first, and the course nia\ be pro- longed. However, if there is rapid and widespread dissemination, a spiking fe\ l the North and South American diseases with special reference to Paracoccidioides brasiliensis, Arch. Dermat. & Syph. 33:31, 1936. Moore, M.: Blastomycosis, coccidioidal granuloma and paracoccidioidal granuloma, Arch. Dermat. & Syph. 38:163, 1938. 9. TORULOSIS (EUROPEAN BLASTOMYCOSIS) This disease is due to a yeastlike organism with a predilection to in- volvement of the central nervous system. In a recent monograph, Cox and Tolhurst stated that more than 100 cases have been reported. In 1895 Busse and Buschke described cutaneous lesions due to yeastlike organisms. In 1905 von Hansemann reported the first recognized case of infection of the brain. In 1916 Stoddard and Cutler first described the clinical and pathogenic characteristics of the disease, the cultural findings and results of animal inoculation of the causal organism. Torulosis has been reported from most parts of the world; in the United States the majority of cases occur along the eastern seaboard or in the South. It is not uncommon in South Australia. (a) Etiology.— The micro-organism, Cryptococcus hominis (Torula his- tolytica), is commonly found as a saprophyte on the skin and also in the throat and the gastrointestinal tract. It is to be found on many plants. It is probable that some strains assume virulence. As a rule the exact portal of entry is obscure, although it is thought that the upper part of the res- piratory tract is the usual route. Men are affected twice as frequently as women. Two thirds of the patients are between 30 and 60 years old (Levin). In over 250 specimens of spinal fluid from patients with syphilis, furnished us by Girsch Astrachan and by Bruce Webster, we found no evidence of infection. (b) Symptoms.— The symptoms are usually referable to the central nervous system. As a rule, the disease begins insidiously. A subacute upper respiratory tract infection may be the first evidence of invasion. Persistent s< \ ere headache, stiffness of the neck and vomiting are characteristic. Later, dimness of vision or actual blindness may occur. Paralysis and convulsions are not uncommon. The patient may be afebrile or may have intermittent low grade fever. Stiffness of the neck, neuroretinitis, choked disks, diplopia, nystagmus, strabismus and hyporeflexia may be found. Laboratory investi- 216 An Introduction to Medical Mycology gation is usually of no help until the spinal fluid is examined. This is usually under increased pressure and contains an increased number of cells, mainly lymphocytes. An increase in the amount of albumin and of globulin and a meningitic colloidal gold curve are sometimes observed; the chlorides may be diminished. There is a progressive loss of weight; after several weeks, months or even years the patient becomes comatose and dies of respiratory failure. Cutaneous lesions, alone or associated with the lesions in the central nervous system, are noted in approximately 5 per cent of patients. These consist of localized abscesses and tumefactions; later, ulcers may form. Enlargement of lymph nodes is present in about 15 per cent of infections and Hodgkin's disease has been confused in at least one case (Wile). According to Weidman, the usual cutaneous lesion is a granuloma, which develops so rapidly that abscess formation is simulated. There is usually no surrounding erythema or pain. The lesion may regress spontaneously in four to eight weeks. In all instances the cutaneous variety later assumes the cerebrospinal form. Wile noted subcutaneous and deep-seated nodules resembling ecchymoses, ranging from a small plaque to involvement the size of a hand and having no tendency to ulceration. Generalization with particular involvement of the lungs is a rare possi- bility. In the case reported by Fitchett and Weidman, there was wide- spread visceral involvement and Hodgkin's disease was also present. It is uncommon for the disease to affect the mucous membranes, the bones or the joints. (c) Differential diagnosis.— Tumors of the brain, tuberculous menin- gitis, syphilis and other disorders affecting the central nervous system may be ruled out by the symptoms, by the physical findings and by cul- turing spinal fluid on dextrose agar. The last-mentioned procedure may be the only possible means of definitely deciding the diagnosis. Torulosis should be considered whenever symptoms are referable to the central nervous system. The diagnosis is rarely made before death. (d) Pathology.— Various sites of the central nervous system may be involved, and the findings are various. Cysts and gelatinous tumors are common. The inflammatory reaction is usually slight, but endothelial hyper- plasia is marked, and giant cells are usually noted. Caseation is sometimes seen, and in the case of Cudmore and Lisa there was a cicatrix in the brain. The organism may usually be seen in large numbers. In cutaneous torulosis a granulomatous process is present, with enor- mous numbers of giant cells of the foreign body type, very little inflam- matory reaction and a peculiar form of caseation which may lead to ulceration. The Deep Mycoses (Essentially or Potentially Systemic) -17 (e) Diagnosis. -This is established In demonstrating In the India ink technic, or by culture, the thick-walled budding cells in centrifuged speci- mens of spinal Quid, sputum, blood or mine (see pp. 336 II. ). (I 1 Phogxosis.— When the disease affects the central nervous system the outcome is invariably fatal. This may be partly because in most cases the diagnosis is not made until alter death and suitable treatment lias not been instituted. (g) Treatment.— Symptomatic measures are indicated; these include sedation and repeated withdrawal of spinal fluid. Fever therapy may be considered, although we have had no experience. Treatment with the sul- fonamide drugs has been advocated and there are several favorable reports. Tt is advisable to administer both sulfadiazine and penicillin in large dosage and. if improvement is noted, to continue both drugs for several weeks after all symptoms have disappeared. The administration of iodides to the point of intolerance may also be considered. BIBLIOGRAPHY Hi wham, H. W.: Cryptococci, J. Infect. Dis. 57:255, 1935. , and Hopkins, A. M.: Yeast-like fungi found on skin and in intestines oi normal subjects, Arch. Dermat. & Syph. 28:532, 1933. Buschke, A.: Ueber eine durch Coeeidien hervorgerufene Krankheit des Mensehen, Deutsche med. Wchnschr. 21:14, 1895. Busse, O.: Ueber Saccharomyeosis hominis, Virchow's Arch. f. path. Anat. 140:23, 1895. Cox, L. B.j and Tolhurst, J. C. : Human Torulosis (Melbourne: Melbourne University Press, L947). I in mitt. M. S., and Wkidman, F. D. : Generalized torulosis associated with Hodgkin's dis- ease, Arch. Path. 18:225, 1935. Freeman., W.: Torula infection of central nervous svstem, J. f. Psychol, u. Neurol. 43:236. 1931. , and Wkidman, F. D.: Cystic blastomycosis of cerebral gray matter caused by Torula histolytica Stoddard and Cutler, Arch. Neurol. & Psychiat. 9:589, 1923. \o\ Hansemann: Ueber eine bisher nicht beobachtete Gehirnerkrankung durch Hefen. Verhandl. d. deutsch. path. Gesellsch. 9:21, 1905. Levin, E. A.: Torula infection of central nervous system, Arch. Int. Med. 59:667, 1937. \l wisiiAi.i., M., and Teed, R. W.: Torula histolytica meningoencephalitis: Recovery following bilateral mastoidectomy and sulfonamide therapy, J. A. M. A. 120:527, 1942. Mitchell, L. A.: Torulosis, J. A. M. A. 106:450, 1936. Mook, W. H., and Moore, M: Cutaneous torulosis, Arch. Dermat. & Syph. 33:951, 1936. Stoddard, J. L., and Cutler, E. C: Torula infection in man. Monograph 6, Rockefellei Institute for Medical Research, 1916. Wkidman. F. D. : Cutaneous torulosis, South. M. J. 26:851, 1933. W'ii.k. I'. [.: Cutaneous torulosis, Arch. Dermat. & Syph. 31:58, 1935. 10. RHINOSPORIDIOSIS This mycosis is uncommon in the United States, the majority of cases being reported from India and Ceylon, with only a few eases from widely scattered parts of the world. 218 An Introduction to Medical Mycology (a) Etiology.— Almost all humans affected are children and young men. Horses, cattle and mules have been found infected. Trauma has been con- sidered a factor. There is no evidence that the fungus causing the disease ( Rhinosporidium seeberi) is air-borne. Stagnant water is suspected as a source. (b) Clinical characteristics.— In a predominant number of cases, the disease is confined to the anterior nares. Occasionally it spreads to other sites on the face or to the posterior nares. At first there is a mucoid discharge and pruritus is troublesome. The lesions develop slowly, are sessile but later tend to become pedunculated and may eventually weigh up to 20 Gm. The tumor mass is red, soft, moist, friable and lobulated. Older lesions become verrucous and may resemble a cauliflower. When the disorder is neglected, the pharynx and larynx are not uncommon sites for extension, and obstruc- tion is produced. The conjunctiva may be involved; the lesions are red, polvpoid and speckled, and bleed readily. (c) Histology.— There is downgrowth of the epithelium, which is some- what acanthotic. The connective tissue proliferates, and new blood vessels are present in large numbers. Chronic granulation tissue is present in the cutis. The predominant inflammatory cell is the plasma cell. Fungi sur- rounded by leukocytes may be present in clumps in the upper cutis, de- tectable clinically as white or yellow specks. (d) Differential diagnosis.— The site of the lesion, the readiness to hemorrhage and the mottled appearance of the lesion are suggestive points, and a definite diagnosis can usually be established by direct examination of material from the lesion or from the nasal secretion. The lesions of blas- tomycosis and of paracoccidioidal granuloma are not vascular but are firm, papillomatous and crusted. Tuberculosis affecting the anterior nares would be present only if the patient had pulmonary involvement. Car- cinoma is rarely seen in this site and usually shows a rolled edge. Granu- loma pyogenicum bleeds easily but is a firmer, more rapidly growing tumor. (e) Prognosis.— The lesions are usually only of local significance. Unless thoroughly destroyed, they tend to recur. (f) Treatment.— Some form of local destructive treatment, such as electrodesiccation, is indicated. BIBLIOGRAPHY Allen, F., and Dave, M. L.: Treatment of rhinosporidiosis in man based on study of 60 cases, Indian M. Gaz. 71:376, 1936. Ashworth, J. H., and Turner, A. L.: Case of rhinosporidiosis, Edinburgh M. J. 30:337, 1923. Barnshaw, H. I., and Read, W. T., Jr.: Rhinosporidiosis of conjunctiva. Arch. Ophth. 24:357, 1940. Karunaratne, W. A. E.: Rhinosporidiosis in Man (Ceylon: Columbo Catholic Press, 1939). The Deep Mycoses (Essentiallti or Potentiallt/ Si/stemic) 219 11. ASPERGILLOSIS 'Tin's is an uncommon and ill defined disorder which usually affects the Lungs. It is due to one or more species o\ Aspergillus. (a) Etiology.— In our routine work we commonly isolate by accident one ol many species ol Aspergillus. The assumption is that tin's genus is widespread in nature. Thorn and Church were able to collect 350 different species. Aspergillus fumigatus lias been isolated more frequently from dis- eased tissue than any other species, and the consensus is that it may be pathogenic (see Chapter XXXIV, "Fungi Probably Pathogenic"). Pigeons, parrots and other birds are vulnerable and may be the medium of ex- posure. Bird fanciers, grain handlers and wheat threshers are said to be prone to the infection. In a group of cases reported by Sayers and Meri- wether, A. fumigatus and Aspergillus niger were thought to be the cause of a lung infection simulating miliary tuberculosis. (b) Symptoms.— The lungs may become primarily involved. The course max be acute or chronic. Acute bronchopneumonia is simulated in the first instance and tuberculosis in the second. According to Jacobson, hemoptysis is commonly associated with this infection. There is less emaciation than with pulmonary tuberculosis of similar involvement. The recovery of a species of Aspergillus from lesions on the skin may at times be significant (see section on otomycosis, pp. 168 f. ), but careful controls and experiments are required, since the organism is notoriously a secondary invader. (c) Differential diagnosis.— If the lungs are infected, the chief dis- ease to be differentiated is tuberculosis. Repeated failure to isolate tubercle bacilli, the freedom of the apexes of the lungs as seen by roentgen study, the atypical onset and course and at times the history of exposure all favor the diagnosis of mycotic infection. Infection with M. albicans may be readily differentiated by microscopic and cultural studies. Before making a diagnosis of probable aspergillosis, one must exclude other diseases and must repeatedly isolate the micro-organism in massive quantities. Asper- gilli may be cultured from normal sputum. (d) Prognosis.— The course of the disorder may be prolonged. (e) TREATMENT.— 1. The origin of the infection should be ascertained if possible, and the patient may be' advised to change his environment or occupation in order to escape further exposure. A gauze mask should be worn by grain threshers, if susceptible. 2. If tuberculosis can be definitely excluded, potassium iodide should be employed in ascending dosage. 3. Bed rest, wholesome food and fresh air are advisable. 220 An Introduction to Medical Mycology BIBLIOGRAPHY Hethehington, L. II.: Primary aspergillosis <>1 lungs, Am. Rev. Tuberc. 47:107, 1943. [acobson, II. P.: Fungous Diseases (Springfield, 111.: Charles C Thomas, Publisher, 1932), p. 270. Sayers, R. R., and Meriwether, K. V.: Miliary lung diseases due to unknown cause, Am. T. Roentgenol. 27:337, 1932. Schneider, L. V.: Primary aspergillosis of lun^s, Am. Rev. Tuberc. 22:267, 1930. Thom, C, and Church, M.: The Aspergilli (Baltimore: Williams & Wilkins Company, 1926). 12. MYCOSES OF THE LUNGS Of the invasive, deep-seated and potentially fatal mycotic infections, coccidioidomycosis is the only one that is regularly acquired by inhala- tion. This results in an acute inflammation of the lungs simulating one of the common acute upper respiratory diseases. Most patients recover spon- taneously. The lungs may be involved late in the course of the disease in the occasional instance in which there is not complete recovery from the initial acute infection. It is probable that a primary and benign form of histoplasmosis affecting the lung parenchyma is not uncommon in Ten- nessee and in some other sections of the United States. With spontaneous healing calcification occurs, with the final roentgen appearance of a miliary nodular calcific process. With the other rare invasive fungous infections, the lungs may share in a widespread involvement of many tissues and organs. Infections due to B. dermatitidis, S. sehencki or A. bovis ma}' become systemic and the lungs become invaded through the blood stream. Another fungous disease of the lungs, due to inhalation of A. fumigatus, is frequently of occupational origin among grain workers and is usually comparatively banal, with a good prognosis for cure. In general, these infec- tions are not difficult to diagnose provided the possibility of fungous dis- ease is kept in mind. Tuberculosis may be simulated. The latter disease is distinguished by the history, the sputum examination and the appearance of the roentgenogram. In general, tuberculosis has a predilection for the apexes, while the typical sites of involvement of the mycoses are the middle and lower pulmonary fields. Positive identification of the causative fungus is requisite to establishment of diagnosis. This is accomplished by study of a fresh mount (as in actinomycosis), by examination of a specimen mounted in hydroxide (coccidioidomycosis), by culture (sporotrichosis) or by a combination oi these methods. Skin tests using specific antigens may be useful, particularly with histoplasmosis of the benign type. It should be remembered that tuberculosis also may be present. In addition to the aforementioned well defined and well recognized types of involvement of the lungs, there is a considerable number of cases The Deep Mycoses (Essentially or Potentially Systemic) 221 in which tlu* lung disease is assumed to be caused by Fungi, usually with- out substantial proof. Monilia albicans may be particularly singled out as frequently blamed because it is found in the sputum of patients with an atypical disorder ol the lungs. During the past few years we have studied the role of fungi in chest diseases. The results show that M. albicans is a frequent secondary invader of diseased tissue (such as carcinoma) but rarely initiates disease. It was thought to be the primary cause of death in only one instance, a conclusion which could not be substantiated by postmortem examination. In three other cases there was good evidence that M. albicans was the causal invader and cure followed the administration of iodides. Our study included specimens from 250 patients. In over 100 ambulatory patients in a control series with no pulmonary symptoms, there was a high percentage of air-borne fungi in the sputum, but fewer instances in which M. albicans showed so vigorous a growth. From our observations and study we conclude that one must be careful in assigning a pathogenic role to fungi because they are found in sputum. The air-borne molds, with the exception of A. fumigatus, may be dismissed as unlikely patho- gens. Monilia albicans may very occasionally be pathogenic. The finding of known pathogens such as A. bovis (in granules) and C. immitis must always be considered significant. BIBLIOGRAPHY Carter, L. A.: Pulmonary mycotic infections, Radiology 26:551, 1936. Doub, H. 1'.: Roentgenologic aspect of bronchomycosis, Radiology 34:267, 1940. CHAPTER XI Fungous Diseases and Compensable Dermatoses AN ACCURATE (cultural) diagnosis of fungous disease or adequate JTx. proof that such a disease is not present may be of special importance to patients who apply for help under one of the state laws on workmen's compensation. If a mycotic disease is contracted while at work, the worker is entitled to compensation. The hands are the usual site of the rash. There is no good evidence that contact dermatitis predisposes to the invasion of fungi. Fungi certainly would not select inflammatory tissue such as an eczematous patch from choice. The dermatophytes prefer noninflammatory tissue. However, we have frequently observed that an acute tinea may be followed by increased susceptibility to sensitizing and irritating agents, ex- pressed as an eczematous eruption, often supervening on and becoming more serious than the original fungous disease. 1. PRIMARY DERMATOPHYTOSIS OF THE HANDS Sometimes the patient's work may be directly responsible. For instance, the occurrence in a bank teller suggests an occupational origin, since han- dling of paper money may be the source. A fellow worker who has the dis- ease may be the important focus. The diagnosis of primary dermatophytosis of the hands should not be based solely on clinical grounds but should be verified by microscopic and cultural studies. Each case presents an individ- ual problem, and it is important at least to attempt to trace the origin of the proved infection. In this way additional proof is gained of the occupa- tional or nonoccupational origin of the infection, and prevention of further spread may be obtained. In many instances, taking an accurate history will reveal other cases. While the diagnosis of primary fungous infection of tin hands is probably too frequent, the disease should not be overlooked. 222 Fungous Diseases and Compensable Dermatoses 223 2. DERMATOPHYTID SECONDARY TO A FUNGOUS FOCUS The criteria tor the diagnosis of dermatophytid are given in another part of the 1 hook. This diagnosis should never be made from clinical inspection alone. There must be a fungous focus elsewhere, a positive reaction to trichoph) tin and a reasonable certainty of exclusion of all other possible cutaneous disorders, particularly dermatitis venenata. 3. NONMYCOTIC DISEASE There are numerous types of rash which may appear on the hands. A negative reaction to the intracutaneous trichophytin test will exclude dermatophytid. It is beyond the province of this work to discuss further the differential diagnosis of eczematous eruptions of the hand, such as dermatitis venenata, pompholyx, acrodermatitis and pustular psoriasis (see the section on differential diagnosis of dermatophvtosis, Chapter IX, pp. 120 ff.). 4. THE RARE MYCOSES Such infections as sporotrichosis may be of occupational origin. Pul- monary moniliasis and aspergillosis in grain handlers have been reported. Lane classified fungous diseases of employees who are examined for industrial disability as follows: (a) Primary mycotic infection due to poor working conditions or con- tact with an infected fellow worker. (b) Exacerbation of a previous mycotic infection due to working con- ditions. (c) Fungous infection superimposed on industrial dermatitis. (d) Industrial dermatitis following fungous infection. (e) Mycotic infection bearing no relation to occupation. BIBLIOGRAPHY Downing, J. G: Dermatophytosis and occupational dermatitis, J. A. M. A. 125:196, 1944. Lane, C. G: Mycotic Skin Infections in Relation to Industrial Dermatoses, in Deliberationes Congressus dermatologorum internationalis (Leipzig: Johann Ambrosius Barth, 1935), p. 216, and in Wise, F., and Sulzberger, M. B.: The 1937 Year Book of Dermatology and Syphilology (Chicago: The Year Book Publishers, Inc., 1938), p. 29. Peck, S. M.; Botyinick, I., and Schwartz, L.: Dermatophvtosis in industry, Arch. Dermat. & Syph. 50:170, 1944. PART TWO LABORATORY METHODS Platl-: II. Many fungi show characteristic colors in culture. The color is inherent and not dependent on exogenous Factors. Upper left, Microsporum ferrugineum; upper right, Microsporum fulvum; loner left, Achorion schoenleinii loner right, Tricho- phyton violaceum. CHAPTER XII Introduction THE procedures for laboratory investigation of mycotic disorders arc on the whole, not difficult to master. The methods outlined here arc those which we use in our mycologic laboratory at the New York Hospital and in private practice. They have been proved by experience to be efficient. We realize that one cannot instruct the novice in all the minute details without practical demonstration. The mediums and technic of the mycologist differ somewhat from those of the bacteriologist. Since most lungi grow well at room temperature, a higher temperature is usually un- necessary. Moreover some fungi which grow luxuriantly at room tempera- lure will scarcely develop when incubated at body heat. This effect may be in part due to desiccation of the agar (lack of moisture) as well as to unsuitable temperature. Culture of bacteria requires incubation in an ele- \ ated temperature. For this reason bacterial contamination of fungous cul- tures is rarely seen; although many species of bacteria normally are present in the mouth, scrapings from the tongue on acid dextrose agar incubated at room temperature are singularly and strikingly free from bacterial contami- nation. The chief contaminants are other fungi, such as Penicillium or Scopulariopsis. Elaborate mediums are not required, and except in detailed work and investigation of minute points only a few mediums arc necessary, unless one is attempting to isolate Actinomyces (closely related to bacteria or Blastomyces. In the former case, incubation at body heat and the use of blood for enrichment may be requisite. In addition, some strains grow only under anaerobic conditions. Blastomyces dermatitidis usually requires in- cubation at 37 C, with blood agar for the primary isolation. At other times growth occurs at room temperature. Another difference between growth of bacteria and growth of fungi on artificial mediums is partly due to the method of incubation. Whereas bacteria multiply and colonization is detectable after a few hours or within a few days, a comparable status with fungi requires from several days to 228 An Introduction to Medical Mycology three or four weeks. On the average, seven to 10 days elapse before a defi- nite report of the species of infecting fungus can be delivered. The large majority of specimens intended for mycologic examination are derived from the cutaneous surface. These include scales, macerated skin, pieces of nail, the roofs of vesicles, pustules or bullae and hairs. At times the specimen may consist of pus from deep cutaneous lesions (either open or closed) or from an internal source (such as an appendiceal abscess). The material may be one of the body fluids, such as blood (for histoplasmosis?), spinal fluid (for torula?) or bile. The sputum usually contains one or more species of fungi. Due care must be exercised in differentiating between the pathogenic and the saprophytic fungi which will be obtained. Study of the oral mucosa (particularly of the tongue) and of the stool (especially in cases of moniliasis ) is frequently an integral part of the mycologic examina- tion. Routine examination of a vaginal discharge is probably a good policy. Pathologists are frequently called on to make an unequivocal diagnosis from specimens of tissue taken by biopsy or post mortem. There is often a close resemblance between the mycoses of granulomatous nature and tuber- culosis and, in the absence of the infecting micro-organism, a definite diag- nosis without directive clinical information may be impossible. As in tuber- culosis, the fungous disease may be acute, in which abscess formation results, or chronic, with the development of giant cells, often in tubercle- like fashion, together with plasma cells, lymphocytes, epithelioid cells and occasional mast cells. CHAPTER XIII Precautions against Laboratory Infections IT IS important never to leave infected slides or instruments where they may be accidentally handled. When they have been used, it is better to dispose of them immediately or to place them in a 10 per cent solution of cresol. The use of rubber gloves may be advisable in theory, but it is seldom carried out in practice. The use of soap and water at frequent intervals is a wise routine. With most of the dermatophytes there is little danger of in- halation of spores from colonies. For this reason it has not been our policy to wear masks when working with them. When one is working with cultures of C. immitis, danger of inhalation is real and a mask should be worn; moreover, care should be taken that there is no draft, as from an open win- dow or from a fan. Another important consideration has to do with old cultures. When the medium dries, it may be incorrectly assumed that the fungi are dead. Through insufficient sterilization they may still be viable and able to cause infections. The floors, the table tops and other accessible and used parts should be frequently cleaned. Sponging with a 3 per cent solution of cresol followed by the use of soap and water is effecth e. The use of a motorized burr to remove nail tissue has become fairly com- mon. We advise against using this device in a laboratory, clinic or office. Sterilization of the instrument is difficult, and it is difficult to keep the in- fected nail material, which is pulverized by the rapidly revolving burr, from being disseminated through the air. If the instrument is used, a mask should be worn and newspapers on which the dust has been collected should later be burned. 2-!!) CHAPTER XIV The Microscope THE microscope is an important instrument in mvcologic work. A be- ginner should become familiar with the various parts and learn the few necessary details of its proper care. The oil immersion objective is only occasionally necessary, as in the examination of scales from a lesion sus- pected of being erythrasma. The low power objective is useful in locating the most desirable field for examination. A trained observer may detect fungi by their appearance under low magnification (approximately X 100). For finer details and for confirmation of the original observation, study of the material under the high dry objective ( above X 400 ) is usually profita- ble. We have found a third objective giving an intermediate magnification (about X 200) useful for the closer examination of many slides. This has a larger field and a greater depth of focus than the ordinary high dry objec- tive; at this power, identification of structure is readily attained. If the prep- aration is flooded with solvent, some of it is almost certain to run over onto the stage of the microscope. If the slide is then removed and the stage washed with a damp cloth, no harm will result. Unless the solvent is removed, the stage will become tarnished and discolored. If the objective accidentally touches the solvent, the solution should be wiped off promptly with a wet microscope paper; otherwise vision is interfered with. Only soft lens paper, especially made for the purpose, should be used to clean the lenses in the eyepiece and objective. The beginner often makes the mis- take of opening the diaphragm too far, allowing an overabundance of light to pass through. Since the material is usually unstained, the light must be subdued in order that fungous elements may be visible. 230 CHAPTER XV Collection of Diseased Tissue SELECTION of suitable material for direct examination and culture is most desirable if. one is to elicit information of value. There are several rules of procedure, but one cannot always give directions for the individual case. Here, as in most technical fields, experience is valuable. If possible, tissue should be removed from a lesion of recent origin. Since treatment may affect the abundance and the stage of development of the fungus, untreated areas are preferable. The components in the medica- ment may obscure the fungus or confuse the observer by their similarity to fungi; i.e., oil droplets may look like yeast cells. When secondarv infection due to pus-forming bacteria has obscured the primary fungous infection, mild bactericidal therapy for a few days will usually enhance the proba- bility of recovering the fungus. Removal of incidental saprophytic fungi from the broken surface of the lesion may usually be accomplished by cleaning with 70 per cent ethyl alcohol. If there are many types of lesion, specimens from all should be secured. An abundance of material is usually desirable, but a small quantity of good material is better than a large amount of unselected tissue. With ringworm of the scalp the infected hairs should be selected while the patient is observed under filtered ultraviolet rays. Samples of many hairs may be obtained by scraping across the infected patch with a sharp scalpel. The first scrapings are used for direct examinations. Further scrap- ings from this cleared surface are transferred directly to the culture me- dium by cutting into its substance with the scalpel. Filtered ultraviolet rays reveal the sites of tinea versicolor, which may not be readily discerned in daylight. When infection results in a porous condition of the nail, the deeper part of the invaded tissue is most apt to contain the pathogenic fungus in pure form. The affected portion of the nail should be cut away; this is advan- 231 232 An Introduction to Medical Mycology tageous not only for obtaining a satisfactory specimen from the exposed base but is also important in therapy (see under treatment of onychomy- cosis, pp. 135 ff. ). For direct examination, a small portion of material from the nail bed is more desirable than large clippings or even the entire nail. When there is little horny (scaly) material, it is impracticable to attempt to identify the fungus by direct examination. In this case one must rely on cultural methods. With the lesions under treatment, the amount of material to be obtained may be reduced, and cultural methods alone will be effec- tive in demonstrating the continued presence of a pathogen. It may be mentioned here that fungi are frequently to be found at the sites of appar- ently cured lesions; in such a case, unless treatment is continued, the infec- tion may recur. If mycosis of the lungs is suspected, a specimen of sputum or a fragment of tissue should be obtained bronchoscopically. Thus one may determine whether Monilias, Actinomycetes or other organisms noted in a direct smear or in culture from a casual specimen of sputum are actually invading the lung or are merely present in the mouth as saprophytes. If the fungous material is found in large amounts or if the same species of micro-organism is repeatedly isolated in the presence of negative results of studies for tuberculosis, carcinoma and other pulmonary diseases, primary fungous disease may be considered probable. While it is often customary to collect a pathologic specimen from a patient and place it on a sterile slide or in a sterile container for inoculation of mediums and examination at a later time, we prefer to transfer material directly from the patient to the culture medium. This makes possible the selection of tissue most favorable for culture and also cuts down the inci- dence of contaminants. CHAPTER XVI Care of Instruments THE following instruments are placed on our tray to be used in obtain- ing specimens: 1. Bard-Parker scalpels (curved blade) 2. Heavy duty cuticle clipper, to remove infected nail tissue 3. Scissors (sharp, pointed, curved) 4. Forceps 5. Syringe (tuberculin) with 20 gage needle, to aspirate pus 6. Safety razor of standard make, to shave scalps when indicated If sterilization is effected by boiling, the cutting edges of the instruments soon become dulled. In order that this may be prevented, the instruments after use are immersed in a 10 per cent solution of cresol for at least half an hour. They are then washed in water and placed in a 70 per cent con- centration of alcohol (saturated with sodium bicarbonate), where they are left until used. There is no rusting in either solution, and the instruments can be left in either for an indefinite period. The syringe and the needle are sterilized by placing in boiling water for 10 minutes. It is well to have from four to six scalpels available so that examination of patients will not be retarded because of the time necessary for steriliza- tion. The sharpest blade, which may be identified by placing a piece of adhesive plaster on the handle, should be used when working on nails. 233 CHAPTER XVII Care of Glassware USED slides are first separated from the cover slips; both are then placed separately in 10 per cent solutions of cresol, which cleans and sterilizes. After a few days they are rinsed in water and dried for use. The same solutions of cresol may be used repeatedly. Discarded tubes of used mediums may be conveniently sterilized and cleaned in the following manner. With the cotton pledgets in place, the tubes are put in an upright position and left under a steam pressure of 15 lb. for one hour. All growth is thus destroyed. While the agar is still liquid, the pledgets of cotton are removed and the tubes are filled with hot water. The water dilutes the agar so it cannot again harden, and the con- tents of the tubes now may be safely discarded into a drain without causing trouble. The tubes require little more than a soaking in a solution of de- tergent, such as Soilax, and a rinsing in clear water to be ready for use again. With this teehnic, breakage is reduced. Petri dishes are best sterilized separately. After sterilization, as outlined in the preceding paragraph, they are allowed to cool. The agar is then re- moved with a spatula and the dishes are washed with soapy water or with a solution of detergent. If anv tubes have been sealed with paraffin, cleaning them separately will prevent the filming of other glassware. If wax pencil has been used to label tubes or Petri dishes, it is preferable to remove the marks with benzene as the dishes are discarded and before sterilizing. 234 CHAPTER XVIII The Direct Examination THE purpose is to determine the presence of fungous material. In many instances this is sufficient to establish the diagnosis. With tinea versi- color and a few other mycoses, this is the sole method of confirming the clinical diagnosis. A positive result is much more valuable than a negative one, since the latter is based only on a sample and this may fail to contain fungous elements which are present elsewhere. Furthermore, treatment decreases the amount of fungous material to be seen. The direct examination does not establish the identity of species except in certain instances, which will be described later. The reason is that in the filamentous stage usually observed, most fungi appear similar. 1. SOLVENTS AND STAINS For ordinary routine use we have not found anything better than a 10 per cent solution of potassium or sodium hydroxide. With more concen- trated solutions crystallization may occur, and this prevents or interferes with the examination. Furthermore, the more caustic solutions are hard on the hands. Other solutions which have been advocated include xylene, sodium sulfite and chloral hydrate in acacia, but there are disadvantages in the use of these and of other advocated solvents which we have tried. A solvent which may be used when time can be allowed for clearing of the material and which offers a semipermanent specimen is an aqueous solution containing 5 per cent potassium hydroxide and 25 per cent glycerin. With this, little or no crystallization occurs and the material does not dry. In the examination of pus, when for instance actinomycosis or blastomvcosis is suspected, this solution is advantageous as a sob cut since the pus cells are destroyed and the fungous material becomes more apparent. Stained slides are seldom practical for the routine demonstration of fungi which cause superficial diseases. It is difficult to hold stain with potassium 235 236 An Introduction to Medical Mycology hydroxide, which tends to decolorize. The use of lactophenol, as first de- scribed by Amann and later endorsed or modified by Langeron, Linder, Henrici, Swartz and Conant, and others, is probably the best method of staining fungi in fresh tissue. The following formula is used: Phenol crystals 20 Gm. Lactic acid, syrup 20 Gm. Glycerin 40 Gm. Water 20 Gm. Cotton blue (C 4 B Poirrier) 0.05 Gm. The last ingredient is added after the other materials have been dissolved with gentle warming. The fresh tissue is first partially digested on a glass slide, using a 10 per cent solution of potassium hydroxide. When sufficiently softened, the preparation is flooded with water which is then removed by absorption, using blotting paper. When the hydroxide has been entirely removed, the tissue is stained by the lactophenol solution and a cover slip applied. If desired, cement may be placed around the edges of the cover slip. When it is desired to hold for examination at a later time a slide prepared with 10 per cent potassium hydroxide, a drop of a 50 per cent aqueous solution of glycerin is placed at the edge of the cover slip. It will slowly mix with the hydroxide, producing a homogeneous mount which may preserve the specimen for several weeks or even months. Care must be used that the cover slip is not disturbed. Such a method as this is useful when one does not at first find the material which should be present or if a thorough search must be delayed. Thin scales, such as those of tinea versicolor, erythrasma or pityriasis capitis, may be placed on a slide, washed in acetone to remove fat and mixed for three minutes with methylene blue, which is then drawn off with blotting paper. The specimen is then dehydrated with a 95 per cent con- centration of alcohol and xylene and is mounted in Canada turpentine. This method gives a permanent stained mount, but it is not suitable for thick sections. Huber and Caplin use a preparation of polyvinyl alcohol, a plastic, for mounting thin tissue as well as for preserving material from cultures (see section on binding agents, Chapter XXIV, p. 262). 2. MAKING THE PREPARATION Place the material on one end of a clean glass slide and add a small drop of a 10 per cent solution of potassium hydroxide. Put on a cover slip and add almost enough hydroxide to fill in the 1 space between the cover slip and the slide. Pass the slide through the (lame of a Bunsen burner three the Direct Examination 237 or lour times. Examine il under the microscope. II the preparation is nol clear, reheat it and examine it again. Repeat tliis until the tissue is clear enough to provide satisfactory examination. The material is placed on one end ol the slide so that the fingers are not burned when the slide is being heated, and the potassium hydroxide is added cautiousl) to avoid flooding. As an alternative method il an immediate examination ol the mount is unnecessary, the prepared slide ma\ be left warming over a microscope lamp. 'This prevents disorganization ol the tissue to be examined. Care should be taken thai evaporation docs not cause crystallization. II the slide becomes dry, water may be added, rather than more hydroxide, so that the crystals are redissolved. Many other methods and reagents have been described. Reports of some are mentioned in the bibliography. BIBLIOGRAPHY \i mi w k /., J., and Gohny, W.: Uebcr eine vereinfachte Farbungsmethode zur Darstellung von Fadenpilzen in Schuppen und Haaren in der ambulanten Praxis, Dermat. Wchnschr. 101: 1031, 1935. \\iw\. |.: Conservierungsfliissigkeiten und Einschlussmedien fiir Moose, Cloro und Cyano- phyceen, Ztschr. f. wissensch. Mikr. 13:18, 1896. CoRNBLEET, T. : Reagent for demonstrating fungi in skin scrapings and hair, J. A. M. A. 95: L743, L930. Kesteven, H. L.: New method of staining skin and hairs for detection of fungi, Brit. |. Dermat. 49:500, 1937. Langeron, \I.: Precis de microscopie (Paris: Masson & Cie, 1925). Linder, D. H.: An ideal mounting medium for mycologists, Science 70:430, 1929. Moore, M.: Mycologic technic in dcrmatologic practice, Arch. Dermat. & Syph. 34:880, 1936. Schubert, M.: Zur Farbung der Hautpilze, Dermat. Wchnschr. 105:1025, 1937. Swartz, J. II., and Conant, N. F. : Direct microscopic examination of skin: Method for de- termination of presence of fungi, Arch. Dermat. & Syph. 33:291, 1936. CHAPTER XIX Appearance of Fungi on Direct Examination THE various Hyphomycetes which cause infections may be seen in the skin or its appendages either in the filamentous or in the spore stage. In the earliest phase of the infection the filamentous form is noted exclu- sively. Later, spores are observed, and in older infections they predominate. We have thought it best to describe the findings in the sections on the various tissues. 1. HAIR Filaments are rarely noted except in hairs infected with A. schoenleini. Spores vary in size, being largest in the endothrix Trichophyta (T. vio- laceum, T. crateriforme, T. sulfureum). The hair shaft may be noticeably invaded when infection is due to these micro-organisms and less so when it is due to one of the Microspora (such as M. lanosum or M. audouini). With the last-mentioned fungi, the spores are present in the sheath of Henle, externally to the hair shaft. The position of the spores (whether they are external to or are invading the shaft) may sometimes be deter- mined in a freshly made specimen, before the hair becomes too flattened, by moving the objective up and down. The appearance of infected hair may be noted in the accompanying illustrations. The predominant infections in hairs are caused by several Microspora. With these, small round spores in mosaic form are seen on the shaft of the hair. In the endothrix infections, the spores are usually seen in linear formation, since they are derived from the filamentous stage by segmentation. When the infection is due to A. schoenleini, the amount of material is less than with other infections, and filaments, which may be irregularly segmented, are commonly observed. In addition, air bubbles are often present. Because of this characteristic picture, favus may be 238 Appearance of Fungi on Direct Examination 239 recognized on microscopic examination. In ectothrix infections (T. gyp- seum, T. niveum, T. purpureum), the spores arc of medium size and occur in irregular groups, compact or loose, outside the hair shaft. We seldom see follicular infections due to ectothriv 2. SCALES With tinea glabrosa the fungus is usually present in the scales as fila- ments (Fig. 69). If the infection is of long duration, numbers of spores may he noted. It should he mentioned here that spores may be readily confused with artefacts such as oil droplets. With tinea versicolor there are groups of spores (double-contoured) and numerous filaments which readily become segmented (Fig. 88). When scales from lesions of tinea cruris are removed and examined, filaments or spores in chains are seen. If the infecting micro-organism is E. inguinale, the elements are large. The number of elements present in a specimen may vary, but with E. inguinale the number is usually greater than with T. purpureum or T. gypseum. 3. MACERATED SKIN The appearance of T. gypseum, T. purpureum or E. inguinale is similar to that noted in scales; i.e., the fungus occurs as chains of spores. Monilia albicans is sometimes revealed as clusters of spores and nonseptated hyphae. 4. ROOFS OF VESICLES Here again septate mycelium or chains of spores may be noted, sometimes in profusion. It is in this tissue particularly that one is apt to note mosaic fungi, the exact nature of which is as yet imperfectly understood (see the section on artefacts, Chapter XX, p. 246). 5. NAIL TISSUE In leukonychia trichophytica, fungi are noted on the surface of the nail. When there is overlapping of toes, the nail on which an adjacent toe rests is frequently infected. In other infections due to T. gypseum and in those due to T. purpureum the infection is often seen in the deeper part of the nail. One may observe hyphae similar to those noted in scales, macerated skin or the roofs of vesicles. These seldom branch; the elements are fairly homologous, and they are not seen in a tangled network. Many spores may B > D Fig. 69. Appearance of ringworm fungi in scales, roofs of vesicles, macerated tissue or nails. A and B, hyphae showing no septations, as frequently seen in infections of short dura- tion. C and D, sporulated mycelium characteristic of infections of longer duration and com- monly noted with tinea unguium; X 400. E and F, short filaments, the result of disintegration. 240 Appearance of Fungi on Direct Examination -II In' present. One rarely observes the fructification bodies which are seen when pathogenic fungi are cultured on artificial mediums. Alter treatment, nail tissue may be the only available source ol infected material in which fungi can be demonstrated. In nails invaded In M. albicans, when the marginal discolored and under- mined tissue is examined, clusters ol round cells in mosaic pattern are to be found. Filaments are rarely seen. Oil droplets must he differentiated from the yeastlike cells. 6. PUS When material from the contents of superficial pustules or blebs is .ex- amined, fungi are rarely found. Pus aspirated from deeper lesions or re- moved from a discharging sinus should be examined for the structures of one ol the fungi which produce granulomas. Granules or noticeable small clumps of organisms may be quickly observed when a drop of fresh pus on a slide is covered with a cover slip. They usually denote an Actinomvces. Sporotrichum schencki is difficult to demonstrate in direct preparations. The budding micro-organism of Blastomyces and the endospores of Coc- cidioides may be found. More detailed descriptions will be found in the section on the various deep mycoses. 7. SPUTUM The direct examination usually is not reliable, even if the specimen is centrifuged, since contamination is hard to eliminate. However, Actino- myces bovis and M. albicans are both recognizable in the forms in which they appear. It is well known that fungi are notorious as secondary invaders in pathologic tissue. As such, they may also harm the host. Cultural studies followed by critical analysis and correlation with clinical facts are here doubly advisable. Dickson has shown that C. immitis is not uncommonly observed in the sputum of patients in the San Joaquin Valley of California who have a febrile pulmonary disorder. 8. FECES In routine examination for M. albicans, cultural technic alone is gen- erally used. If care is taken that the specimen is not contaminated with air-borne fungi, there is usually no difficulty in obtaining a growth of M. albicans. Bacteria in the specimen do not grow well on acid dextrose agar at room temperature. 242 An Introduction to Medical Mycology 9. BLOOD In searching for H. capsulatum both stained and unstained mounts should be examined. The micro-organism is usually found intracellularly. 10. STAINED SECTIONS Sections of pathologic specimens from lesions in the skin or in other organs may reveal fungi of many different species. If one is trained in observing the appearance of unstained slides, the staining characteristics and the shrinking of the specimen are apt to cause difficulty in recogni- tion of the fungus. Practice will overcome this difficulty, although one may hesitate to make a definite diagnosis from a given slide. Structures such as those observed in blastomycosis or coccidioidomycosis are characteristic even in stained preparations. CHAPTER XX Dubious Fungous Forms and Artefacts T HE forms to be described will be observed fairly frequently, and their appearance should be readily learned. 1. THE MOSAIC FUNGUS The majority of those who have examined many scrapings have expressed the opinion that the so-called mosaic fungus (Weidman) is an artefact. Stumpf claimed that the mosaic fungus is made up of free fatty acids. Davidson and Gregory stated that the mosaic fungus consists of choles- terol crystals; Cornbleet and his eo-workers agree with this observation on the basis of their experiments using fluorescence microscopy. Some still hold that it is a degenerate form of a pathogen. Dowding and Orr re- viewed the literature and cited their own experiments as evidence that the mosaic fungus is transformed from T. gypseum. They have observed ( as we have ) that ordinary hyphae and mosaic segments are occasionally to be seen in apposition; that normal spores and hyphae are sometimes part of the mosaic formation, and that the amount of mosaic material increases while the numbers of living fungi decrease during the healing of lesions. The appearance of the mosaic form was described by Weidman as follows: The segments are irregularly shaped, and are separated from each other by nar- rower or broader, but definite spaces; they have a moth-eaten appearance, and their edges and corners are rounded off. The) do not have any organized internal struc- ture; arthrospores are not visible within the segments. But it is the arrangement ol the mycelium that raises the question whether this is fungus— not so much that it occurs in smaller and larger patches, but that the mycelium ramifies and anastomoses around the individual epidermal cells in such a way as to suggest that air or other relraetile matter had become imprisoned between the cells. These hyphae vary in width, until finally one recognizes only threadlike filaments coursing between the ceils. It requires fine discrimination to come to the conclusion that these are fungus and not inert inter- 243 V 6 H Fig. 70. Foreign material frequently found in skin .scrapings. A, cotton fiber. B, wool fiber. C, plant fiber. D, mosaic fungus, the exact nature of which is in dispute. E, wood fiber and air bubble. F, crystals of potassium hydroxide which have dried on the surface of the cover slip. G, amorphous debris from lesions treated with zinc ointment. II, oil globules, which may simulate fungus spores. 244 *-..-v B Fig. 71. Elastic fibers present in a deep section of skin or in pus may be confused witli hyphae (see text, p. 246). Magnification: A, X 220; B, X 480. 245 246 An Introduction to Medical Mycology cellular accumulations. I have applied the term "mosaic" to this form because, follow- ing as they do the intercellular clefts, the hyphae come to surround smaller and larger polyhedral spaces, which collectively give the "pavement" effect. The remarkable fact that this form is seen only in locations and usually in lesions suggesting a fungous origin has not yet been satisfactorily ex- plained. In lesions equally inflammatory or in scaly conditions of the skin remote from the hands and feet it is seldom isolated. Thus in the scales of psoriasis, pityriasis rosea, or seborrheic dermatitis, the mosaic form is unknown. The mosaic fungus may indicate a fungous infection without being of definite fungous structure. 2. SAPROPHYTES If the amount of vegetative fungous material is large, if there is branch- ing, if there is a green or brown tone or if the individual segments are large or of different sizes, one is fairly certain that the fungus is not a pathogen, judicious selection of material after one discards superficial scales or nail tissue will usually obviate the necessity of deciding whether the fungus is a saprophyte or a pathogen. In open lesions, particularly those of long duration, saprophytic fungi may colonize in the diseased tissue and will perhaps produce clinical symptoms. 3. ARTEFACTS Oil and grease, air, hairs, cotton fibers, feathers and many other sub- stances may cause trouble for the novice. One should mount specimens of various artefacts and become familiar with their appearance. The varia- tions in size of the oil droplets or air bubbles stand out in contrast to the relative uniformity in size of spores or yeast cells. With structures such as cotton fibers, examination of the ends will show a ragged or square effect, whereas a fungous filament is always rounded at its ends. Green and Shepard drew attention to the possible confusion with elastic fibers when the specimen is a shaving of skin extending into the cutis. Elastic fibers may be observed at times in pus. The profusion of fibers, the absence of cross-walls, their translucency and the variability in size serve to differen- tiate them from fungi. BIBLIOGRAPHY Cornbleet, T.; Schorr, H. C, and Popper, H.: Mosaic fungus: An intercellular artefact. Arch. Dermat. & Syph. 48:2l water l>\ heating. 3. \li\ tlu- corn meal and the agar. I. Filter through cotton. This is a slow process, and the agar will cool and harden unless the flask is placed in a steam bath or sterilizer. r>. Measure the mixture into test tubes. 0. Autoclave the tubes for 20 minutes at a pressure of 15 lb. 7. Slant the tubes and leave them until the medium is solid. POTATO-CARROT AGAR This agar is useful in demonstrating the color characteristics ol a colony. Carrots 20 Gm. Potatoes 20 Gm. Vgar 15 Gm. Distilled wain 1,000 cc. 1. Wash and peel the vegetables and cot them into small pieces, then add them to TOO ee. of water and boil the mixture down to 500 cc. Filter through paper. 2. Dissolve the agar in 500 cc. of water by heating. 3. Mix the vegetables and the agar. 4. Measure the mixture into test tubes. 5. Autoclave the tubes for 20 minutes at a pressure of 15 lb. 6. Slant the tubes and leave them until the medium is cooled. WORT AGAR This commercial medium, a Difco product with a pi I of 4.8, is a good substrate for the isolation and differentiation of the yeasts and yeastlike organisms, as it almost entirely eliminates the growth of bacterial con- taminants. This is due to the high hydrogen ion concentration, which, while not harmful to yeastlike fungi, inhibits the growth of bacteria. WORT AGAR ENRICHED WITH FAT To freshly made Wort agar, a sufficient quantity of ether extract of crude lanolin or butter is pipetted over the surface and allowed to dry. Benham recommends this agar for the isolation of Pityrosporum ovale. ANAERORIC MEDIUM (RREWER) This medium is chiefly used to isolate Actinomyces. Pork infusion solids 1.0 Gm. Peptone (thio) 1.0 Gm. Sodium chloride 0.5 Gm. Sodium thioglycollate 0.1 Gm. Agar 0.05 Gm. Water q.s. ad. 100.0 cc. 254 An Introduction to Medical Mycologij To tin's basic Formula may be added: Methylene blue 0.0002 Gm. Dextrose 1.0 Gm. The methylene blue is an indicator; the dextrose is for enrichment. This medium may be obtained from Baltimore Biological Laboratory, 432 North Calvert Street, Baltimore. BIBLIOGRAPHY Benham, R. W. : Cultural characteristics of Pityrosporum ovale: Lipophylic fungus, J. Invest. Dermat. 2:187, 1939. Brewer, J. H.: Clear liquid mediums for "aerobic" cultivation of anaerobes, J. A. M. A. 115:598, 1940. Hodges, R. S.: Cultures of ringworm fungi on Sabouraud's proof mediums and on mediums prepared with American peptones and sugars: Comparative study, Arch. Dermat. & Syph. 18:852, 1928. Lewis, G. M., and Hopper, M. E.: Pigment production by fungi, Arch. Dermat. & Syph. 44:453, 1941. Sabouraud, R.: Les Teignes (Paris: Masson & Cie, 1910). Southworth, W. H. : Specific chemical medium for pathogenic fungi, Arch. Dermat. & Syph. 36:302, 1937. Weidman, F. D., and McMillan, T. M.: Comparison of ingredients of ringworm culture mediums, Arch. Dermat. & Syph. 4:451, 1921. ■ , and Spring, D.: Comparison of ringworm culture ingredients: II and III, Arch. Dermat. & Syph. 18:829, 1928. Williams, J. W.: Effect of variation of ratios of dextrose to peptone on colonies of certain pathogenic fungi, Arch. Dermat. & Syph. 32:893, 1935; ibid. 34:15, 1936. 2. INOCULATION OF MEDIUM The area of skin from which material is to be taken is washed with 70 per cent alcohol. Then it is scraped with the blade of a sterile scalpel, and the material is transferred directly to the agar slant. The material is left on the surface when the scalpel is cut several times across the medium. We use this method for the culture of macerated skin, scales, nail tissue, material from a moist, exuding surface and hair from the scalp. Hair can probably be best removed from the beard by epilating forceps. When hair is removed for the direct examination, a forceps is usually employed so that the entire hair can be examined. The scalpel scraped over the tongue gives one a good specimen from the mouth. Transferring the material im- mediately from the patient to the agar gives a high percentage of cultures free of contamination. A platinum loop of medium strength is useful in transferring a specimen of stool to the surface of the agar slant. The same implement is useful in transferring specimens of serum, spinal fluid, bile or sputum from specimen bottles. Here it may again be emphasized that fresh material is desirable, since most normal and pathologic body fluids are good mediums for the Cultural Methods 255 incubation ol Fungi, and small foci of contaminants, which might be dis- regarded at first, arc soon found in such massive quantities that the) er roneousl) impress one as being of pathogenic titer. Pus is transferred by moans of a sterile syringe or a flamed platinum loop, it the lesion is open. The material should be plaeed near the center of the agar slant. The month of the tube may be flamed over a Bunsen burner after the cotton is taken Out, before and alter inoculation. We have not found that this procedure reduces the incidence of contamination, so we have discarded it as unnecessary and burdensome. Care should be taken that the cotton ping is not contaminated while the inoculation is being made. For instance, it must never be laid down. It should not be withdrawn until the material is on the blade of the knife and is reinserted as soon as the inoculation has been completed. Contamination starting at the upper pole of the agar slant or away from the line of inoculation usually has originated from the outside, while the tube was open. If contaminating organisms appear near or in the lines of inoculation, they have probably been carried into the tube in the substance of the inoculum. To culture Actinomyces from material in which granules are present, add a large volume of saline and shake. The granules settle. The super- natant fluid is drawn off. The granules are washed a second time and are then drawn up into a sterile pipet and transferred to the depth of the anaerobic medium. CHAPTER XXII Characteristics of Fungi on Culture SPECIES of fungi may usually be recognized by their cultural appear- ance. With experience one may recognize many species, as one would a human acquaintance, without having to see all the features. At other times, particularly when variants appear, all the characteristics of the micro-organism may be required in order to determine its nature. The information to be mentioned in this chapter will usually suffice for diagnosis. It is well to examine the inoculated culture medium after two or three days (to see if contaminating organisms are present), after five to seven days (for the early characteristics) and finally after 10 days to three weeks (for the characteristics of the full-grown prime colony). 1. ROUTINE EXAMINATION 1. The date of inoculation should be placed on the label of the culture tube together with some means of identification. When the colony is exam- ined, the age may then be readily determined. 2. The kind of medium used should be noted. It may again be empha- sized that even slight differences in the composition of the medium may alter the cultural appearance. On growths sent to us for identification, we often find it necessary to transfer the culture to our own standard medium to develop the characteristics of the colony with which we are familiar. 3. The number of days before growth is first noted is significant. 4. Rapidity of growth is indicative. If a colony is at prime in seven to 10 days it may be considered a fast grower; if three weeks elapse before it can be recognized, it is a slow grower; most fungi are of intermediate character. The rate of growth is influenced by many factors, such as tem- perature, the depth of the agar and the type of culture medium. In the summer the rate of growth of fungi is noticeably faster than during the winter months; the greater the deptli of agar the faster and more luxuriant 256 Characteristics of Fungi on Culture 257 the growth; culture mediums containing dextrose or other nutrient sub- stances support more vigorous colonies than starvation mediums without these substances. 5. The luxuriance ol growth is characteristic. Fungi differ in their capac ity to develop. One Fungus covers the entire surface of an agar slant within two weeks; another fungus, such as A. schoenleinii, never covers more than a small portion. YVeidman pointed out that there is a difference between volume and luxuriance of growth, although the two are usually seen to- gether. The same factors which influence the rate of growth also affect the character of the colony. 6. Surface 1 configuration aids diagnosis. The gross topographic char- acteristics of colonies (probably due in part to inequalities in growth) vary considerably. A colony may be Hat, rounded, fissured, cerebri form, urn- bilicated, folded or concentrically ringed. More than one feature may be present in the same colony. Changes in the composition of the medium may affect the gross appearance of a colony. The depth of the agar influences the appearance; this can be seen when a growth is present along the entire length of an agar slant where there is considerable variation in thickness. In general, the depth of agar required for mycologic specimens is greater than that used ordinarily in bacteriologic technic. 7. The margin of the colony may be sharply defined or may lade into the medium. 8. The texture of colonial growths of fungi varies a good deal. One ob- serves a downy or filamentous growth when the vegetative aerial mycelium predominates and is loosely arranged. If the mycelium is closer together, the growth appears compact or velvety. A granular surface is due to the presence of spores. A pasty surface denotes a yeastlike micro-organism, and a waxy appearance is characteristic of A. schoenleini. 9. The color both of the colony and of the medium is occasionally an important feature. A violet hue of the colony of T. violaeeum is character- istic. The typical port-wane stain of T. purpureum rarely appears in the growth until after two or three weeks. Pigment usually appears first on the under side of the colony. A brownish discoloration of the medium is ob- served with many different fungi. Many fungi lose their colors after re- peated subcultures. The character of the culture medium is important, since some mediums (like potato) will demonstrate pigment that ordinarily is not present. 10. Submergence of the colony is seen in cultural growths of A. schoen- leini and of several other fungi. Splitting of the medium (due to the wedge of growth) is not uncommon in old, compact growths. The same strain of fungus is subject to a range ot variation in cultural 258 An Introduction to Medical Mycology appearance which may be due to temperature (season), moisture, or other factors. It is difficult to obtain a characteristic colony of T. violaceum or T. crateriforme during the winter months. In winter the early growth of different strains of T. purpureum is fairly uniform, but in summer consid- erable variation in the gross cultural characteristics is common. 2. PLEOMORPHISM After prolonged isolation on a culture medium, many fungi assume a vegetative character, as evidenced by a white fluffy growth almost always starting at the point of inoculation. Within a shor