CHARACTERISTICS OF FUNGOUS DISEASES'ARTHUR T. HENRICI

Medical School, University of Minnesota, MinneapolisSicut enim ex certo vegetabilium semine certa planta et non alia,ita ex certo contagioso miasmate certus et determinatus affectuset non alia evolvitur et propagatur.-Plenciz, 1763.

Infectious diseases present specific earmarks which are deter-mined by the species of microbes which cause them; nosologyreflects taxonomy. This fact, so shrewdly surmised by Plencizmany years ago, and so thoroughly established by the painstakingexperiments of Koch and his students, seems to me to be one ofthe foundation stones of our science, a fact so important that Ihave often been astonished by the attitude of indifference, if notactual hostility, exhibited by some medical bacteriologists towardproblems of taxonomy, and by the reluctance of some taxonomiststo accept the pathogenic properties of bacteria as good charac-ters for classification.Of the four great groups of infectious diseases-those caused

by protozoa, viruses, bacteria, and fungi-the last has beenstudied least of all. The common fungous diseases are mild andsuperficial, while those that are deep-seated and endanger life areso rare that one man can seldom see enough cases to make any ex-tensive study of them. The mycoses have therefore been lookedupon as of little practical importance. It is a truism of sciencethat a study of rare and curious objects and events in nature oftenbrings to light general phenomena or principles, which may beexaggerated in the rare but overlooked in the commonplace.Examples are the development of the theory of organic evolutionfrom Darwin's observations of the faunas of the GalapagosIslands, and the development of much of modern physics and

'Presidential address delivered before the Society of American Bacteriolo-gists at its forty-first annual meeting, New Haven, December 29, 1939.

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chemistry from the Curies' observations of the properties ofradium.An investigation of the characteristics peculiar to diseases

caused by a major group of microbes is thus a proper study forbacteriologists, and a study of rare diseases may throw some lighton the mechanisms of commoner ones. It is from these twopoints of view that I propose to discuss the characteristics ofthose diseases of man and higher animals which are caused byyeasts and molds. I have assumed that in an address of thissort it is permissible to stray beyond the confines of establishedfact and to indulge in conjecture.When one begins to go over in his mind what seem to be char-

acteristics of the fungous diseases, he is immediately confrontedwith noteworthy exceptions, and as he jots down these exceptionshe finds that instead of listing common characteristics, he isclassifying the fungous diseases into two great divisions. Oneof these comprises the common, superficial mycoses such asringworm and athlete's foot and thrush, which are almost alwaysmild, do not involve the deeper tissues, endanger life, or evenimpair the general health. The other group includes suchdiseases as sporotrichosis and blastomycosis and coccidioidalgranuloma, which are deep-seated and often fatal. The divisionof the mycoses into these two groups is so sharp, the differencesare so great, that at first glance it seems that they do not haveenough in common to warrant a discussion of the characteristicsof mycoses as a whole. I hope, however, to show that in certainfundamentals they are alike. But it will clarify later discussionif at first I point out some of the differences.Most important of these is the fact that those fungi which

cause superficial mycoses, the dermatophytes and monilias, arenormally parasites of man and animals. Although they haveonce or twice been observed growing free in nature, there is nodoubt that diseases caused by these fungi result either fromcontagion, as in the dermatomycoses, or from an invasion of thetissues by organisms which had previously been existing on thebody as surface parasites, as appears to be the case in moniliasis.On the other hand, the deep-seated mycoses are caused by fungi

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which are known to live normally as saprophytes, or by fungiwhose normal habitat is unknown, but which by all evidenceavailable live free in nature as saprophytes.The evidence that these fungi live free in nature rather than as

parasites is to a large degree circumstantial, but neverthelessconvincing. We cannot find the causative organisms in thenormal human body, and we cannot trace cases of the disease topreceding cases. There have been cases of accidental autopsyor surgical infections, of transmission by bites of rodents andhorses, but these few cases of direct transmission merely serve

TABLE 1Differential characters of superfcal and deep-seated fungous diseases

Normal habit of growthLesions

Age incidence

Occupational incidence

Geographic distribution

Course

Su C MYCOSUS (DMUA-TOMYCOSM, MOSS)

ParasiticMild, superficial, re-

strictedUsually children andyoung adults

No particular occupations

World-wide,stricted

not re-

Self-limited; almost neverfatal

DIEP-SEATED MYCO8E (BeAuro-MYCOS, SPOROTICE&OS, v.)

SaprophyticSevere, deep, spreading

Usually older people

Occupations exposing thetissues to soil or vege-table matter by woundsor inhalation

Restricted, or if world-wide much more preva-lent in certain areas

Progressive; often fatal

to emphasize the general observation that the source of the infec-tion in the majority of cases cannot be determined, that it appearsto be from some place other than the human or animal body.The occurrence of numerous cases resulting from wounds bythorns or splinters, or from wounds contaminated with soil orvegetable matter, their age and occupational incidence, andgeographic distribution,-all tend to confirm the opinion thatfungi capable of causing deep-seated diseases occur naturally assaprophytes.But for the most part the occurrence of these fungi in nature

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ARTHUR T. HENRICI

has not been observed. Those species which cause aspergillosis,mucoriasis and cephalosporiosis may be isolated from almostany rich soil; but these diseases are among the rarest of themycoses. The fungi which cause sporotrichosis, European blas-tomycosis, chromoblastomycosis, and possibly American blasto-mycosis have been recovered once or twice from grains or fruitsor other materials. The remaining pathogenic fungi have neverbeen observed free in nature. It should be noted, however, that asearch for such fungi in soil or other habitats is a difficult pro-cedure, and that only a small number of adequately trainedobservers have been occupied in such research in a rather desul-tory way. A comparable problem is the isolation of typhoidbacilli from water known to give rise to epidemics, a feat whichhas been accomplished only rarely. Admitting, then, that theevidence is imperfect, it seems a good assumption that the fungiwhich cause deep-seated mycoses exist normally as saprophytes.Theobald Smith, in the Vanuxem lectures, explained clearly

the relationships between parasitism and disease. A, successfulparasite is one which in the course of its evolution establishesrelationships with its host such that it may continue to existindefinitely at the expense of its host. If the host is killed, theparasite is also destroyed. If the host tissues are injured, theresulting inflammatory reaction may expel or destroy the para-site. The various pathogenic fungi illustrate very clearly thisrelationship.The dermatophytes and monilias are successful parasites.

They give rise to only a very slight inflammatory reaction of theskin or mucous membranes. They are, however, very primitiveparasites according to the criteria of Theobald Smith. Theyinvade only the skin or mucous membranes. Here they multiplyas mycelium, which gives rise to unicellular forms by fragmenta-tion or budding. These are distributed to new hosts by direct orindirect contact. There is no invasion of the body cavities, nocomplicated life-cycle, no intermediate host to assure distributionto a new host.The dermatophytes have developed a certain degree of host

specificity. Skin lesions of man caused by human species of

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dermatophytes are mild and superficial. They give rise to red-ness and scaling of the skin, to loss of hair, and in some cases tovesicles or eczema-like lesions. Such infections are usually oflong duration. Human dermatomycoses caused by fungi derivedfrom lower animals exhibit more marked and deep-seated inflam-matory reactions. Pus is often formed in the hair follicles, andoccasionally extensive granulomatous lesions may develop. Suchinfections tend toward a self-limited course of shorter duration.The dermatophytes growing upon a strange host are thus lessperfect parasites, but more virulent.The fungi which cause deep-seated mycoses must be considered

very unsuccessful parasites. They have no immediate invasivepower. They are introduced into the tissues through wounds orby inhalation. They burrow deeply into the tissues. Smallnumbers are discharged in pus or sputum, but it is only in therarest of instances that these become transferred to anotherindividual to start a new infection. Mostly they remain buriedin the tissues of their host, upon the death of the latter to bereturned to the earth whence they came. In the sense of Theo-bald Smith these fungi are not parasites at all, yet they invadedeeply, spread widely, and eventually cause death.

It may be suggested that the superficial mycoses caused byparasitic fungi are older in evolution than the deep-seated infec-tions caused by essentially saprophytic species, which may belooked upon as just beginning to experiment with a parasiticmode of life. This may be supported by a consideration of theirgeographic distribution. Moniliases and dermatomycoses arethe same in character the world over. The deep-seated mycosesshow a marked tendency to a restricted distribution. A few,like aspergillosis and sporotrichosis, occur in widely distant areas.But sporotrichosis is more prevalent in the Missouri valley thanother parts of the United States. Chromoblastomycosis hasbeen reported from Russia, Japan, Java and Africa, but fully 90%of the cases have been reported from America, most of them fromBrazil. It is noteworthy that a number of these diseases-Ameri-can blastomycosis, coccidioidal granuloma, paracoccidioidalgranuloma and histoplasmosis-are peculiar to the Western

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Hemisphere. European blastomycosis and the disease knownin America as torula meningitis are caused by an organism whichby all morphological, cultural and serological tests is a singlespecies. But in Europe most cases are primary in the skin orsubcutaneous tissues, and are characterized by multiple abscessesor granulomata in various organs; while in America most casesare primary in the lungs (or are cryptogenic) and are character-ized by lesions of the central nervous system of the "histolytic"type, without any cellular exudate.The restricted geographic distribution of the deep-seated

mycoses has been explained by assuming that they may be causedby fungi which are parasites of plants indigenous to particularareas. No one has as yet demonstrated that this is the case,but this failure may be due to insufficient observation. Cocci-dioidal granuloma is most prevalent in the San Joaquin valley,but some cases do occur in other parts of the United States. Asomewhat similar status obtains in sporotrichosis and chromo-blastomycosis. It is difficult to explain such a distribution onthe basis of plant distribution. Since most of these diseasesbegin as wound or lung infections, insect vectors cannot be in-volved. According to the "age and area" theory proposed someyears ago by Willis, species which are old in an evolutionary senseare more widespread in distribution than younger ones becausethey have had a longer time in which to be distributed over theworld. Although the theory has received considerable oppositionbecause of numerous exceptions that may be noted, it seems to bea reasonable generalization. Perhaps this theory may also beapplied to diseases. The deep-seated mycoses, restricted indistribution and occurring largely in the New World are possiblyvery new in origin. One may suggest that in the evolution ofsaprophytic fungi there occur rarely strains or races in restrictedlocalities which by chance are able to survive and multiply inanimal tissues when accidentally introduced there. Europeanblastomycosis and American torula meningitis may be causedby a single world-wide species which is evolving as two differentsorts of parasites in two different areas.Such diseases as trichophytosis and microsporosis and monili-

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asis appear to occur more frequently in children than in adults,and athlete's foot occurs more often in young adults than in olderpeople. Conversely, the deep-seated mycoses appear to occurmore frequently in later life. Published case reports indicatethat in such diseases as blastomycosis, sporotrichosis and coc-cidioidal granuloma the modal age is about thirty-five years.This age difference in the two groups of mycotic infections maybe considered as further evidence of the parasitic and saprophyticnatures of the two groups of fungi. Children may be exposedby contact with others to infection with dermatophytes whichhave a definite though slight invasive power of their own. Suchinfections give rise to some degree of immunity, since they healspontaneously. The deep-seated fungous diseases require theintroduction of the fungus into the tissues through wounds or byinhalation, and an ability of the fungus to survive and multiplyin the tissues, properties which probably occur but rarely in fungifree in nature. These infections do not give rise to any appre-ciable immunity, since they do not heal spontaneously. Onemay thus explain the incidence of such diseases in later life becausethe longer one lives, the greater are the chances for an accidentalintroduction of rare potentially pathogenic fungi into the tissues.If, as I suspect, there is often required a repeated inoculationbefore infection can occur, this explanation becomes still moreplausible.

Renon, many years ago, reported a series of cases of pulmonaryaspergillosis in people engaged in two peculiar household occupa-tions, the "peigneurs des cheveux" who cleaned hair for wigs withcorn-meal, and the "gaveurs des pigeons" who fattened squabsfor the market by filling their mouths with grain, chewing itfinely, and then forcing the grain into the gullets of the squabswith their tongues. In both cases it was demonstrated thatAspergillus fumigatus was abundant in the grain used. Herethe occupations exposed the workers repeatedly to inhalation ofthe spores. Although not so obvious in other deep-seated fungousdiseases, there is strong evidence that in all of them occupationis an important factor, that they occur most frequently in occu-pations which expose one repeatedly to the danger of fungi

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ARTHUR T. HENRICI

becoming introduced into the tissues from soil or vegetable mat-ter. Farming is, of course, the one occupation which comes tomind at once, and the great majority of serious mycoses haveoccurred in farmers, with general laborers next in frequency.But farmers and laborers comprise the most numerous occupa-tional classes. Fungous disease has been reported as occurringfrequently in other occupations, such as workers in tanyards,persons who pack bottles in straw, cigar makers, trimmers ofbarberry hedges, where one may suspect an increased danger ofinhaling mold spores or of having them introduced into the tissuesthrough wounds. Similar in significance to the occupationalincidence of the deep-seated mycoses is the occurrence of mycosesof the feet, madura foot and chromoblastomycosis, in tropicalcountries where the natives habitually go barefoot. Here thecontinued contact of the feet with the earth, and the repeatedoccurrence of small wounds, may cause repeated inoculations offungi into the deeper tissues. Farmers and others who handleanimals are obviously more subject to skin diseases caused bydermatophytes from lower animals. Fruit pickers and washer-women and others whose hands are constantly wet are subjectto moniliasis of the fingers. Otherwise there is no evidence for aparticular occupational incidence of the superficial fungousdiseases.The theory that the age, occupational, and geographic distribu-

tions of the deep-seated fungous diseases are to be explained bythe saprophytic habit of the causative organisms, as contrastedwith the parasitic habit of those species which cause superficialinfections, is somewhat disturbed by a consideration of the com-mon form of actinomycosis, caused by the anaerobic Cohnistrepto-thrix israeli. In all of its characteristics this is a deep-seatedmycosis. Although world-wide, it occurs more abundantly bothin man and cattle in certain areas, as the north central part of theUnited States. It occurs most frequently in those occupationswhich subject one to the introduction of bits of vegetable matterinto the tissues, and such bodies have been found in the primarylesions far too frequently to be considered accidental. It doesnot seem likely, however, that such a delicate anaerobic organim

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could grow on grain or straw, and it has never been found there.Conversely, Naeslund and Emmons and others have cultivatedorganisms apparently identical with Cohnistreptothrix israelifrom the normal mouth and tonsils. One of my students, Mr.John Slack, has recently succeeded in producing actinomycosiswith typical sulphur granules by repeatedly inoculating rabbitsand guinea pigs with cultures from the normal mouth. Certaincases of actinomycotic osteomyelitis are of such a character thatthey may be explained only on the basis that, as in staphylococcicosteomyelitis, the organism was in the blood at the time of injury.Here then the evidence is conflicting. It does not seem likely,however, that such obvious organisms as the higher fungi whichcause deep-seated mycoses will ever be found to occur as normalbody parasites, and the case of actinomycosis need not thereforedisturb too much the general theory that the character and severityof the lesions, geographic distribution, and incidence by age andoccupation all express the essentially saprophytic nature of thecausative fungi.The deep-seated mycoses differ further from the superficial

fungous diseases in their course. While some cases of ringwormor of thrush may persist for months or even years, or may berecurrent, there is a definite tendency for these diseases to be self-limited and eventually to heal spontaneously. This is moreevident when we study dermatomycoses caused by fungi normallyparasitic on another host. When guinea pigs are inoculatedwith Trichophyton gypseum one may predict very precisely whenthe first inflammatory reaction will occur, how far the lesion willextend, when it will reach its height, and when it will subside.Such a course is characteristic of the majority of bacterial andvirus diseases. The deep-seated fungous diseases exhibit typ-ically a progressive course of long duration, indefinite in itsbeginning, eventually spreading throughout the body and almostinvariably terminating in death. Such a course is similar tothat of tuberculosis and leprosy. It is no mere fancied resem-blance in morphology which justifies our use of the prefix "Myco-"in the generic name of the acidfast bacteria.

Cases differ markedly, of course, and are often altered or

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ARTHUR T. HENRICI

terminated by treatment, but from the collected case historiesone may obtain a general impression which can apply to most ofthe serious fungous diseases. They begin slowly, insidiously.The patient is often unable to tell precisely when his symptomsbegan. These symptoms may have persisted for weeks or monthsor even years before he considers them sufficiently severe to see adoctor. The latter often enough looks upon the lesion as somerelatively harmless chronic non-specific bacterial infection, andtreats it as such for weeks before he becomes alarmed by the

/- ~~Setf-timited Course of :

d. /Superficial Mycoses

0

Progressive Course ofOeep-seated Mycoezs and ofTuberculosis anrd Leprosy

TimeFIG. 1. CURVES EXPRESSING THE COURSES OF SELF-LIMITED AND PROGRESSIVE

INFECTIOUS DISEASES

inexorable spread of the process and seeks expert advice. As thedisease spreads it also accelerates in rate of spread, and frequentlyterminates by hematogenous distribution. Such a course mightbe considered typical for actinomycosis and blastomycosis, bothEuropean and American. It would be somewhat more rapid insporotrichosis and coccidioidal granuloma, slower and incom-plete in chromoblastomycosis.

If one could obtain a quantitative expression of the extent of thelesions and plot these against time, he would obtain a curve that

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rises very slowly at first, then with continually acceleratingvelocity, to end with a terminal sharp rise. Such a curve ex-presses an autocatalytic reaction, and one must assume that indiseases of this sort, the fungus is at first unable to multiply andspread through the tissues, but that its continued presence in thetissues results in a change either in itself or in its environment,so that it eventually can do so. A change in the fungus itselfimplies an adaptation to life in the living host tissues. If thisoccurs, the organism should now be able to infect a new host, thedisease should become transmissible and produce more acuteinfections. We have already noted that nothing of this sortoccurs. A change in the environment implies a decreased re-sistance, or more properly an increased susceptibility, on the partof the host tissues. If one assumes that the fungus can multiplyonly in dead tissues or products of these, that it has very littletoxicity itself, but that its continued presence in the host eventu-ally gives rise to hypersensitivity to the products of the fungus,then one can explain the characteristic course of such infections.The organism cannot immediately extend into new tissue, but itsensitizes first the cells in the vicinity, which are now destroyedby products of the organism, so that it may grow further, to sensi-tize further, and thus continually accelerating finally give rise to ageneralized disease. One may thus explain the apparent occupa-tional character of the severe fungous diseases on the basis thatcertain occupations repeatedly expose the individual to inocula-tions of the organism over a period of time. A first exposure, oreven a second or third, may not result in infection, but may giverise to a state of hypersensitivity so that a later inoculation willresult in infection. There is much clinical evidence to indicatethat in tuberculosis and leprosy a similar condition obtains.These diseases are not likely to result from a single chance con-tact, but from long-continued association with other cases.Such a theory requires a consideration of the mechanisms by

which the pathogenic fungi injure the tissues. No one nowseriously considers that mechanical pressure can explain thelesions of these diseases. Exotoxins have not been demonstratedand it seems highly improbable that they will ever be found.

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ARTHUR T. HENRICI

There remain the two possibilities which have been discussed soextensively in connection with bacterial diseases, the endotoxintheory of Pfeiffer and the allergic theory of von Pirquet. Theformer postulates that the invading microorganism contains withinits protoplasm poisonous substances which act upon the hosttissues only after the death and disintegration of the cells of theparasite. The latter assumes that the parasite is not injuriousdirectly, but becomes so after the host cells have become sensitizedto its products. I do not propose to enter into any discussionof the many arguments that have been advanced to support oroppose these theories, but I would like to point out that they arenot mutually exclusive. Both mechanisms may be operative.There are but two species of pathogenic fungi, Aspergillus

fumigatus and Monilia allicart, which will produce acute diseaseimmediately when inoculated into laboratory animals. In allother instances days or weeks are required for the developmentof lesions and death. In these two cases one may well expect tofind endotoxins. There are mechanical difficulties which haveprevented me from expressing the cell sap from the small yeast-like cells of Monilia albicans, and extracts have proved non-toxic,but from the finely minced mycelium of AspergiUus fumigatusI have been able to obtain a fluid which has distinctive toxicproperties, and which may be looked upon as containing a trueendotoxin. It resembles the poison of the mushroom, Amanitaphalloides, in many of its properties. Similar endotoxins prob-ably occur in some other molds not known to be pathogenic,notably Rhizopus nigricans, and offer, together with the poisonousmushrooms, an interesting field of investigation in toxicology andimmunity. But it seems doubtful that such toxic substanceswill be found in the other pathogenic fungi, since no immediatetoxic reactions occur in animals even when massive doses areinjected.A study of experimental aspergillosis in rabbits provides some

interesting data bearing upon the mechanism of infection in thedeep-seated mycoses. Only intravenous inoculation will producea generalized disease. The nature of the resulting disease de-pends upon the dose inoculated. If one inoculates a large series

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CHARACTERISTICS OF FUNGOUS DISEASES 125

fflow l ..4....s~:t'>irAm li;E

FIG. 2. MYCELIUM OF ASPERGILLUS FUMIGATUS IN A GLOMERULUS OF THE KIDNEYOF A RABBIT KILLED 24 HOURS AFTER INTRAVENOUS INJECTION OF SPORES.

BEGINNING NECROSIS OF THE KIDNEY CELLS

t...., .. '.0

FIG. 3. ABSCESS IN THE KIDNEY OF A RABBIT WHICH DIED 3 DAYS FOLLOWINGINTRAVENOUS INOCULATION WITH SPORES OF ASPERGILLUS FUMIGATUS

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of animals with graded doses, a variety of lesions are obtained.Those animals which receive the largest doses die in a day or two.Congestion and hemorrhages of the lungs, punctate hemor-rhages in the kidneys and other viscera, are the only gross lesionsseen. Microscopic study of the tissues shows that the sporeshave lodged in many tissues and have germinated. The tissuesurrounding the growing mycelium is necrotic, often hemor-rhagic. This then is an acute toxic effect, attributable to theendotoxin mentioned, and the animals undoubtedly die of tox-emia. The amount of toxin formed is probably small, however,for if smaller doses of spores are injected, the animals live longer,and the growing mycelium now becomes surrounded by a collec-tion of pus cells. The mycelium continues to extend into thetissues, and to be surrounded by more and more leucocytes, sothat in animals living four to six days one finds well definedabscesses visible to the naked eye, especially in the kidneys.With still smaller doses the animals survive longer, and thereoccurs a marked change in the lesions in the period from seven toten days after inoculation. The masses of pus cells are nowfound to have become completely necrotic, to have been convertedto a solid caseous material. About this material numbers ofmacrophages accumulate, and many of them fuse to form giantcells. In short, the lesion is converted from an abscess to atubercle.

In the abscess the fungous mycelium is abundant and deeplybasophilic in staining. After caseation necrosis occurs, thismycelium becomes pale and acidophilic. Much of it is phago-cyted by giant cells which wander into the lesion from the periph-ery, and one may follow in many of the giant cells the finaldigestion of this mycelium. But in some instances the myceliumis seen to grow again in the phagocytic cells, not as myceliumproper, but as the peculiar radiating bodies known as the actino-mycetoid form of the fungus. In animals examined earlier thana week after injection it is my impression that the lesions areconfined to the points where the spores have lodged, that therehas been no extension of the process. In animals living tendays or longer there are obviously new lesions, which develop

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CHARACTERISTICS OF FUNGOUS DISEASES 127

FIG. 4. CASEATION NECROSIS OF ABSCESS, WITH FAINTLY STAINED MYCELIUM.SECTION OF KIDNEY OF RABBIT WHICH DIED 8 DAYS FOLLOWING INTRAVENOUS

INOCULATION WITH SPORES OF ASPERGILLUS FUMIGATUS

FIG. 5. PHAGOCYTOSIS OF MYCELIUM BY GIANT CELLS AT PERIPHERY OF LESION.SECTION OF KIDNEY OF RABBIT WHICH DIED 10 DAYS FOLLOWING INTRA-

VENOUS INOCULATION OF SPORES OF ASPERGILLUS FUMIGATUS

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128 ARTHUR T. HENRICI

FIG. 6. EARLY DEVELOPMENT OF THE ACTINOMYCETOID FORM OF ASPERGILLUSFUMIGATUS IN A GIANT CELL. SECTION OF KIDNEY OF RABBIT WHICH DIED 10DAYS FOLLOWING INTRAVENOUS INOCULATION WITH ASPERGILLUS FUMIGATUS

T*u ; vnq

.=~~~~~~~~~~4An

A n d~~~~~~~-P

FIG. 7. ACTINOMYCETOID FORM OF ASPERGILLUS FUMIGATUS IN THE LUNGOF A RABBIT

Note the macrophages which are gathering around the fungus. These eventu-ally form true tubercles.

'JAS41F

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especially in the lungs. These are pure tubercles, with thefungus found as actinomycetoid bodies, now free and growing inthe necrotic material in the center of the lesion.

In such a series of animals death may occur at any time up to amonth or more, but there are two modal times, one at two daysand one at ten days. The former occurs only with very largedoses, and may be attributed to the endotoxin. The latter isshortly after the period when the lesions have changed fromabscesses to tubercles, and coincides with the time when theanimals become hypersensitive to products of the fungus, asdemonstrated by intracutaneous inoculations of cell sap. Suchskin tests may be slightly positive as early as the fifth day, and avery marked response with purpura and necrosis is obtained bythe tenth day. It is obvious, therefore, that after the infectionhas persisted for seven days or more, something happens whichleads simultaneously to hypersensitivity; to an altered responseof the host tissues, the tubercle; to an altered morphology of thefungus, the actinomycetoid form; and to a dissemination of thedisease to new areas.The actinomycetoid forms of the fungus, peculiar to the later

stages of the disease after sensitization has occurred, consist ofshort filaments of mycelium much thinner than those foundearlier in the disease, radiating from a portion of mycelium ofnormal size. The ends of the filaments are often capped with abit of acidophilic material as in the sulphur granules of actinomy-cosis. Beginning with the experiments of Dienes and Mallory,there is growing evidence that the histological tubercle is itself amanifestation of allergy. Sulzberger has recently shown thattypical tubercles are the end result of the inflammatory reactionwhich occurs when tuberculin, trichophytin or "oidiomycin" areinjected intradermally into sensitized individuals. Although notyet proved, it seems a justifiable assumption that in experimentalaspergillosis the actinomycetoid form of the fungus and thetuberculoid character of the lesion result somehow from theallergic state which develops.Some of the characteristics of experimental aspergillosis may

be found in spontaneous or experimental cases of all of the deep-

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seated mycoses. Actinomycetoid forms of the fungus occur incoccidioidal granuloma, paracoccidioidal granuloma, sporotri-chosis, and possibly histoplasmosis, and the radiating lobulat-edgranules found in actinomycosis and madura foot are examplesof the same phenomenon. Similar radiating bodies have beenobtained experimentally with certain acidfast bacteria andactinomycetes. They are rare in spontaneous disease, obviouslycorrelated with a slow, chronic course. The severe fungousdiseases present lesions sometimes suppurative, sometimes

FIG. 8. RADIATING OR "PRICKLY" FORM OF COCCIDIOIDES IM1MITISSection of omentum of an inoculated guinea pig. The author considers this

to be the actinomycetoid form of the fungus.

tuberculoid, usually mixed. But there is a tendency for themto become more and more granulomatous in character as thedisease progresses. Pure tubercles may be found in all, includingthe more deep-seated cases of trichophytosis and moniliasis.Tubercles or tubercle-like lesions occur in glanders, tularemia andlymphogranuloma inguinale, all diseases which exhibit hyper-sensitivity of the tuberculin type. All of the deep-seated fungousdiseases which have been adequately studied also exhibit hyper-sensitivity manifested by skin reactions of the delayed type.

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Clearly all of these diseases have a common character, tendingtoward a progressive course, the formation of tubercles, and thedevelopment of allergy. Syphilis and leprosy present similarcharacters, but the occurrence of allergy has not been certainlydemonstrated because of the difficulty or impossibility of pre-paring test materials.The general occurrence of an allergic state in the fungous

diseases is further manifested by the appearance of the skineruptions which the dermatologists designate by the ratherpeculiar term "ids." These are nodular or papular or vesicularlesions, sometimes eczema-like, sometimes psoriasis-like, whichappear on various parts of the body distant from the primaryinfection. They are seen most frequently in the dermatomy-coses, where they are called "trichophytid." But a "moniliid"may occur in very prolonged, chronic cases of moniliasis, and a"sporotrichid" in cases of sporotrichosis. These cutaneouslesions do not contain fungi, and it now seems definitely estab-lished that they are caused by a generalized sensitization of theskin, followed by a blood-borne distribution of antigens absorbedfrom the primary lesion. One may produce a generalized erup-tion in guinea pigs sensitive to ringworm fungi by inoculating thepolysaccharide fraction of the fungus into the peritoneal cavity,and may provoke a trichophytid in humans by injecting tricho-phytin. "Tuberculids" occur in tuberculosis, and the "syphilid"or secondary eruption of syphilis and the lepra reaction of leprosymay be similar phenomena, but in these cases there is definitely ablood-borne distribution of the causative organisms to the skin,which may be sensitized.

Coccidioidal granuloma presents some remarkable featureswhen considered from the standpoint of hypersensitivity. Thebrilliant observations of the late Ernest Dickson have establishedthat this disease occurs in three stages, an initial acute bronchialinfection, followed after several weeks by a nodular eruption(erythema nodosum) over the shins, with a chronic stage thatmay appear months or even years later. The erythema nodosummay be considered as the "id" of coccidioidal granuloma. Itloes not appear until the skin tests are positive. It is interesting

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to note that erythema nodosum also occurs in tuberculosis, as asequel to rheumatic fever, and in rare cases of deep-seated orgranulomatous trichophytosis; that in all of these diseases tuber-cles or tubercle-like lesions occur; and that in all of them there is aproved or suspected allergic basis for the lesions. The acutebronchial form of coccidioidal granuloma, known locally as"valley fever," is fairly common, self-limited, and benign. Thechronic stage is much less frequent, not an invariable sequel tothe primary stage. It is progressive in character, usually fatal,and very similar to a severe form of pulmonary tuberculosis inits course and pathology. There is thus a very close parallelismbetween these two stages of coccidioidal granuloma and whatclinicians call "first infection type," and "second infection type,"of pulmonary tuberculosis. The first occurs in children, is cir-cumscribed, and almost invariably heals. The second occurs inyoung adults, is progressive, and often fatal.The material which I have presented, while not conclusive,

strongly suggests that the progressive course and the lesions of thedeep-seated mycoses are dependent upon the state of hypersensi-tivity which develops in the patient. This does not, however,preclude the possibility that a similar mechanism is involved inthe self-limited superficial mycoses. In the dermatomycoses wehave conclusive evidence that the allergic state is responsible forthe injury to the tissues and the consequent inflammatoryreaction. In the experimental disease the fungus grows in theskin for nearly a week without injury to the host cells. Theoccurrence of an acute inflammatory reaction is contemporaneouswith the appearance of hypersensitivity as demonstrated by skintests. After hypersensitivity has developed to a sufficientdegree, a lesion practically identical in character with that ofthe original infection may be produced by an inoculation of asterile solution of polysaccharide extracted from the fungus. Thisis proof that the primary lesion itself is due to the allergic stateof the animal, as clear cut as the proof that diphtheria toxincauses diphtheria. In human cases the degree of skinsensitivityroughly parallels the severity of the lesions, being greatest inthose cases with more deep-seated and purulent infections.

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We have, however, equally definite evidence that in the derma-tomycoses the ultimate healing of the lesions is due to this sameallergic state. For in the, experimentally infected guinea pig,as hypersensitivity continues to develop, the lesion eventuallyclears up. If reinoculated with living spores while still allergic, anew infection develops without any incubation period, i.e., thereis a typical accelerated reaction. But the new lesion is less inextent, and heals much more rapidly. And by continued reinocu-lation, the animal may become immune, at least in the previouslyinfected area of the skin.How can the allergic state be both injurious and protective,

apparently leading to eventual immunity in the dermatomycoses,and to continued spread of the disease, and death, in the deep-seated fungous diseases? I believe that the answer is found inconsidering the seat of the allergic reaction. The Koch phe-nomenon definitely protects the guinea pig against a reinoculationof tubercle bacilli, but an inoculation of tuberculin sufficient toelicit a marked constitutional reaction may lead to a disastrousextension of human pulmonary tuberculosis. In one case theorganisms and the products of the reaction are cast off to theexterior, in the other they are liberated into the tissues. In thismanner an allergic reaction in the skin or on other body surfacesmay be protective, in the lung or kidney it may result in an ex-tension of the disease.

If the hypothesis is correct that the injury to the tissues andthe continuously accelerating spread of the fungus in the deep-seated mycoses are to be explained by the development of hyper-sensitivity to products of the invading organism, it should bepossible to make almost any saprophytic fungus pathogenic byrepeated reinoculations. I do not like to contemplate the longseries of rabbits and guinea pigs which I have sacrificed in vainexperiments of this sort. Such organisms as Cephalosporiumacremonium, Neurospora sitophila, Trichoderma klningi, speciesof Alternaria and Hormodenrdrum, and numerous soil actinomy-cetes have been inoculated in large doses and repeatedly reinocu-lated at varying intervals, with results entirely negative both inthe development of skin sensitivity and of progressive lesions.

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Two series of experiments have yielded some positive results.One concerned the anaerobic actinomyces which causes thecommon form of actinomycosis. This organism has only veryrarely caused infection when inoculated into guinea pigs. I havefound that by reinoculating at intervals, lesions containingsulphur granules can be produced very regularly. Similar andeven more striking results had been previously reported byNakayama, working with the acidfast Proactinomyces asteroides.A second series of experiments concerned Aspergillus nidulans, amold which has been reported as the causative agent in only twoor three very dubious cases of spontaneous infection. Whenguinea pigs are inoculated intraperitoneally with large doses of thespores of this fungus, they remain well. If killed and examined afew days after inoculation, a few small abscesses containingspores may be found in the omentum. If such animals arereinoculated two or three weeks later, they develop an acutefibrinopurulent peritonitis and usually die in two days. Skintests with cell sap show that they have acquired a very highdegree of sensitivity. Injected intravenously into rabbits,Aspergillus nidulans causes paralyses and other nervous symp-toms probably due to an endotoxin in the spores, but suchrabbits rarely show abscesses or other signs of infection, andapparently the spores do not germinate. Rabbits reinoculatedintravenously often show tubercles in various viscera, in whichthe fungus is found growing in the actinomycetoid form. Herewe are possibly dealing with a borderline organism which canmultiply in the tissues and cause infection only when introduced asecond time.From the available experimental evidence we may conclude

that only pathogenic fungi can give rise to hypersensitivity.This is in accord with what has been taught for many yearsregarding the tuberculin reaction, that allergy can develop onlyas the result of infection. The recent experimental productionof hypersensitivity to tuberculin by inoculation with cell-freesubstances extracted from the bacteria completely upsets thisconcept. Infection and hypersensitivity are concomitant phe-nomena, but there is nothing to indicate which is cause and whichis effect. The facts may be satisfied as readily by the converse

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statement, that in diseases like tuberculosis infection can resultonly from hypersensitivity. If this view is correct, only thosefungi can be pathogenic which produce substances that can giverise to allergy of the tuberculin type.At this point it becomes necessary to define our terms more

precisely, to distinguish between the different sorts of hyper-sensitivity. Aside from the obvious differences in the charactersof the reactions, we have very good reasons for believing thatthe allergy of infection is different in mechanism from the formsof hypersensitivity exemplified in anaphylaxis, the Arthus phe-nomenon, and such atopic diseases as asthma and hay fever.Sensitivity to tuberculin is not accompanied by the developmentof humoral antibodies, and cannot be passively transferred.Aronson, and also Rich, working with tissue cultures and withthe cornea, have shown that the tuberculin reaction is independ-ent of the circulation, apparently all cells being sensitive, whilethe Arthus phenomenon requires the presence of capillaries whichare probably the primary seat of the reaction.Almost any antigen may serve to produce anaphylaxis or the

Arthus phenomenon, or to provoke asthma in the atopic indi-vidual, and such antigens may be derived from any sort of or-ganism, including both pathogenic and harmless fungi. It iswell known that mold spores of various kinds often give rise toasthma. But the antigens, if such they may be called, which areconcerned in the tuberculin type of allergy, appear to be of a par-ticular sort, not widely produced by living organisms, but peculiarto certain pathogens. With the tubercle bacillus, the activesubstance is a heat-stable protein; with the ringworm fungi it isa nitrogen-containing polysaccharide; in the case of Aspergillusfumigatus, the active substance appears to be neither protein norpolysaccharide, but to be identical with the unknown substancewhich gives toxic reactions in non-sensitized animals when in-jected in large doses. In other cases the nature of the activesubstance has not been determined. It must be borne in mindthat a single organism may contain antigens capable of producingthe anaphylactic type of hypersensitivity, and also those whichwill produce the tuberculin type. Antigens have been extractedfrom tubercle bacilli and from ringworm fungi which will produce

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anaphylactic shock, but it is not certain that these are the samesubstances concerned with the delayed reactions characteristicof infection. One may obtain skin tests of the immediate whealtype in asthmatics sensitive to mold spores. Such reactions areto be carefully distinguished from the delayed reactions character-istic of infection. In any definitive study of hypersensitivity inthe mycoses it will be necessary to fractionate the antigens con-cerned.

In hypersensitivity of the anaphylactic or atopic type, thenature of the reaction is independent of the chemical constitutionof the antigen; anaphylactic shock and asthma are the same nomatter what substance is used to provoke them. This indicatesthat the nature of the reaction is determined solely by the tissueswhich are sensitized. In the allergy of infection, the reactionsnot only differ from those occurring in anaphylaxis and atopy,but they differ among themselves according to the nature of theantigen. The reaction of the sensitized guinea pig is differentwhen tuberculin, trichophytin, or the active substance of Asper-gillus fumigatus are inoculated. Tuberculin inoculated intra-dermally produces a rather slowly developing circumscribed in-flammatory reaction followed, if the dose is large enough, bynecrosis; given intraperitoneally it produces punctate hemor-rhages on abdominal surfaces, and the delayed tuberculin death.Trichophytin injected intradermally gives rise to a rather diffuseerythema with overproduction and desquamation of epidermis;intraperitoneally it produces no reaction in internal viscera, butresults in a generalized skin rash. Aspergillus cell sap intra-dermally produces immediate purpura followed by deep necrosis;intraperitoneally it gives rise to a massive gelatinous exudate andcharacteristic necrosis of the liver and the kidney tubules. Thisevidence is as yet slight, but it is very strongly suggestive thatin these cases the nature of the reaction is determined not by thetissues, but by the chemical constitution of the substances inocu-lated. In this respect the active substances behave like truetoxins. All of these considerations indicate that in the allergyof infection we are dealing with substances having peculiarproperties not common to all antigens.Viewed from this standpoint it might be possible to relate the

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allergy of infection to a phenomenon discussed in the earlier daysof immunology, namely toxin-hypersensitivity. A second in-jection of a subminimal dose of toxin results, not in anaphylacticphenomena, but in symptoms and lesions characteristic of thetoxin. One may visualize the reaction by recourse to Ehrlich'sside-chain theory, assuming that a first injection of toxin givesrise to excess receptors on the tissue cells. If these are cast off,

Arnphylaxis arndAtopy Toxi-5Sermsitivity Allerqy of Infectiors

N ~~~~~~~~~~~~~~ormrat1 Cet1 Cett

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3enitized 3ensitized Sen.sitized

FIG. 9. DIAGRAM TO SHOW, BY MEANS OF EHRLICH'S SYMBOLS, DIFFERENCESBETWEEN ANAPHYLAXIS, TOXIN-SENSITIVITY, AND THE ALLERGY OF INFECTIONThe mechanism of injury in anaphylaxis is unknown, but it is not specific

since all antigens produce the same sort of lesions; this is indicated by the ab-sence of a fringe on the antigen molecules. In toxin-sensitivity (as with A8per-gillus cell sap) and the allergy of infection (as with tuberculin and trichophytin)the author suggests that injury may be due to a specific toxic effect, indicatedby the fringe, or toxophore group, on the antigen molecules. In the allergy ofinfection, normal cells are not affected, hence the absence of receptors; andcirculating antibodies are not formed.

the animal is protected, but if they remain sessile, the animal isnow injured or killed by subminimal doses. Something of thissort appears to occur in experiments with the endotoxin of Asper-gillus fumigatus. Reinoculations of subminimal doses give rise,not to anaphylactic symptoms, but to necrosis of the liver and thekidney tubules, to an effusion into the abdominal cavity. Inthe case of substances like tuberculin and trichophytin, it isnecessary to assume that normal cells do not possess enough re-

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ceptors to permit of a toxic effect with any dose, but that suchreceptors develop in the course of the infection. The injury tothe cells is not to be explained by any hypothetical reaction be-tween the antigen and antibodies, either cellular or humoral,but by the toxophore group of the antigen itself. Since little orno humoral immunity develops in tuberculosis and the fungousdiseases, it is further necessary to assume that these substanceshave a peculiar tendency to give rise to sessile rather than cir-culating antibodies. If these assumptions are correct, there isno incompatibility between the endotoxin theory and the allergictheory of infection; they become complementary. All of this is,however, pure speculation which can be refuted or confirmed onlyby a careful fractionation of the various antigens or active sub-stances, and a study of each from the standpoint of infection andimmunity.

In conclusion, I submit as the outstanding characteristic of thefungous diseases their marked tendency to give rise to hyper-sensitivity of a type best designated as the allergy of infection,distinct from other categories of hypersensitivity. I believe thatthe other characteristics of the mycoses, age and occupationalincidence, course and pathology, are strongly colored by. or de-pendent upon this allergy. This characteristic distinguishes thefungous diseases from most of the other microbic diseases, butclosely relates them to tuberculosis, and in some aspects toleprosy, syphilis, glanders, tularemia, and lymphogranulomainguinale. These diseases present a common problem in im-munology more or less peculiar to themselves. I suggest thatthis characteristic is determined by the ability of the pathogenicfungi and related microbes to produce peculiar antigen-like sub-stances having specific properties not common to all antigens, andthat the deep-seated mycoses are caused by occasional speciesof saprophytic fungi which, evolving in restricted areas, have bychance acquired the ability to synthesize such substances. I donot claim any originality for this concept of the fungous diseases.The general theory has been discussed more or less vaguely bydermatologists, clinical allergists and specialists in tuberculosisfor some years. I commend this field as a fertile one for preciseinvestigation by immunologists.

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