The Fungous Diseases of Man

By J. Walter Wilson and Orda A. Plunkett

This title is part of UC Press's Voices Revived program, which commemorates University of California Press’s mission to seek out and cultivate the brightest minds and give them voice, reach, and impact. Drawing on a backlist dating to 1893, Voices Revived makes high-quality, peer-reviewed scholarship accessible once again using print-on-demand technology. This title was originally published in 1965.

• Language: English
• Publisher: University of California Press
• Release date: Dec 22, 2023
• ISBN: 9780520308947

J. Walter Wilson

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The fungous diseases of

man

The fungous diseases of man

J. WALTER WILSON, M.D.

Clinical Professor of Medicine (Dermatology), University of California, Los Angeles, and Chief of Dermatology, Long Beach Veterans Hospital, Long Beach, California

ORDA A. PLUNKETT, PH.D. Professor Emeritus of Botany (Mycology) and Research Professor, Department of Dermatology, University of California, Los Angeles

University of California Press

BERKELEY AND LOS ANGELES 1967

University of California Press

Berkeley and Los Angeles

Cambridge University Press

London, England

© 1965 by The Regents of the University of California

All Rights Reserved

Library of Congress Catalog Card Number: 65-23461

Second Printing, 1967

Designed by Betty Binns

Printed in the United States of America

Color Plates Printed in Switzerland

Preface

DURING THE last thirty years the field of medical mycology has been reasonably well covered in a series of textbooks, listed at the end of the Preface. Although appearing with ever-increasing frequency, these books have recently been published somewhat too far apart to keep pace with a rapidly advancing state of factual knowledge. It was not from a desire to fill any such quantitative deficiency, however, that the impetus to write the present volume was drawn. The principal motivating factor was the ever-growing conviction that good fortune had provided us with excellent opportunities to study and acquire experience concerning fungous diseases, perhaps affording some elements of value which we should attempt to make available to others. We now realize that we have matured about as much as our life spans will permit, and that, if we are ever to make any more contributions, we had better be about it.

It has long been evident that the best understanding of a microbial disease could be gained only through close collaboration between clinicians and persons expert in laboratory technical procedures. We formed such a team more than twenty years ago, after each of us had spent almost an equal time span in his chosen profession. The combination of a clinical dermatologist possessing an exceptional interest in the laboratory phases of mycology, and a cryptogamie botanist deeply interested in human fungous diseases, has accomplished much more than either of them could have done alone.

Another tremendous advantage we have enjoyed has been a better- than-average opportunity to learn to know the persons interested in medical mycology, not only in our own country, but in many parts of the world, first through correspondence, and later by frequent personal visits, either by us or to us. The importance of this asset is that many fungous diseases are rather sharply limited to one geographic region, making it impossible for any one person to acquire enough personal experience to write authoritatively about all such diseases.

Two especially good examples of this form of collaboration deserve mention. Late in 1960, one of us (J. Walter Wilson) was asked to write a paper on The Therapy of Systemic Fungous Infections for publication in the AMA Archives of Internal Medicine. The ensuing correspondence made it clear that one person could not possibly write such a paper from his own experience alone. Because of geographic limitations he could speak authoritatively on only one or two such diseases; he would need to seek for the rest of the material in the literature, and hence that part of his article would be hopelessly out of date. The result was a symposium. Contributions were solicited for February 1, 1961, from twenty carefully selected collaborators, each of whom was a renowned expert in one or more of these diseases. All these authorities responded on time, the material was edited as compactly as possible within a month, and the symposium appeared in print in August, 1961.

Participating in the symposium were the following persons, whose inestimable help is once again gratefully acknowledged: Peter Abbott, Teheran, Iran; Gerald L. Baum, Cincinnati, Ohio; Guillermo Fernández Baquero, Havana, Cuba; Arturo L. Carrión, San Juan, Puerto Rico; Norman F. Conant, Durham, North Carolina; Arthur C. Curtis, Ann Arbor, Michigan; Sharat C. Desai, Bombay, India; Michael L. Furco- low, Kansas City, Kansas; Antar Padilha-Gonçalves, Rio de Janeiro, Brazil; Antonio González-Ochoa, Mexico City; E. Richard Harrell, Ann Arbor, Michigan; John H. Lamb, Oklahoma City, Oklahoma; Fernando Latapi, Mexico City; M. L. Littman, New York; Donald B. Louria, New York; Pablo Negroni, Buenos Aires, Argentina; Victor D. Newcomer, Los Angeles, California; Sebastião Sampaio, São Paulo, Brazil; Francisco Scannone, Caracas, Venezuela; Jan Schwarz, Cincinnati, Ohio; Charles E. Smith, Berkeley, California; William A. Winn, Springville, California. The opinions of these experts have been incorporated even more recently into the present volume, and some paragraphs have been reproduced here through the courtesy of the AMA Archives of Internal Medicine.

The second example of collaboration is the Symposium on Immunologic Aspects of Fungous Diseases held as a part of the Twelfth International Congress of Dermatology in Washington, D.C., in September, 1962. Nine similar authorities participated in this symposium, each in his own chosen field: Antar Padilha-Gonçalves, Michael L. Furcolow, Sebastião Sampaio, Norman F. Conant, A. Salazar Leite, Antonio González-Ochoa, Pablo Negroni, Sharat C. Desai, and Kasuke Ito, from whose contributions some of our text has been taken. Credit is also owed to Donald M. Pillsbury and Clarence S. Livingood, editors of the proceedings of the Congress, and to the publishers, the Exerpta Medical Foundation of Amsterdam.

One of our strongest inducements to complete this task was the opportunity to illustrate the volume largely in color. Color illustration has never before been practical because of its prohibitive expense, particularly for a volume likely to have only a limited sale. The generous collaboration of three pharmaceutical companies, each interested in antifungal drugs far beyond the usual profit motive, has made such illustration possible. About six years ago we were asked by F. Hoffmann La Roche, Ltd., Basel, Switzerland, through Dr. J. R. Frey, to assemble photographs in color adequate to serve as illustrations for a series of pamphlets, each devoted to one of the systemic or deep mycoses, and intended for use in the dissemination of knowledge about such diseases. Individual pictures, selected for excellence in teaching value, were solicited from many foreign countries as well as from numerous colleagues in the United States, and the response was very gratifying. We hereby gratefully acknowledge such contributions from Sharat C. Desai, Bombay; Pablo Negroni and Flavio Niño of Buenos Aires; João Aguiar Pupo, Sebastião Sampaio, Floriano P. de Almeida, and Carlos da Silva Lacaz of São Paulo, Brazil; João Ramos e Silva, Antar Padilha-Gonçalves, José Lisboa Miranda, and Arêa Leão of Rio de Janeiro; Tancredo A. Furtado of Belo Horizonte, Brazil; Francisco Scannone, Francisco Kerdel- Vegas, Jacinto Convit, and Dante Borelli of Caracas, Venezuela; Arturo Tapia of Panama; Antonio González-Ochoa, Fernando Latapi, and Pedro Lavalle of Mexico; and Guillermo Fernández Baquero and Francisco Trespalacios of Cuba. Other fine pictures were received from colleagues in the United States through the courtesy of Arthur C. Curtis and E. Richard Harrell of Ann Arbor, Michigan; Vicente Pardo Castellò of Miami, Florida; Edward A. Oliver, Herbert Rattner, and Samuel M. Bluefarb of Chicago; Chester W. Emmons of Washington, D.C.; Morris Moore of St. Louis, Missouri; Norman F. Conant of Durham, North Carolina; Fred D. Weidman of Philadelphia; Michael L. Furcolow of Kansas City, Kansas; Lucille K. Georg of Atlanta, Georgia; Leslie M. Smith and Henry Garrett of El Paso, Texas; John H. Lamb and Rollin Koons of Oklahoma City, Oklahoma; and Carlyn Halde of San Francisco. These pictures, in the form of transparencies, were assembled into thirty-two composite plates by Avis Gregersen, F.B.P.A., of the University of Southern California School of Medicine.

When griseofulvin was discovered by J. C. Gentles of Glasgow, we became active in its evaluation and in instruction in its use, in collaboration with the Schering Corporation of Bloomfield, New Jersey. Through the generosity of this company twelve plates were prepared to illustrate the superficial fungous infections, and ten were prepared to show the gross appearance of colonies of all the fungi pathogenic for man, together with the most common contaminants likely to be encountered by the medical mycologist. The selection of components and the composition of these plates were also the work of Avis Gregersen.

Finally, Glaxo Laboratories of Greenford, Middlesex, England, provided funds for the actual printing of these plates onto paper, another excellent example of international collaboration among Switzerland, England, and the United States. Without such cooperation this volume would never have appeared.

Additional illustrations not in color were gratefully received from Carlyn Halde of San Francisco, Harry Van Velsor of Wilmington, North Carolina, and Frances Keddie of Los Angeles.

Radiographs of the deep mycoses were contributed from the files of the Los Angeles County General Hospital through the courtesy of George Jacobson, who also wrote the legends for them.

We are greatly indebted to Roy H. Wishard of Los Angeles for the diagrammatic drawings illustrating the characteristics of the fungi and their life cycles. The photomicrographs of fungi have been contributed by Lily Clark Davis of Los Angeles. Frank E. Swatek assisted in several phases of mycology.

We gratefully acknowledge permission from Charles C Thomas Publishers to utilize sections of the volume, Clinical and Immunologic Aspects of Fungous Diseases, by J. Walter Wilson, as part of the framework of the present volume.

We are indebted to the editors of the AMA Archives of Dermatology (Walter C. Lobitz, chief editor) and to the American Medical Association for permission to quote from some of our own recent papers published therein.

Finally, the tedious labor of typing and retyping the manuscript several times was done, not only swiftly and indefatigably, but with an unusual degree of accuracy and excellence, by Doris Gihon and Marie C. Plunkett, without whose enthusiastic support the task would never have been finished.

J. W. W.

O. A. P.

Bibliography

Ajello, L., L. K. Georg, W. Kaplan, and L. Kaufman. 1963. Laboratory manual for medical mycology. U.S. Department of Health, Education, and Welfare. Communicable Diseases Center, Atlanta, Ga. Public Health Serv. Publ. no. 994.

Conant, N. F., D. S. Martin, D. T. Smith, R. D. Baker, and J.,L. Callaway. 1944. Manual of clinical mycology. 2d ed., 1954. Philadelphia and London: W. B. Saunders Co.

Emmons, C. W., C. H. Binford, and J. P. Utz. 1963. Medical mycology. Philadelphia: Lea & Febiger.

Gohar, N. 1948. Mycoses and practical mycology. Baltimore: Williams & Wilkins Co.

Lacaz, C. da S. 1953. Manual de micologia medica. 2d ed., 1956; 3d ed., 1960. Rio de Janeiro and São Paulo: Livraria Atheneu S/A.

Langeron, M., and R. van Breuseghem. 1952. Précis de micologie. 2d ed. Paris: Masson.

Lewis, G. M., and M. E. Hopper. 1939. An introduction to medical mycology. 2d ed., 1943; 3d ed., 1948. Chicago: Year Book Medical Publishers.

Lewis, G. M., M. E. Hopper, J. W. Wilson, and O. A. Plunkett. 1958. An introduction to medical mycology. 4th ed. Chicago: Year Book Medical Publishers.

Moss, E. S., and A. L. McQuown. 1953. Atlas of medical mycology. Baltimore: Williams & Wilkins Co. 192 pp.

Skinner, C. E., C. W. Emmons, and H. M. Tsuchiya, revisers. 1947. Molds, yeasts, and actinomycetes, by A. T. Henrici. 2d ed. New York: John Wiley & Sons.

Van Breuseghem, R. 1958. Mycoses of man and animals. Trans. J. Wilkinson. Springfield, Ill.: Charles C Thomas.

Wilson, J. W. 1957. Clinical and immunologic aspects of fungous diseases. Springfield, Ill.: Charles C Thomas.

Contents

Contents

Introduction

PART I The systemic mycoses

1 Comparative pathogenesis

2 Comparative immunologie aspects

3 Therapeutic aspects

4 Coccidioidomycosis

5 Sporotrichosis

6 Histoplasmosis

7 North American blastomycosis

8 South American blastomycosis (Paracoccidoidomycosis)

9 Cryptococcosis

10 Actinomycosis

11 Nocardiosis

12 Mycetoma

PART II The intermediate mycoses

13 Candidiasis

14 Chromoblastomycosis

15 Phycomycosis

16 Aspergillosis

17 Rhinosporidiosis

PART III The superficial mycoses

18 Dermatophytosis

19 Tinea versicolor

20 Tinea nigra

21 Piedra

22 Miscellaneous superficial disorders sometimes attributed to fungi

23 Mycoses of the eye

24 Fungi as occupational hazards

PART IV Fundamentals of medical mycology

25 Morphology of fungi

26 Nutrition of fungi

27 Variation, pleomorphism, and dimorphism in pathogenic fungi

28 Classification of fungi

29 Identification of fungi of importance in medical mycology

30 Laboratory methods of diagnosis

Glossary

Index

Introduction

MYCOLOGY as applied to the study of the cause of disease in plants and animals is the oldest of the microbiological sciences. Far back in antiquity, it was realized that disease was often attributable to parasites that were visible to the naked eye, and with the passage of time it was increasingly believed that forms of life too small to be thus visible were often equally responsible. For want of more detailed factual knowledge, the causes of disease were vaguely referred to as humors or bad air, in a manner reminiscent of that used until quite recently, before the clarifying advent of the electron microscope, in discussing the group of etiologic agents known as filterable viruses.

Not surprisingly, therefore, soon after the discovery that the acuity of the naked eye could be markedly extended by artificial magnifying lenses, such instruments were directed toward the discovery of tiny plant parasites. In 1677, by using the crude hand lenses available at that time, Hooke was able to point out that the disease occurring as yellow spots on rose leaves actually consisted of tiny threads of a living parasitic plant. In 1835 Bassi discovered that a disease of silkworms known as muscardine was caused by a fungus (Beauvaria bassiand), thus proving that plants could parasitize forms of animal life. Shortly thereafter, in 1839, Schoen- lein demonstrated, by discovering the organism causing favus, that a fungus could be the etiological factor in human disease, and three years later Remak reproduced the disease in animals and in himself. Gruby accomplished the same feat independently at about the same time, and succeeded in culturing the causative fungus on artificial media by inoculating specimens taken from the sites of the original infection. He then reproduced the disease by inoculating such culture material onto the areas of intact skin of patients possessing the disease, as well as on normal persons. Gruby thereby fulfilled what later became unjustifiably famous as Koch’s postulates, comprising the criteria necessary for the acceptance of a microbe as the cause of a specific disease. In the succeeding three decades a number of other fungi, such as several species of Microsporum and Trichophyton and those now known as Candida albicans and Malas- sezia furfur, were proved to be the cause of human skin disease. The first discovery that there were systemic or deep fungal infections was Bollinger’s identification of actinomycosis (lumpy jaw) in cattle in 1877, almost simultaneously with Ponfick’s delineation of the equivalent disease in human beings. In contrast with all the above, the science of bacteriology did not begin until the monumental work of Koch in 1876, and that of Pasteur on anthrax in 1877.

In spite of its early precedence, medical mycology was soon far outdistanced by bacteriology and other similar sciences in popularity and scope. Not until R. Sabouraud’s monumental work, Les Teignes, was published in 1910 was any noticeable momentum gained, and only during the last two decades has knowledge of mycology been extensively disseminated. Perhaps the principal reason for such delay lies in the fact that no fungous disease is both dangerous to life and of common occurrence, whereas several of the diseases caused by bacteria, such as plague, cholera, and typhoid fever, formerly killed so many persons yearly that veritable crusades were organized against them. The study of fungi and the diseases they produce could not be expected to attract adequate personnel until at least the easily discoverable answers about such scourges were known. It is difficult, however, to resist the temptation to point out that the subjugation of mycology to bacteriology almost certainly deprived the former science of many workers, some of whom might have discovered penicillin and streptomycin in less than the hundred years that history must record. The entire heavy-metal phase of the therapy of syphilis might have been avoided.

Nevertheless, even with such handicaps, medical mycology slowly but steadily grew in stature. Between 1892, when coccidioidomycosis was discovered by Posadas and Wernicke, and 1908, when Lutz delineated South American blastomycosis, the causative organisms were firmly established for North American blastomycosis (1894), cryptococcosis (1895), sporotrichosis (1898), nocardiosis (1895, and perhaps as early as 1890), and histoplasmosis (1906).

The greatest of all mycologically oriented dermatologists was Sa- bouraud, who began writing in 1892. He completed his first book, Les Trichophyties humaines, in 1894, and his twelfth in 1938. The fifth book in the series (the third directed toward diseases of the scalp) was Les Teignes (1910), a veritable bible for workers concerned with dermatophytes . In 1908 Whitfield established that some types of foot disease are caused by fungi, and discovered the ointment that bears his name by treating his own infection. In 1902 trichophytin was isolated by Plato and Neisser, who called attention to the reaction it could elicit when used on some patients infected with dermatophytes. This remedy was developed much further by Bloch in 1928. In 1925 Margarot and Deveze discovered the phenomenon of fluorescence of hairs infected by Microsporum when viewed under ultraviolet radiation (Wood’s light).

Several factors that retarded the progress of mycology deserve discussion, principally because it is not generally realized that fungous diseases are now so easily controllable that any practitioner can acquire whatever degree of mycological knowledge he may find of practical value in his chosen field. The complicated nomenclature and classification have been greatly simplified; the delineation betweeen pathogenic and nonpathogenic organisms has been clarified; and simple, practical methods have been evolved for direct examination of tissues, for culture and identification of organisms, and for preservation of specimens of value in teaching.

Differentiation between disorders of fungous and nonfungous origin on clinical grounds alone is highly inaccurate. This deficiency always becomes apparent whenever a community acquires for the first time the services of a practitioner interested in mycology; occasionally his laboratory work reveals faulty diagnosis by the most experienced clinicians, and, more often, by those less qualified. After mycological study, better treatment schedules may be selected and a much more accurate prognosis may be made. It is easier to gain and hold the patient’s confidence if scientific mycological methods are employed.

Depending on whether certain fungi are classed as separate species or considered as variants within a species, approximately fifty species of fungi are capable of causing human disease. The resulting clinical syndromes are extremely variable. Some are encountered frequently; others are met very rarely. Some are closely confined to a certain geographic locality, while others are universally distributed. Some are so superficial that the patient is unaware of any abnormality, but others may lead to extensive systemic involvement ending in death. Some fungi are so highly pathogenic and they probably can cause actual infection in all adequately exposed persons; others, called opportunistic fungi, do so only if presented with abnormal human tissues, either localized in certain areas of the body, or generalized because of systemic disease. The rest of the many thousands of species of fungi in the world never cause human disease under any circumstances, although many are parasites on plants.

By strict definition, the title The Fungous Diseases of Man might be expected to include certain toxic conditions caused by the ingestion of fungi, such as the gangrene of ergotism (Claviceps purpurea), the hallucinations of Psylocybe, the poisoning effects of certain mushrooms (Amanita, etc.), the occasional undesirable side effects of the otherwise extremely valuable antibiotics derived from fungi, and perhaps even acute and chronic alcoholism (Saccharomyces cereviseae). This book, however, is devoted only to actual infections caused by fungi in the human species.

In the overall view, fungi cause man more satisfaction than trouble. They raise his bread, ferment his wine and beer, carbonate his champagne, flavor his cheeses, furnish him edible mushrooms, produce drugs to stop bleeding, work diligently to form antibiotics to help him fight bacterial and fungal infections, and help industry to produce many organic acids and other compounds. To the cryptogamie botanist they are even beautiful to behold, and their unending variation is fascinating.

PART I

The systemic mycoses

1

Comparative pathogenesis

FUNGOUS INFECTIONS in man are capable of causing so wide a variety of clinical pictures that it is always wise to include them in the differential diagnosis of almost any disease, with the possible exception of certain acute surgical or medical emergencies. In fact, it has been customary to emphasize so strongly the differences among the disorders produced by various species of fungi that certain fundamental similarities, potentially of even more significance, were relegated into obscurity, or, in fact, failed to be recognized at all until recently. It is obvious that numerous factors are capable of influencing the pathologic picture that emerges from a certain infection.

A tiger will starve to death rather than make any attempt to eat grass, and a cow shows the same reaction if presented with nothing to eat except living animals. We must recognize that in their pathogenic phases different species of fungi are similarly very particular about their diet, although not quite so exclusively as in the above example. Histoplasma capsulatum prefers to live within the cells of the reticuloendothelial system ; Cryptococcus neoformans has a predilection for the tissue of the central nervous system of susceptible persons; Blastomyces dermatitidis especially likes the skin; Paracoccidioides brasiliensis prefers mucous membranes and lymph glands. The dermatophytes luxuriate in the keratin of skin, hair, and nails, but Malassezia furfur limits its diet to the keratin of the skin. Thus, if each of these fungi was contacted by identical human beings in exactly the same manner, the resulting diseases could not even remotely be expected to produce the same clinical picture.

Some fungi are so highly pathogenic that they are probably capable of causing disease in all adequately exposed persons, whereas others invade only tissues presenting an abnormally low resistance. Many factors inherent in the characteristics of the host, even if all other factors are equal, therefore influence the outcome. Age, sex, race, skin color, state of health, and nutrition bring about tremendous variations.

Some fungi cause disease only in certain localized areas or tissues, but others create significant differences in clinical syndromes by becoming widely disseminated through the bloodstream and finding certain regions less resistant than others (though not consistently the same regions in different persons). Variations are also characteristic of the progressive stages of some infections.

If all factors are taken into consideration, interesting similarities may be found among fungous diseases that at first glance appear to be totally different. One of the most neglected factors is determination of the portal of entry of the fungus in infections that are capable of becoming systemically widespread. Formerly, if a fungous infection was first observed as a lesion in the skin, it was concluded that the causative organisms had been inoculated at that point. The wide differences in the appearance and the clinical course of the cutaneous lesions of different deep mycoses were attributed entirely to variations in the activities of the different fungi. Although this explanation is undoubtedly true to a certain extent, it does not account for all the differences, some of which are owing to the manner and locality of the inoculation, while others result from the efforts of the host to resist the disease. Thus, we have not always been certain that we were comparing these diseases in similar stages.

For example, until about ten years ago it was accepted as fact that the inoculation into the skin of three different species of pathogenic fungi routinely caused three different clinical pictures. It was thought that Sporotrichum schenckii produced a chancriform syndrome, characterized by an initial ulcerative nodule at the inoculation site, lymphangitis with nodules along the lymphatic vessels draining the area, and mild regional lymphadenopathy, the entire pathologic process almost always remaining limited to this region; that Coccidioides immitis caused a subcutaneous abscess, whence the infection spread by hematogenous dissemination throughout the body; and that Blastomyces dermatitidis, when similarly inoculated, resulted in a chronic, verrucous skin disorder, slowly spreading peripherally and superficially for many years, but practically never disseminating internally.

These discrepancies were partly resolved by the discovery of several cases in which Coccidioides or B. dermatitidis, known beyond a doubt to have been inoculated into the skin, produced a chancriform syndrome practically identical with that usually seen in sporotrichosis. The original case of primary cutaneous chancriform coccidioidomycosis, reported in 1953 by Wilson, Smith, and Plunkett, was soon confirmed by another case observed by Trimble and Doucette, and later by still another presented by Wright and Newcomer. Winn has observed three more such cases. Keith Maddy has furnished details of three chancriform cases in dogs, which became infected by inoculations into injuries in their paws while digging in animal burrows contaminated by Coccidioides, The status of primary cutaneous chancriform North American blastomycosis still rests on the reports of Schwarz and Baum and of Wilson, Cawley, Weidman, and Gilmer, totaling four cases.

Although few in number, these cases were definitely known to have been intracutaneously inoculated. The study of them has led to the conclusion, supported by ever-increasing evidence, that many, if not all, of the other cases of these two diseases in which the initial lesion appeared in the skin were nevertheless not caused by inoculation at that point, but by dissemination from a previously unrecognized or subclinical primary infection elsewhere in the body, usually the lungs.

Curtis and Harrell have reported a case of histoplasmosis which followed the same chancriform pattern, as also have Tosh and Furcolow. Baumgarten has described a case clinically like the usual form of lymphatic sporotrichosis, except that Nocardia asteroides was the organism recovered by culture. Alarcon, Obadia, and Borelli have reported a similar case caused by N. brasiliensis. In 1927 Guy and Jacob reported a chancriform syndrome caused by Nocardia; the species was not identified.

The chancriform syndrome has thus been observed, with little variation in the clinical picture, in infections resulting from six different species of pathogenic fungi when intracutaneously inoculated. In addition, and again with only slight variations, this picture is also well established as the expected result when several other species of microorganisms result in disease by intracutaneous inoculation, particularly those causing tuberculosis, syphilis, American leishmaniasis, and yaws. The chancriform syndrome, however, has not been reported to have occurred in some of the remaining deep mycoses, notably cryptococcosis, actinomycosis, maduromycosis, South American blastomycosis, and chromoblastomycosis. In some diseases, it is probable that the chancriform syndrome never occurs, while it may do so in others, but only under special obligatory circumstances.

Clearly the first of these circumstances is that the organisms must be acquired by direct inoculation through the skin by means of a wound.

We know the source in nature from which the organisms that cause sporotrichosis, coccidioidomycosis, and histoplasmosis are obtained, and hence we have a clue as to how frequently intracutaneous inoculations may be expected to occur. Sporotrichum grows as a closely adherent moist mat on plants and wood which can furnish thorns and splinters capable of inflicting wounds and leaving therein fragments containing many fungal spores. Conversely, Coccidioides and Histoplasma grow in soil as fluffy mats, with spores so lightly attached and fragile as to blow away in the slightest breeze; it is easy to understand why they are seldom inoculated in any large quantity through the skin, but are almost universally acquired by inhalation. The source in nature of B. dermatitidis was obscure until very recently, when Ajello recovered it from soil. If his finding is confirmed, it will place this organism in line with Coccidioides and Histoplasma.

Cryptococcus neoformans also grows in soil, particularly that contaminated by fecal material from birds and fowl. Some of the species of Nocardia and Streptomyces and the organisms of mycetoma are also soil organisms. All these may behave as Coccidioides and Histoplasma do, and thus may seldom be intracutaneously inoculated. The source in nature for Paracoccidioides brasiliensis is not known, nor has it been proved for the fungi that cause chromoblastomycosis, although species closely similar to these latter are known to grow on dead vegetation from which intracutaneous inoculation could certainly occur.

It is not enough, however, to speculate only on whether or not cutaneous inoculation can occur; we must also consider what happens when it does. The chancriform syndrome is characterized by initial multiplication of the fungal organisms at the site for a brief period, probably only a few days. Then a specific immunologic resistance of the host begins to develop, soon causing an intense infiltration of leucocytes and marked induration and inflammation. The regional lymphatic system becomes involved in this inflammatory process. Immediately the concentration of fungal organisms begins to decrease, and soon they are present in numbers so small that usually they are discernible in histopathologic preparations only by searching carefully through several slides. It has long been known that in sporotrichosis the organisms are too small and sparse to be found in the affected tissues by histologic study, although they are easily cultured. Fetter has recently succeeded in revealing them; but they are so sparse that previous digestion of all polysaccharide material not of fungal origin, followed by intensive periodic acid-Schiff (PAS) staining, is necessary to find them. Similarly, in chancriform histoplasmosis the causative organisms have not been discoverable in the tissues, because they are also very small. These organisms could, however, be found in this stage of coccidioidomycosis and blastomycosis because they are large and easily seen, even though present in very small numbers.

In several microbial diseases, such as malaria and trypanosomiasis, the causative organisms are inoculated through the skin without necessarily producing any lesion at that point. Hence the chancriform syndrome is almost entirely the result of that which the host contributes to the clinical picture in resisting the disease, and it can therefore develop only if the invasion is resisted locally by systemic immunologic means to a fairly high degree. In the chancriform cases of coccidioidomycosis, North American blastomycosis, and histoplasmosis thus far recorded, the resistance has been sufficiently strong to result in complete, spontaneous cure. In sporotrichosis it is usually not quite so effective, as evidenced by the fact that this disease tends to persist if untreated. It is, however, at a sufficiently high level to keep the infection limited to a single limb, and to furnish so much immunologic assistance that cures have been obtained, not only regularly by the favored potassium iodide, but at times by many other drugs, including griseofulvin, amphotericin B, stilbamidine, sulfonamides, and antimalarials. All these remedies fail miserably when pitted against other deep mycoses, and indeed against sporotrichosis in its more dangerous, less well-resisted phases.

This fact may explain the failure of the chancriform syndrome to occur in Cryptococcus infections. This organism is apparently not in the slightest degree pathogenic for normal persons, and those abnormal ones who do become infected usually do not resist the invasion to any degree by immunologic means, certainly not to the extent necessary to produce the chancriform syndrome.

Baquero reports some evidence that the usual chronic cutaneous form of chromoblastomycosis, formerly assumed to have originated by direct cutaneous inoculation, may in reality occur by dissemination from a previously unrecognized primary pulmonary focus. Such dissemination is now widely believed to occur in North American blastomycosis and coccidioidomycosis.

Such variations as these lead to speculation that, if the chancriform syndrome is to appear, the individual must not have been previously infected by the organism. Perhaps intracutaneous inoculation of an appropriate fungus cannot produce the syndrome if the recipient has been previously infected by the same organism via another route, and therefore altered in his capacity to react allergically or immunologically to subsequent exposures. It is even possible that this alteration may be produced by allergic means through the inhalation, not of the specific pathogenic fungi, but of nonpathogenic fungi closely allied to them.

Bibliography

Convit, J., D. Borelli, R. Albornoz, G. Rodríguez, and J. Homez. 1961. Mycetoma, chromomycosis, sporotrichosis, and Jorge Lobo’s disease, [In Spanish.] Myco- pathologia, 15:394.

Littman, M. L. 1959. The systematic mycoses. Amer. J. Med., 27:1.

MacKinnon, J. E. 1959. Revisión critica de la investigación y de la literatura micològica en el Uruguay en el periodo 1946-1956. Mycopathologia, 9:692.

Pillsbury, D. M., and A. M. Kligman. 1951. A new histo-chemical tool for the definitive diagnosis of fungous infections. Trans. N.Y. Acad. Sci., 2d ser., 13:145.

Wilson, J. W. 1956. Comparative pathogenesis of the deep mycoses: the influence of the port of entry. In F. R. Schmidt, ed., Clinical selections in dermatology and mycology, P. 113. Springfield, 111.: Charles C Thomas.

—. 1957. Clinical and immunologic aspects of fungous diseases. Springfield, Ill.: Charles C Thomas.

—. 1963. Cutaneous (chancriform) syndrome in deep mycoses. Arch. Dermatol., 87:81.

2

Comparative immunologie aspects

AT FIRST GLANCE the systemic fungous infections appear to present the most extreme variability conceivable in their immunologic aspects. It is only necessary to compare the almost perfect immunologic response engendered in human beings infected with histoplasmosis (resulting in a death rate of perhaps 1 in 10,000 to 30,000) with the almost complete lack of immunologic resistance usually exhibited by those infected with cryptococcosis. Until recently it was customary to emphasize these differences so strongly as almost completely to ignore several very interesting similarities, whose importance now seems likely to transcend that of all the differences. In fact, it is becoming ever more probable that many of the differences alluded to do not in truth deserve the name, but are simply the result of gaps in our knowledge of the basic processes. One such gap has now been partly closed by the delineation of the chancriform syndrome discussed in chapter 1, which has demonstrated to us that we were previously trying to compare these diseases in what appeared to be the same stage of development, when in fact they were in entirely different stages.

in his excellent monograph The Pathogenesis of Tuberculosis, Arnold Rich pointed out that Nature, in the pursuance of her ends, is frequently profligate with materials, but she is always singularly conservative with methods. The totality of life existing on this planet depends ultimately on one single biochemical reaction, the ability of chlorophyll-containing plants to form nutritive carbohydrates from carbon dioxide and water under the stimulus of sunlight. With but little fundamental variation, hemoglobin carries oxygen in the blood of a fantastically large number of otherwise different forms of animal life.

As Nature does not bother to invent numerous basic processes where one will serve adequately, it is extremely unlikely that she has furnished the human body with a different mechanism for resisting each infectious disease. Instead of emphasizing the differences in immunologic response, we should seek diligently for similarities, hoping eventually to find enough clues to reveal the basic pattern followed in all diseases. In this regard the systemic mycoses apparently have much to offer to the study of immunology, for a few potentially valuable clues are already known, and are constantly becoming better understood and are being more accurately interpreted.

In the example of the extremes mentioned above, the all but complete difference between the immunologic responses to histoplasmosis and cryptococcosis is almost entirely explainable without postulating any basic differences in immunologic mechanisms. It is probably correct to state that Histoplasma capsulatum can infect all normal human beings and cause disease, whereas Cryptococcus neoformans never causes actual disease except in abnormal persons. Of the tremendous number of persons infected by Histoplasma, only a tiny percentage die, and they die because they are abnormal enough to fail to develop acquired immunologic resistance of sufficient quality to result in spontaneous cure. As a result, the death rate of histoplasmosis is actually very close to that of cryptococcosis. The real difference between the two diseases lies in the fact that Cryptococcus causes infection only in individuals who are immunologically defective, whereas Histoplasma may cause disease in all persons and then kill only those who are immunologically defective.

Among the systemic mycoses there are intermediates between the above extremes. Coccidioidomycosis is similar to histoplasmosis, but the death rate is higher (about 1 in 3,000), indicating that the degree of immunologic response is quantitatively lower in a significant percentage of persons. Sporotrichosis calls forth a high degree of immunologic resistance, but still not so high as does histoplasmosis, for it often results in a chronic disease unless treated, though the death rate is very low. North American blastomycosis is considerably lower on the scale of immunologic resistance, and probably still lower is South American blastomycosis. Mucormycosis and aspergillosis are closely comparable to cryptococcosis.

Keeping the above thesis in mind, it is interesting to search for similarities in what little we know of the basic mechanism of immunologic responses to these several diseases. Immunology makes use of a number of tools in studying these responses, such as intradermal and serologic tests of various types designed to reveal the presence of the factors that confer immunity in response to infection.

In the majority of infections where the mechanism is understood, acquired resistance results from the formation of antibodies by the tissues as a result of contact with the organisms. These antibodies are highly specific globulins (proteins) which apparently are closely related chemically to the antigens that stimulated their production. The ability of these antibodies to attach themselves to the organisms and cause them to become mutually adherent, to interfere with their respiration or metabolism, or to cause them to be more easily attached to and engulfed by phagocytes is an integral part of the immunologic process. Apparently a single antibody can, under appropriate circumstances, cause several of or all the reactions known as complement fixation, precipitation, agglutination, lysis, and opsonization, but more frequently such antibodies seem to be separate and able to fluctuate independently.

A question yet to be answered conclusively is whether or not the immunity so quickly acquired by most persons exposed to histoplasmosis or coccidioidomycosis is caused by the production of specific antibodies effective against the disease, although it is almost impossible to explain the specificity of the immunity thus conferred by any other theory. Because coccidioidomycosis has been studied in this regard much longer than histoplasmosis, and many of its immunologic reactions are easier to understand, it serves well as a basis for continued discussion here, upon which some comparisons can later be made.

As early as 1915 researchers began to develop testing procedures for coccidioidomycosis, utilizing extracts of cultures of that fungus as an antigen by intradermal injection and in serologic procedures, but almost twenty years passed before the procedures were sufficiently well understood and interpreted to be useful for diagnosis and prognosis. Their reputation in this regard has now become well established, and they are considerably more constant and reliable than similar processes in other systemic mycoses. A good part of their superiority stems from the fact that it is comparatively easy to obtain an active antigen from Coccidioides in a remarkably pure form without any important variation in the test results caused by the method of its production. Using such an extract, called coccidioidin, at least two antibodies specific for coccidioidomycosis are easily demonstrated in the serum of infected patients.

The complement-fixation reaction, using coccidioidin as the antigen (performed as in the quantitative form of the Kolmer modification of the Wassermann test), reveals an antibody in the serum of many patients with coccidioidomycosis, in titers as high as 1:4,096. This antibody, however, cannot be given credit for helping the human body to resist the disease; it is often entirely absent in persons who are resisting the disease almost perfectly, while it is always present in more serious cases, and continues to rise in titer ever higher as the disease becomes worse, even up to the time of death. It has thus become accepted as a means by which the clinician can measure the severity and the extent of the infection, but not the degree of the patient’s resistance.

The precipitin reaction using coccidioidin as the antigen also reveals an antibody in the serum of persons with coccidioidomycosis. This antibody is entirely different from that of the complement-fixation test, because either may be present without the other, and they cannot be correlated in any way with each other. The precipitin antibody cannot assist the patient in resisting the disease, for it is present only in the first few months of the infection and then disappears, regardless of whether the patient recovers completely or dies. It is at once evident that death from coccidioidomycosis cannot be attributed to the inability of the human body to produce any specific antibody in response to the infection, for specific antibodies, especially of the complement-fixation type, are produced in large quantities. The antibody-production mechanism is therefore not paralyzed; it is working energetically, but its products are useless in the fight against the disease.

Other methods of demonstrating these and perhaps other antibodies in serum are the immune adherence phenomenon, the fluorescent-antibody techniques, and the gel-diffusion procedures, which are presently being intensively studied. Nevertheless, by the methods thus far developed, no effective antibodies have been discovered in the circulating blood of persons who have demonstrated resistance to coccidioidomycosis. This failure does not, however, deny the possibility that such antibodies exist. In fact, there are suggestive phenomena. For example, multiple transfusions of whole blood have often been employed with some apparent benefit in disseminated coccidioidomycosis. It is very likely that in many instances such blood was obtained from donors who had become immune to reinfection by recovering completely from the primary pulmonary form of the disease; in fact, in endemic areas up to 95 percent of the population have acquired specific immunity in this fashion. It is entirely possible that such blood may have helped the patient by furnishing specific antibodies that actually perform the desired function.

The intracutaneous test using coccidioidin reveals an antibody in many persons infected with coccidioidomycosis which parallels rather closely the ability of the patient to resist the disease. Although there is no proof that this antibody is the one actually responsible for conferring immunologic resistance, it is heavily relied upon by clinicians in assessing the prognosis in various stages of the disease. This antibody is usually said to be fixed to the cells and not to be present in the circulating blood (at least not in the serum, although it may be present in circulating cells).

The above-mentioned three forms of antibodies have been similarly demonstrated in several other systemic mycoses, and in many aspects the reactions follow the same pattern as in coccidioidomycosis. It is, however, more difficult to obtain uniform extracts from cultures of the other causative fungi, some of which require more enriched media than Coccidioides for growth; these media may add materials to the extracts which are capable of causing false positive reactions. Also, several of these fungi are biphasic in culture, and each phase may yield a different antigen. So many investigators have used different methods of producing their antigens that it is not difficult to understand why there is still wide variation in their results. Because the tests are very useful in coccidioidomycosis, it would be worthwhile to try to develop antigens specifically selected for their ability to perform the same service in other systemic mycoses.

Nevertheless, despite all these discrepancies, the ability to react to the intracutaneous test with antigens specific for each disease does seem to parallel rather closely the immunologic resistance to sporotrichosis, histoplasmosis, North American blastomycosis, chromoblastomycosis, and some forms of maduromycosis, as it does in coccidioidomycosis. The same reaction probably occurs also in South American blastomycosis. In persons infected with cryptococcosis, phycomycosis, and aspergillosis, skin tests have not produced positive reactions, a result usually attributed to the fact that these fungi are poorly antigenic. It is much more plausible to place the blame on the patient’s immunologic system, which must have been defective if the fungi were permitted to cause disease at all. In all the other systemic mycoses the skin test is equally negative when the patient is resisting the disease as poorly as are those with cryptococcosis, phycomycosis, and aspergillosis. It might be positive if tested on patients who have recovered from these diseases by immunologic