BACTERIOLOGICAL REVIEWS, Mar., 1967, p. 6-24 Vol. 31, No. I Copyright © 1967 American Society for Microbiology Printed in U.S.A. Comparative Ecology of Respiratory Mycotic Disease Agents1 LIBERO AJELLO National Communicable Disease Center, U.S. Public Health Service, Atlanta, Georgia

INTRODUCrION ...... 6 BACKGROUND ...... 7 B. DERMATITIDIS GILCHRIST AND STOKES, 1898...... 7 Geographic Distribution...... 7 Prevalence-Human . 8 Prevalence-Lower Animals...... 8 Natural Habitat...... 9 C. IMMITIS RIxFoRD AND GILCHRIT, 1896...... 9 Geographic Distribution ...... 9 Prevalence-Human . 10 Prevalence-Lower Animals...... 11 Natural Habitat...... 11 C. NEOFORMANS (SANFELICE) VUILLEMIN, 1901...... 13 Geographic Distribution ...... 13 Prevalence-Human ...... 13 Prevalence-Lower Animals...... 13 Natural Habitat...... 13 H. CAPSULATuM DARLING, 1906...... 14 Geographic Distribution...... 14 Prevalence-Human...... 15 Prevalence-Lower Animals...... 15 Natural Habitat...... 15 CONCLUDING REMARKS AND SUMMARY...... 17 LERATuRE CiTED...... 18

INTRODUCTION ductive. The source of infections and the means In recent decades, much knowledge has been by which they are acquired and disseminated are accumulated concerning the pulmonary mycoses. rather well defined in most instances. Promising The signs, symptoms, and the clinical course of advances have been made in the development of these diseases have been defined, and adequate control measures. laboratory diagnostic techniques involving both In contrast, knowledge regarding the ecology cultural and serological procedures have been of these fungi, i.e., the study of their relationship perfected. With the discovery of amphotericin B, to their environment, is rather superficial and so true appear pre- a significant breakthrough has been achieved in scanty. This is that it might mature the therapy of the pulmonary mycoses, and one and pretentious to discuss the comparative can anticipate the introduction of new and im- ecology of the agents that cause respiratory proved therapeutic procedures. mycotic infections. However, a critical review of Taxonomic studies of the fungi that cause the current status of all available information was pulmonary diseases have resolved the most urgent considered to be well worth undertaking. It problems of classification and identification. should serve to bring together data that are Through biochemical and physiological investi- widely scattered, enable us to scrutinize critically the to areas of gations, an insight has been gained into the information, point ignorance, and, we well-trained metabolic processes of these fungi. hope, inspire others, especially Epidemiological studies have also been pro- ecologists, to carry out studies with the breadth and depth that the science of ecology requires. ' A contribution to the Round Table on Respira- For practical reasons, species of fungi that are tory Mycoses: Comparative Epidemiology, Ecology, rarely, if ever, encountered as primary disease and Immunology, presented at the Annual Meeting of the American Society for Microbiology, Los Ange- agents have been excluded from this discussion of les, Calif., 3 May 1966, with Roger 0. Egeberg as the comparative ecology of the fungi that cause convener. pulmonary diseases. They generally come to 6 VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 7

TABLE 1. Isolation dates of respiratory mycotic agents

Pathogen Date Investigator Ref.

Blastomyces dermatitidis 1898 Gilchrist and Stokes 89 Coccidioides immitis 1900 Ophuls and Moffitt 162 Cryptococcus neoformans 1894 San Felice 181 Histoplasma capsulatum 1934 De Monbreun 51 medical attention as secondary invaders in B. DERMATITIDIS GILCHRIST AND STOKES, 1898 chronic, debilitating diseases such as cancer, diabetes mellitus, and tuberculosis, or when Geographic Distribution chemotherapeutic and immunorepressive meas- This pathogenic fungus was long thought to ures, undertaken for the control of bacterial be confined to the New World. The very name diseases or neoplasms, interfere with the patient's given to the disease that it causes-North Ameri- defense mechanisms. Accordingly, we will not can blastomycosis-implied that it has a restricted take up such organisms as Aspergillus fumigatus, geographic distribution. Indeed, the vast majority Candida albicans, Geotrichum candidum, and of reported cases have originated within the various species of zygomycetes. United States (34) and in lesser numbers in We will discuss only those fungi that are almost Canada (96). In both countries, the endemic areas invariably primary pathogens and that are most are apparently restricted to their eastern sections. frequently encountered as pulmonary disease Various cases reported from Mexico (139), agents. These species are: Blastomyces dermatitidis, South America (132), Europe (30, 57), and Asia Coccidioides immitis, Cryptococcus neoformans, (16, 106, 156) were diagnosed erroneously or and Histoplasma capsulatum. occurred in individuals who had contracted their infections in the United States or Canada or were BACKGROUND in contact with fomites of North American origin. All of the fungi under discussion are exogenous Of interest is a case of North American blasto- parasites, since they are not normally harbored mycosis reported from Tunisia by Broc et al. (31) by humans and lower animals. They are known and Haddad (98), with further amplification by to exist or, in the case of Blastomyces dermatitidis, Vermeil et al. in 1954 (214). An element of doubt are presumed to occur in nature as free-living exists concerning the accuracy of the diagnosis saprophytes. They differ from the overwhelming in this case. A subculture of the Tunisian isolate majority of saprophytic fungi in their highly (I.P. 268; CDC B-190), kindly furnished by E. specialized ability to survive, multiply, and cause Drouhet, Institut Pasteur, Paris, France, in 1957, disease once they have entered the body of a proved to be nonpathogenic to mice and guinea susceptible mammalian host. Whatever knowl- pigs. In addition, all attempts to convert the or- edge we possess regarding their relationship to ganism to a yeast form ended in failure. the environment is of relatively recent origin. All However, in 1964 autochthonous cases of in- of these fungi were isolated and cultured for the disputable B. dermatitidis infections were reported first time less than 75 years ago (Table 1). Until virtually simultaneously from the Republic of media and procedures were developed for their the Congo (Leopoldville) (88), from Tanzania, isolation and growth in vitro, little could be Uganda, and the Republic of South Africa (81, learned regarding such fundamental facts as their 106), and from Tunisia (55). These African cases morphology, taxonomy, and physiology. reveal that environmental conditions suitable for Speculation regarding their nature, prior to the growth and survival of B. dermatitidis exist isolation, led to the erroneous supposition that not only in Canada and the United States but also some were protozoans [C. immitis (169), H. on the vast African continent. capsulatum (48)]. But, more importantly, eco- The possibility also exists that B. dermatitidis logical studies, primitive as they might be, could occurs in Latin America. Apparently autochtho- not be initiated until the investigator knew what nous cases of infection by this fungus were de- the fungi looked like, grossly and microscopically, scribed from Mexico by Arias Luzardo (19) and in their saprophytic form. from Venezuela in 1954 by Montemayor (154) Each of the species will be discussed under the and by Polo et al. (167). following headings: geographic distribution, Thus, our concept regarding the geographic prevalence, hosts, and natural habitat. distribution of B. dermatitidis must be broadened 8 AJELLO BACTERIOL. REV.

TABLE 2. Anniiual deaths i/l the Uniited States due to respiratory mnycotic disease agelits (1952-1963)-

Disease 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1902 1963 year 12tyteal avg Blastomycosis. 27 23 24 19 27 28 24 13 15 16 17 24 21 257 Coccidioidomycosis 60 85 78 62 54 53 50 48 55 62 55 71 61 733 Cryptococcosis 46 48 56 74 66 55 39 84 71 86 90 73 66 788 HistoplasmosiS .. 51 55 59 53 67 77 73 63 80 90 82 70 68 820

Totals ...... 184 211 217 208 214 213 186 208 221 254 244 238 216 2,598J a From Morbidity and Mortality Weekly Report, Communicable Disease Center, Atlanta, Ga. AnnUal Supplement, vol. 11, 16 September 1963; vol. 13, 30 September 1965.

to meet this new reality. The geographically re- 2) indicate that, in 1953, 23 individuals had died strictive term of North American blastomycosis from infections caused by B. dermatitidis. The should be dropped, and the disease caused by yearly average for the 12-year reporting period B. dermatitidis should be simply and uncommit- was 21, with a grand total of 257. tedly referred to as blastomycosis. Use of generi- Canadian records summarized by Grandbois cally derived designations for mycotic diseases is in 1963 (96) revealed that 114 cases of blastomy- well established in medical mycology. If infections cosis had been reported since Primrose described caused by the Candida species, Cryptococcus neo- the first case in 1906 (170). The majority of these formans, and Paracoccidioides brasiliensis were cases, 102 (89%Cc), occurred in two provinces: consistently referred to as candidiasis, cryptococ- Quebec, 68 (60%c), and Ontario, 34 (30%). The cosis, and paracoccidioidomycosis, respectively, remaining 12 (116-l) cases had the following dis- there would be no confusing ambiguities and tribution: Manitoba, 8; New Brunswick, 2; Nova cause for misunderstanding. In the past, and even Scotia, 1; and Saskatchewan, 1. today, the term blastomycosis has been used in In a comprehensive review of blastomycosis, reference to any infection caused by a yeast. For Chick et al. (42) plotted the distribution of all the sake of clarity such loose use of the term reported cases (735) that had occurred within the blastomycosis should be ended. United States. The states with the highest preva- lence of cases either bordered on the Mississippi Prevalence Human River or were situated east of that river. The states with 15 or more cases were: Arkansas, 15; Illinois, Definitive information on the incidence and 74; Indiana, 18; Iowa, 24; Kentucky, 37; Louisi- prevalence of blastomycosis, as well as all the ana, 101; Mississippi, 16; Ohio, 38; South Caro- other mycoses, is lacking. As long as the mycoses lina, 90; Tennessee, 90; and Wisconsin, 81. remain in the category of non-notifiable diseases, an appreciation of their public health importance, Prevalence-Lowver Animals relative to bacterial and viral diseases, will remain nonexistent. It is obvious from the United States data that However, there are data available that cast B. dermatitidis infections are prevalent in the light on the prevalence of blastomycosis. A re- human population. Infections in lower animals view by Busey (34) showed that in 170 U.S. are also quite common. The dog apparently is Veterans Administration Hospitals, during the the most susceptible of the lower animals. Menges period of 1946 through 1957, 198 proven cases of (145) noted that 113 canine cases had been re- blastomycosis had been diagnosed, an average of ported within the United States and 3 from Can- 18 cases per year. ada. The states with 10 or more cases were: Ala- In 1955, Schwarz and Goldman (185), through bama, 10; Illinois, 21; Iowa, 13; and Kentucky, replies to a questionnaire from 1,125 dermatolo- 27. Later, as the result of an intensive study on gists and 196 chest surgeons, found that within the canine blastomycosis in Arkansas, a total of 79 United States 99 cases of blastomycosis were un- cases was credited to that state (152). dergoing treatment during the first 6 months of The only other known animal victims of B. 1953. Three of these patients died during that dermatitidis have been a horse in Iowa (24) and a study period. captive Steller's sea lion (Eumetopsias jubata) in Statistics on deaths from non-notifiable acute Illinois (218). Easton (58) reported a case in a diseases in the United States for 1952-1963 (Table Siamese cat. However, on the basis of the infor- VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 9 mation presented, the diagnosis is considered after storage at room temperature. Unsterilized doubtful. soil, when placed directly upon growing colonies of B. dermatitidis, produced a marked lysis of Natural Habitat the mycelial growth within a 2-week period. Yeast-form cells of B. dermatitidis were also It is apparent from these data that blastomy- lysed by natural soils. McDonough attributed cosis is not a rare disease and that B. dermatitidis this lysis to a mycolytic agent present in soil. must flourish in the environment of the endemic Sterilization of soil by heat or ethylene oxide areas. Yet, the natural habitat of this fungus re- destroys its lytic activity. It is believed that micro- mains elusive. This is stated despite recent reports organisms are associated with this phenomenon. of the isolation of B. dermatitidis from soils in Lysis of fungi in soil has been observed and in- Kentucky and Georgia (53, 54). vestigated by a number of workers (13, 43, 87, Denton and di Salvo's studies raise more ques- 130, 160). Bacteria and actinomycetes have been tions than they solve. In the Augusta, Ga., area, shown to lyse filamentous and unicellular fungi 10 of 356 soil samples yielded cultures of B. in soil under natural conditions and in vitro. dermatitidis. The positive sites included a cattle Extracellular enzymes, notably chitinase, lyse loading ramp, chicken houses, an abandoned living mycelium (103). However, mycolysis is not kitchen in a wooden shack, a mule stall, and a simply explained by the production of extracel- rabbit hutch. A correlation between a specific lular enzymes by soil microorganisms. Lloyd, habitat and B. dermatitidis could not be drawn. Noveroske, and Lockwood (129) believe that The isolations would seem to indicate, at best, an autolysis, stimulated by toxic products released apparent preference for animal habitats in gen- by soil microorganisms, may also play a role. eral, rather than to one specific type. Mycolysis is a highly complex biological activ- The study had certain other frustrating aspects. ity that merits intensive study. Just what role Repeat samples from a site, once found to be posi- mycolysis plays in the occurrence and survival tive, consistently turned out to be negative. In of various fungi in soil remains unknown. The addition, with one significant exception. B. derma- discovery that B. dermatitidis mycelium and yeast- titidis did not survive for long in the original pos- form cells are rapidly lysed in soil does not pre- itive soil samples. After storage of samples at clude the possibility that B. dermatitidis exists in room temperature or in a freezer, (-20 C), B. a free-living state in nature. Although various dermatitidis could no longer be recovered from phytopathogenic molds are found to be lysed in them. The one exception, apparently, was a Ken- soil, they survive there and continue to grow, re- tucky soil specimen that had been collected in a produce, and carry on their destructive activities. tobacco stripping shed by McDonough (142). It All available clinical and epidemiological evi- had been stored in a screw-capped glass bottle at dence strongly suggests that somewhere in nature room temperature for a least 16 months before B. an ecological niche exists that favors B. dermatiti- dermatitidis was isolated from it by Denton. Para- dis. We can be certain that through diligent field doxically, when tested shortly after collection by and laboratory work its natural habitat will the original collector, this soil specimen had given eventually be discovered. negative results (142). As with the other positive soils, despite repeated efforts, the "positive" Ken- C. IMMITIS RIxFoRD AND GILCHRIST, 1896 tucky soil never yielded the fungus again. In ad- dition, a large group of new soil specimens col- Geographic Distribution lected in the same Kentucky tobacco barn were C. immitis appears to be restricted to the New negative (E. S. McDonough, personal communi- World. Its endemic areas are situated within cation). specific areas of the United States (Arizona, In the laboratory, natural soils inoculated with California, Nevada, New Mexico, Texas, Utah); B. dermatitidis and stored in a refrigerator or a Mexico (Baja California, Chihuahua, Colima, freezer yield the fungus after storage periods as Coahuila, Durango, Guanajuato, Guerrero, long as 2 months (E. S. McDonough, personal Jalisco, Michoacan, Nayarit, Nuevo Leva, San communication). Survival of B. dermatitidis in Luis Potosi, Sinaloa, Tamaulipas, Zacatecas); natural soils at room temperature is another mat- Guatemala (Montagua River Valley, Zacapa); ter. Studies by McDonough (140, 141, 143) have Honduras (Comayagua Valley); Colombia (Mag- revealed that 2 weeks after inoculation the fungus dalena); Venezuela (Falcon, Lara, Zulia); Bolivia cannot be recovered from the soil maintained at (Santa Cruz); Paraguay (Boqueron, Olimpo); room temperature. Control soils sterilized with and Argentina (Catamarca, Cordoba, La Pampa, ethylene oxide and then inoculated with B. derma- La Rioja, Mendoza, San Luis, Santiago del titidis gave positive cultures as long as 14 weeks Estero, Tucuman). That an endemic focus may 10 AJELLO BACTERIOL. REV. exist in Nicaragua is suggested by a canine case of Data from the mortality reports published by coccidioidomycosis that apparently originated in the U.S. Public Health Service show that during that Central American republic (159). However, the 12-year period, 1952-1963, 733 deaths were until appropriate epidemiological and ecological attributed to C. immitis. The yearly average was studies are carried out, the question as to whether 61 (Table 2). or not C. immitis occurs in Nicaragua must re- Statistics on the prevalence and incidence of main unanswered. coccidioidomycosis in Latin America either are The several cases of coccidioidomycosis that fragmentary or simply are not available. Skin have been reported from areas outside of the test surveys carried out in Mexico indicate that cited endemic areas stemmed either from visits to C. immitis infections are as prevalent there as in the endemic areas or from contact with fomites the endemic areas of the United States. Glusker from those areas (15, 84), or they represented (91) found the following percentage of reactors misdiagnoses. A series of cases reported as coc- to coccidioidin in Mexico: Baja California, 32%; cidioidomycosis from Ecuador (122), for example, Sonora, 67%; Chihuahua, 37%; Colima, 33%. In clearly appear to have been cases of paracocci- a large-scale and long-term coccidioidin skin test dioidomycosis and leishmaniasis. survey, Gonzalez Ochoa (personal communication) Cases of "coccidioidomycosis" originating found the prevalence of reactors also to be high. within the USSR began to be diagnosed in 1951 The prevalence of coccidioidin skin test reactions and continue to the present day (17, 208). How- ranges from 5% to above 50% in the states of ever, study of a culture (R-Ko), kindly sent by Baja California, Chihuahua, Coahuila, Colima, A. Araviiskii, Pavlov Medical Institute, USSR, Durango, Guanajuato, Guerrero, Jalisco, Micho- showed that the isolate was not C. immitis, as acan, Nayarit, Nuevo Leon, San Luis Potosi, determined by its morphology and lack of patho- Sinaloa, Sonora, and Tamaulipas. Only nine genicity to guinea pigs. C. W. Emmons (personal states are considered to be free from C. immitis: communication) studied four Russian cultures and Campeche, Chiapas, Mexico, Oaxaca, Puebla, concluded that they were haploid forms of basi- Quintana Roo, Tabasco, Veracruz, and Yucatan. diomycetes. In recent years, the Russian cases, In the Central American endemic areas, skin which have originated in widely separated and test surveys have shown that 21% of a group of different geographic areas of the Soviet Union children in the Motagua River Valley of Guate- [Blagoveshchensk (Amurskaya Oblast); Kirghizia mala gave positive coccidioidin reactions, and, in SSR, Kiselevsk (Kemerovskaya Oblast); Kui- the Comayagua Valley of Honduras, skin test bishev (Kuibreshevskaya Oblast); Leningrad; surveys by Trejos and Castro revealed an overall Moscow (225); Novokuznetsk (Stalinsk) (Kemer- prevalence of 25% positivity among the subjects ovskaya Oblast); Sverdlovsk (Sverdlovskaya tested (84). Oblast); and Tomsk (111)] are occasionally re- Indications that coccidioidomycosis exists in ferred to as coccidioidomycosis-like (116). On Colombia are based on publication of two cases the basis of these cultural studies and a critical (176, 179) and personal observation by Angela review of available publications that describe the Restrepo. Until skin test surveys are carried out disease clinically, histologically, and mycologi- in the suspected endemic area in the state of cally (18, 116), it appears that the Russian disease Magdalena and surrounding territory, the size of does not resemble coccidioidomycosis and that, the zone and severity of the infestation will re- if the disease is indeed mycotic innature, an organ- main unknown. ism other than C. immitis is involved. The occurrence of coccidioidomycosis in Venezuela is well established on the basis of case Prevalence-Human reports and skin test surveys. Campins and his In the endemic areas of the United States, co-workers (38) diagnosed the first Venezuelan the incidence and prevalence of C. immitis infec- case in the state of Lara. As a result of their sub- tion is so high that coccidioidomycosis must be sequent work and that of others, it is now es- considered a major disease. Fiese (84) estimated tablished that the disease occurs in three states: that about 35,000 new infections occur yearly Falcon, Lara, and Zulia (37). in California and 5,000 to 10,000 in Arizona. The other known or suspected endemic areas In the most highly endemic areas (San Joaquin for coccidioidomycosis in Latin America are Valley, Calif.; Maricopa and Pima Counties, found in Argentina, Bolivia, and Paraguay. His- Ariz.; and El Paso County, Tex.), virtually torically, Argentina is of the greatest interest be- 100% ofthe inhabitants acquire infection within a cause the first known case was reported by Posa- few years of residence, and about one-fifth of das from that country in 1892 (169). Curiously, these develop symptoms severe enough to require since that time only 27 additional cases have been medical care. diagnosed (Negroni, personal communication). VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 11 Through the distribution of those few cases and thus baileyi, P. intermedius, P. penicillatus; 15% skin test surveys, the endemic areas are considered prevalence in these mice), grasshopper mouse to be situated, in whole or in part, in the follow- (Onchomys torridus), and the kangaroo rat ing states: Catamarca, Cordoba, La Pampa, La (Dipodomys meriami; 17% prevalence in this rat Rioja, Mendoza, Rio Negro, San Juan, San Luis, species). According to Maddy (135), Jellison and Santiago del Estero, and Tucuman. Few coc- his co-workers isolated C. immitis from two cidioidin skin test surveys have been carried out in species of rodents collected in the St. George Argentina, and thus the magnitude of infections area of Utah, P. formosus and Citellus leucurus in the endemic areas is unknown. In Santiago (ground squirrel). del Estero, a skin test survey by Negroni et al. The case of coccidioidomycosis in a rabbit (158) revealed a prevalence of 19% positive reac- (Oryctolagus cuniculus) reported from Hungary tions among 2,213 children aged 6 to 16 years. by Kemenes in 1954 (108) is considered to repre- Little is known about the coccidioidomycosis sent a diagnostic error. In all likelihood, the in- areas of Paraguay and Bolivia. The endemic areas fection was due to Emmonsia crescens rather than are in the Gran Chaco region that both countries C. immitis. The tissue-form cells of E. crescens, share with Argentina. In Paraguay, Gomez (92) and also of E. parva, are easily confused with the reported that coccidioidomycosis was endemic in immature spherules of C. immitis. A similar error the departments of Boqueron and Olimpo. He undoubtedly formed the basis for the reports of found that 44% of a group of Guazurangue coccidioidomycosis in two Townsend moles Indians living in the department of Boqueron (Scapanus townsendii) from the state of Washing- gave positive reactions to coccidioidin. ton (172) and in a cottontail rabbit (Sylvilagus The least studied suspect area is in Bolivia. Our floridanus) from North Dakota (210). knowledge of the probable existence ofthe disease The theory proposed by Emmons (68) that there is based on a sketchy report of a single case coccidioidomycosis is "primarily a rodent disease, described by Mackinnon (131) and Artagaveytia- transmitted frequently but accidentally to man Allende (21). The patient in question had fought through the medium of soil contaminated by in the Gran Chaco during the war between Bolivia rodents" was discredited long ago and has been and Paraguay. The possibility exists that he may abandoned. There is no evidence substantiating have acquired his infection in Paraguay rather that coccidioidomycosis is transmitted from than Bolivia. There is an obvious need for skin animals to man or from person to person, or that test surveys in the Bolivian Chaco to determine the presence of C. immitis in soil is due to "seed- whether or not C. immitis is in reality endemic in ing" by infected animals. AU infections are traced that country's department of Santa Cruz. to a common source-soil. Prevalence-Lower Animals Natural Habitat Lower animals are commonly infected by C. It is well established that C. immitis is a soil- immitis. In nature, infections have been noted in inhabiting organism. From 1932, when Stewart cats (173), cattle, dogs, coyotes (202), equines, and Meyer (200) first isolated this fungus from rodents, swine, and in a variety ofcaptive animals: soil in the San Joaquin Valley of California, there chinchillas, gorillas, llamas, monkeys (84), and a have been numerous isolations of C. immitis from tapir (135). soil samples collected in Arizona (2, 67, 137), Studies by Maddy (133) have revealed that cat- California (49, 62-66, 124, 164, 165, 215, 219), tle infections by C. immitis constitute the infec- and Mexico (194). tious disease most frequently encountered in The casual report of the recovery of C. immitis California abattoirs. Among the 3,173 cases ob- from Rumanian soil by Evolceanu and Alteras served, some had occurred in cattle imported from (83) cannot be accepted as authentic. The investi- the endemic areas in Arizona, New Mexico, and gators presented no proof that their two isolates Texas. On the basis of skin test surveys, it is es- were C. immitis. The mere recovery of one of their timated that probably several million infected isolates from an experimentally infected guinea cattle are present in the southwestern United pig after development of a suppurative orchitis States at any given time (135). does not constitute a valid basis for identification. Canine infections are also prevalent in the en- Many saprophytic organisms survive animal pas- demic areas, as shown by clinical cases and skin sage and may even stimulate tissue reactions. test surveys (135). Development of endosporulating sporangia in an Among wild animals, rodent infections are experimental animal is one of the most fundamen- probably the most numerous. Emmons and Ash- tal and essential criteria for establishing the iden- burn (77) found infections in several Arizona tity of C. inmitis. species of mice and rats: pocket mice, (Perogna- Our knowledge of the ecology of C. immitis is 12 AJELLO BACrERIOL. REV. more advanced than that of other fungi under Plunkett and Swatek (164) showed that C. immitis discussion. It has been unequivocally established remains viable at depths of 6 to 8 inches, despite that C. immitis is a soil-inhabiting fungus superbly the death of its spores and mycelium at the surface adapted to life in semiarid regions. Maddy (137) during the hot summer months. directly observed the development of C. immitis Egeberg and Ely (62) and Elconin, Egeberg, colonies in covered, moistened shallow pits that and Lubarsky (65) found that none of 275 soil he had dug in desert areas near Phoenix, Ariz. samples collected in California at the end of the Mycelial growth, later identified as C. immitis, San Joaquin Valley dry season yielded C. immitis, first appeared on pieces of decaying vegetation in contrast to recovery of the fungus from 31 or that were present in the soil. Kaplan and I (un- 20% of 153 soil specimens collected at the end of published data) have directly observed arthro- the wet season. Also of interest was the finding spores of C. immitis in Arizona soil samples by that among 115 rodent burrow soil samples, 18 staining the supernatant fraction of soil suspen- (or 16%) were positive, whereas only 13 (or 4.3%) sions with fluorescent antibodies. of 313 randomly collected surface or subsurface The Egebergs, Elconin, and Maddy, with their soils were positive. At the end of the 1956 wet associates, have been instrumental in providing season, 43%c7 (13 of 30) of surface soils yielded an insight into the ecological requirements of C. cultures of C. immitis, as did 41% (18 of 44) of immitis. Maddy (134) has shown that the condi- rodent burrow samples. tions that favor the existence of C. immitis as a This work revealed: (i) that C. immitis is most saprophyte in soil occur in those areas that fall apt to be present in soil shortly after a rainy into Merriam's (153) biological entity known as season, (ii) that during such a period C. immitis is the Lower Sonoran Life Zone. In the biotic prov- present in the upper inch of soil or in the lining of ince, summer temperatures are high, winters are rodent burrows, and (iii) that C. immitis is only mild, and rainfall is sparse. Maddy summarized found occasionally during the hot dry season. the conditions that favor C. immitis as follows: However, during that season, the fungus survives "an arid or semiarid climate, alkaline soil, rela- at depths of 4 to 6 inches (164). tive freedom from severe frosts, and a very hot, These observations raised several questions in dry season of several months followed by some the minds of the investigators. Is the scorching rain. July mean temperatures from 26°C to about summer heat necessary to the life of C. immitis? 32°C, January mean temperatures from 4°C Does the heat create a relatively sterile layer of to about 12°C, and an annual rainfall of about soil that only needs moisture to favor the devel- 5 to 20 inches. " opment of fungi living below or adjacent to it? One exception may exist in Mexico. On the Could heat be an ally of C. immitis, producing for basis of skin test surveys, the tropical states of a transitory period of time an environment free Colima and Guerrero have been described as from antagonists and competitors? possessing endemic foci of C. immitis. Ecological Field studies were carried out by the Egebergs and epidemiological studies are needed to deter- and Elconin (64, 66) to seek answers to these co- mine the basis for this anomaly. gent questions. A correlation was found to exist Shreve and Wiggins (188) define a desert as between the presence of C. immitis in soil and being "essentially a region of low and unevenly high concentration of calcium, magnesium, distributed rainfall, low humidity, high air tem- sodium chlorides, and sulfates. It was postulated peratures with great daily and seasonal ranges, that the salts encouraged the growth of C. im- very high surface soil temperatures, strong wind, mitis by acting either as nutritional stimulants soil with low organic content and high content or as inhibitors of microorganisms antagonistic of mineral salts, violent erosional work by water to C. immitis (66). Two antagonists were isolated and wind, sporadic flow of streams, and poor de- from San Joaquin Valley soils-a strain of Penicil- velopment of normal dendritic drainage." As lium janthinellum and two strains of Bacillus sub- Maddy stated (136), "Only certain types of plants tilis. These microorganisms were grown at differ- and animals can survive in this environment. This ent temperatures, 18, 27, and 40 C, in media con- environment, and only this environment, seems taining 0 to 8% concentrations of NaCl and to permit C. immitis to exist in nature as a soil CaCl2. P. janthinellum did not grow at 40 C with organism." or without the salts; growth of the B. subtilis During the hot summer months when summer strains was not adversely affected by the high temperatures 0.5 inch below the surface of the temperature, but it was inhibited by the salts. soil reach 60 to 71 C for almost 100 days, C. im- In contrast, C. immitis not only tolerated the 40 mitis, along with most other microorganisms, is C temperature, but its growth was stimulated by killed, but it survives in the lower depths of the the combination of high salt concentration and soil, especially in and near rodent burrows (137). temperature (64). VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 13 What emerges from these ecological studies is form of cryptococcosis did exist. A breakthrough a picture of a soil fungus adapted to life in a is needed in the preparation of antigens for the desert habitat. During long periods of extreme study of this disease. Announcement of a suc- heat and aridity, it survives just below the un- cessful skin test antigen by Salvin and Smith in inhabitable hot surface of the soil or in rodent 1961 (180) was evidently premature. Evaluation burrows. After the rainy seasons, it reinvades the of a similar preparation by Bennett, Hasenclever, surface area where, in a partially sterilized en- and Baum (25) showed that numerous apparently vironment, it sporulates heavily. Then, as the soil nonspecific reactions occurred in "normal" dries, the winds pick up the infectious spores and subjects. They concluded that their studies left contaminate the air. "the epidemiologic use of the test as yet undeter- Just how far the spores of C. immitis are dis- mined." persed by air currents is unknown. Maddy (137) feels that they are not carried for more than a Prevalence-Lower Animals few miles beyond a given source point. The isola- Cases of cryptococcosis have been diagnosed in tion of C. immitis from air in California (102) a surprisingly large variety of animals. The species and in Phoenix, Ariz. (12), does not cast light on I cited in a previous review (3) were: cats, cattle, this question. The two Arizona isolations were cor- cheetah, civet cat, dogs, ferret, guinea pig, and related with a severe windstorm that developed horses. Subsequently, cases have been reported locally a few days before the positive samples in a gazelle (178), goats (47, 203), koalas (22, 28, were collected. It is known that positive soil sites 29), mink (209), and a wallaby (178). exist in the vicinity ofthe collecting area. The largest number of infections have occurred C. NEOFORMANS (SANFELICE) VUILLEMIN, 1901 among dairy cows suffering from mastitis caused by C. neoformans. More than 186 cows have been Geographic Distribution involved (3, 184). This imperfect yeast, in contrast to the pre- All evidence indicates that the source of human viously described fungi, has a cosmopolitan dis- and lower animal infections is exogenous. Al- tribution. Since the description of the first human though C. neoformans has been isolated from the case from Germany by Busse in 1894 (35), cases equine intestinal tract (213), there is no evidence of cryptococcosis have been reported from all the that this fungus is transmitted from animals to major regions of the world (27, 123). other animals or humans, or that animals play a significant role in the dissemination of C. neo- Prevalence-Human formans into the environment. Again, the absence of data on the incidence and prevalence of mycotic infections in general limits Natural Habitat any discussion of the public health problem posed Soil is the ultimate source of all infections by this important mycotic disease. Littman and caused by C. neoformans. Sanfelice (181, 182), Zimmerman (126) reported that more than 300 who was the first to isolate C. neoformans from a cases had been recorded in the literature by the nonliving source, discovered it while studying the year 1955. The annual number of deaths attrib- organisms that developed in the juices of various uted to C. neoformans within the United States fruits. In retrospect, Sanfelice's isolate is seen as since 1952 has averaged 66 per year; the 12-year an airborne contaminant that entered the un- total (1952-1963) adds up to 788 fatalities (Table sterilized containers that he used to hold 200 to 2). 300 ml of fermenting fruit juices. Airborne con- Utz (211) estimated that 200 to 300 cases of tamination may also have been the source of the cryptococcal meningitis occur annually in the C. neoformans strains isolated from "country" United States. Littman and Schneierson (127) milk by Klein in 1901 (109) and by Carter and postulated that 5,000 to 15,000 cases of subclinical Young in 1950 (40). Emmons (71) was the first or clinical pulmonary cases of cryptococcosis oc- to reveal the presence of C. neoformans in soil. cur in New York City alone. Four isolates of that fungus were recovered from The absence of a sensitive and specific skin 716 soil samples collected in Loudoun County, test antigen has prevented surveys designed to Va. Subsequent soil studies by Emmons (72, 73) determine whether or not a benign self-limited brought to light the significant relationship of form of cryptococcosis exists. Thus, analogies to C. neoformans to pigeons, or, more precisely, to coccidioidomycosis and histoplasmosis cannot their droppings. Most of the 20 isolates of C. neo- be drawn. But, in view of the heavy and wide- formans reported upon in 1954 were obtained spread distribution of C. neoformans in the en- from sites contaminated by pigeon droppings or, vironment, it would not be surprising if a benign most importantly, from "weathered pigeon drop- 14 AJELLO BACrERIOL. REV. pings." With this clue that C. neoformans was (Cereus giganteus), cottonwood (Populus fre- probably significantly associated with pigeons, montii), and desert oak (Quercus oblongifolia). Emmons formed the hypothesis that "pigeon man- C. neoformans also has been isolated from wood ure may provide a suitable or preferential medium (142) and soil (3, 86, 117, 118, 189). These find- for the saprophytic growth in nature of Crypto- ings indicate that C. neoformans may live in soil coccus ." This hypothesis was put to test by free from avian droppings in low numbers, owing collecting 111 samples of old pigeon nests (es- to competitive pressure exerted by other soil mi- sentially composed of excrement) and of pigeon croorganisms. It is postulated that cells from such droppings collected under roosting sites, and areas, carried by wind currents to concentrations screening them for the presence of C. neofonnans. of creatinine-rich bird excrement, are deposited in From these 111 samples, 63 (57%) yielded C. a natural medium favoring their growth and neoformans. The amazing concentration of C. multiplication. Avian habitats thus become the neoformans cells in pigeon manure was reported prime source of human and animal infection. by Emmons (76) to be in the realm of 50,000,000 It should be emphasized that the relationship viable cells per gram of dry fecal matter. of birds to C. neoformans is an indirect one. Nat- It remained for Staib to provide a plausible ural infections of birds by C. neoformans have not explanation for the pigeon dung-C. neoformans been demonstrated. Staib (198) stated that C. neo- association. In a series of studies, he (196, 197) formans is nonpathogenic for canaries and pig- demonstrated that pigeon manure serves as an eons. The yeast, when fed to canaries, was ex- enrichment medium for C. neoformans by virtue creted in a viable state as long as 8 days after the of its chemical make-up. Among the constituents feeding. However, the birds did not become in- of bird urine, uric acid and the purines (guanine fected. In contrast, Takos (205) found that mar- and xanthine) are assimilated by the various mosets (Leontocebus geoffroyi) developed sys- species of Cryptococcus. Creatinine (C4H7N,O) temic cryptococcosis, including brain involve- proved to be an exception. This compound is as- ment, when they were fed banana sandwiches similated only by C. neoformans and not by the with a filler of C. neoformans. other species of that genus. Tests with other yeasts It has been suggested that the high body tem- and isolates of Cryptococcus showed that mem- perature of birds (110) and rabbits (119, 120) is bers of the genera Bullera, Candida, Debaryo- unfavorable for the multiplication of C. neofor- myces, Lipomyces, Pichia, Rhodotorula, Sporo- mans. bolomyces, Trichosporon, and Torulopsis could This hypothesis may not be valid, as was shown not utilize creatinine as a nitrogen source. One by Staib's (198) experiments in which C. neo- isolate of C. laurentli proved to be exceptional formans cells remained viable in the gut of canary in that it did assimilate this compound. Thus, we birds as long as 8 days, and by demonstrations apparently have a biochemical basis to account that pigeons injected by the intracerebral route for the frequent presence of C. neoformans in developed meningitis and systemic infection (128). droppings of pigeons and presumably of other What bearing these experiments have on the birds (195). epidemiology of cryptococcosis is unclear. How- This phenomenon of the predilection of C. ever, spontaneous C. neoformans infections in neoformans for avian habitats is well nigh uni- pigeons and other birds have yet to be demon- versal. C. neoformans has been isolated from strated. bird nests and droppings from: (i) several areas in the United States other than those surveyed by H. CAPSULATUM DARLING, 1906 Emmons (100, 101, 107, 127, 155, 171, 204); (ii) Geographic Distribution Asia (104, 220); (iii) Europe (26, 85, 99, 118, 163, 199, 216); and (iv) Austral-Asia (86). Histoplasmin skin test surveys and soil studies The striking concentration of C. neoformans have definitely established that H. capsulatum in excrement should not make us has a global distribution (4-6, 59-61). Recent bird overlook reports from the USSR added that country to the the existence of this interesting yeast in habitats list of those where histoplasmosis is endemic (20). clearly unrelated, or not obviously related, to On the basis of a critical review of European re- avian habitats. Evenson and Lamb (82) recovered ports of histoplasmosis and soil studies carried C. neoformans from 9 of 20 samples of slime flux out in Italy, it has been established that H. cap- exuded by mesquite trees (Prosopsis juliflora) sulatum occurs in the soil of the Emilia-Romagna growing in the Tucson area of Arizona. That the region of Italy, and that apparently autochtho- slime flux of this tree may have a selective prop- nous cases of histoplasmosis have been diagnosed erty for C. neoformans is suggested by the absence in Albania, Austria, France, Great Britain, Hun- of this fungus from exudates of the saguaro gary, Italy, Portugal, Romania, Switzerland, and VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 15 Turkey (192, 193). The vast territory of China is ranted. Bats are hapless victims of H. capsulatum, the only major region where valid cases of histo- as are all other susceptible mammals. There is no plasmosis have not yet been recorded. evidence that their distribution patterns are changing significantly and that infected bats are Prevalence-Human creating an ever-growing number of new foci of The number of individuals that have been in- infection in nature. The geographic distribution fected by H. capsulatum is estimated in the mil- of H. capsulatum does not appear to be controlled lions. Skin test surveys carried out in the United or governed by bats. States, for example, have revealed extensive areas where 30% or more of the inhabitants give Natural Habitat positive reactions to histoplasmin: Arkansas, Emmons first established the fact that H. Indiana, Kansas, Kentucky, Mississippi, Mis- capsulatum lives and develops in soil. In 1949 souri, Ohio, Oklahoma, Tennessee, and Texas (69, 70), he recovered the fungus from 2 of 387 (61). Similar regions are present throughout Latin soil samples collected in Virginia. Tuberculate America: Brazil, Colombia, Ecuador, French macroconidia, characteristic of H. capsulatum, Guiana, Honduras, Mexico, Panama, Surinam, were directly noted in saline suspensions of the and Venezuela (60). two positive soil specimens. This significant ob- The fortunate fact that histoplasmosis is basi- servation revealed that H. capsulatum actively cally a benign disease is reflected in the data on grew and reproduced asexually in soil, since annual deaths due to the respiratory mycoses in macroconidia are not produced in infected ani- the United States (Table 2). During the 12-year mals. The presence of H. capsulatum could not be period (1952-1963), the average death rate due to attributed to contamination of the soil by animals histoplasmosis was 68, with a grand total for the and to the mere survival of the fungus elements so period of 820. deposited there. As the result of intensive field studies carried Prevalence-Lower Animals out by Zeidberg and Ajello, and their collabora- A large variety of both feral and domesticated tors, in Franklin County, Tenn., it was discovered animals have been victims of H. capsulatum, as that H. capsulatum was not haphazardly distrib- shown in Table 3. Excluded are the reports of uted in soil. The fungus was foundtohavea signif- Collier and Winckel (44, 45) and Wildervanck icant association with chicken habitats (223, 223). et al. (217) on the occurrence of histoplasmosis in Of 493 soils collected, 28 yielded H. capsulatum. a large variety of amphibians, birds, insects, and Analysis of the source of the positive specimens mammals. The evidence presented in their reports revealed that 21 (75%) had been collected either suggests that these investigators were dealing with inside chicken houses or in chicken yards. Among artifacts rather than with the tissue-form cells the other seven positive soils, one had been col- of H. capsulatum. lected near a dwelling at a site grossly contami- Next to man, the dog is the animal most sus- nated with chicken manure. ceptible to infection by H. capsulatum. In a re- On the basis of these findings, it was concluded view, Menges et al. (151) cited 481 cases in that that "H. capsulatum appears to prefer soils upon species. Except for one case each from Brazil, the which chickens have congregated." It was felt that Panama Canal Zone, and Venezuela, all had oc- the association of H. capsulatum with chickens curred in the United States. was indirect. There was no evidence that chickens Recent studies have shown that bats also fall developed histoplasmosis and thus could serve as victim to H. capsulatum (Table 3). The fact that reservoirs for the fungus. Histoplasmin skin tests H. capsulatum has been isolated from their tissues conducted on chickens in Tennessee (223) and and fecal contents has led to speculation that Missouri (144) showed that the prevalence of these flying mammals play an active role in the positive reactors was negligible. Efforts to infect epidemiology of histoplasmosis. Campbell (36) chickens with mycelial suspensions of H. capsula- has suggested that bats might not only be involved tum have ended in failure (149). The experi- in the transmission of H. capsulatum from focus to menters concluded that "chickens were resistant focus but that "the bat is the source of the infec- to infection and that the fungus was rapidly de- tive agent." She also though it "reasonable to stroyed in their tissues." Evidently the normally predict that an increase can be expected in the high temperature of birds (ca. 42 C) prevents the number of microfoci of H. capsulatum in nature growth of H. capsulatum in their bodies. In vitro and-possibly in geographic areas in which the studies have revealed that inocula of the mycelial disease has not heretofore been found." form of H. capsulatum do not grow at 42 C (146, These deductions are considered to be unwar- 224). On the basis of these experimental findings 16 AJELLO BACTERIOL. REV. TABLE 3. Summary of animal cases of histoplasmosis

11 Species Reference Species Reference

CHIROPTERS CARNIVORES Artibeus jamaicensis (fruit bat) 113 Domestic Carollia perspicillata (short-tailed 114 Felix domesticus (cat) 79, 147 fruit bat) Canis familiaris (dog) 79, 151 Chiloniycteris rubiginosa (greater 114, 187 MARSUPIALS mustached bat) Feral Desmodus rotundus (South Amer- 56 Didelphis marsupialis (common 206 ican vampire bat) opossum) Glossophaga soricina (South Amer- 114, 138 D. virginiana (Virginia opossum) 79 ican long-tongued bat) Marmosa mitis (mouse opossum) 206 Lonchorhina aurita (long-eared bat) 56 Philanzder opossum (four-eyed 206 Micronycteris megalotis (little big- 114, 115 opossum) eared bat) RODENTS Mollosus major (small free-tailed 112) 114 Feral bat) Marmota moniax (woodchuck) 79 Phyllostomus discolor (long 113 Mus musculuis (house mouse) 79 tongued spear-nosed bat) Proechimys sernispiniosus (spiny 206 P. hastatus (greater spear-nosed bat) 114 rat) CARNIVORES Rattus norvegicus (brown rat) 79, 190 Feral R. rattus (black rat) 78, 183 Meles meles (badger) 32 Captive Mephitis mephitis (striped skunk) 5, 79 Chinchilla laniger (chinchilla) 33 Procyoni lotor (raccoon) 5, 148 UNGULATES Spilogale putorius (skunk) 78 Domestic Urocyonz cineroargeniteuts (grey fox) 5, 79 Bos taurus (cattle) 151 Vulpes fulva (red fox) 5 Equus caballus (horse) 151 Captive Ovis aries (sheep) 151 Mustela furo (ferret) 125 Sus scorfa (swine) 150 Ursus middendorfii (big brown bear) 46 and the absence of reports of natural infections in currence and distribution of H. capsulatum in chickens (186), there is no basis to consider chick- nature. Other ecological factors also must be at ens as active carriers of histoplasmosis. play, for H. capsulatum is not invariably present Soil surveys and searches for the source of out- in avian and chiropteran habitats. Throughout the breaks of histoplasmosis have revealed that world, there are may areas populated with bats habitats of birds other than chickens harbor H. and birds that are free from H. capsulatum, as capsulatum. Soil from roosts of grackles (Quiscu- determined by negative soil findings and low or lus quiscula), pigeons (Columba livia), and star- negligible levels of histoplasmin reactivity in the lings (Sturnus vulgaris) have been found to be population. infested by H. capsulatum (41, 75), as well as Goodman (95) carried out a series of experi- caves frequented by oil birds (Steatornis caripen- ments on a variety of environmental factors that sis) in Peru, Venezuela, and Trinidad (2, 4, 5, 8, conceivably affected the growth of H. capsulatum 10, 121). in nature. He found that in soil with 12% mois- Soils from bat caves and other areas frequented ture H. capsulatum survived temperatures of - 18, by these mammals, in many different parts of the 4, 10, and 37 C over a 50-week period of observa- world, have also yielded H. capsulatum (1, 9, 11, tion. In contrast, it did not remain viable longer 14, 39, 50. 52. 74, 80, 93, 94, 157, 161, 166, 168, than 2 weeks when incubated at 40 C. Between 37 206, 207). It is believed that soil enriched with and 40 C, there was a dramatic loss of heat toler- bat and bird dung gives a competitive advantage ance. In dry soil (2% moisture), H. capsulatum to H. capsulatum so that it can develop with withstood significantly higher temperatures. At greater success than it would in another habitat. the end of 15 weeks, viable fungal elements were Extracts of chicken and starling manure have still present in soil cultures maintained at 40 C. been shown in have a stimulating effect on the But, after 50 weeks, the 37 and 40 C cultures were sporulation of H. capsulatum (95, 191, 212). dead. The presence or absence of bat and bird dung The temperature range in which H. capsulatum in the environment does not solely govern the oc- survived was considered to be representative of VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 17 that prevailing in the histoplasmosis endemic mains to be done to identify them and to under- areas of the United States. Goodman believes stand their inter-related functions. that "soil temperatures of 40 C are not likely to occur in the endemic areas, especially not in CONCLUDiNG REMARKS AND SUMMARY shaded, moist environments commonly associated This survey will have served its purpose if it with fungal growth." Furthermore, his "data in- spurs more investigators to delve into the ecology dicate that H. capsulatum is not likely to survive of human pathogenic fungi. A long, fascinating, in regions where the temperatures rise to 40°C for arduous, but rewarding road lies ahead for those prolonged periods such as the desert Southwest who take up this study. The relationships of fungi or Southwestern plains." to their environment and to other microorganisms Goodman's observations are in contrast to is complex, and much information remains to be those obtained by Menges et al. (146). In those gathered before we can begin to understand the earlier studies, growth of the fungus was obtained host of factors that influence their survival, under laboratory conditions only at 100% relative growth, and distribution in nature. humidity with no growth at 5 or 10 C. B. dermatitidis presents one of the greatest Physical and chemical analyses of soils showed ecological challenges. As yet, its natural habitat that H. capsulatum would not grow at pH levels remains unknown. It is difficult to imagine the below 5 or above 10. Between those extremes, precise ecological conditions it requires that growth was abundant. Earlier, Zeidberg et al. permit its existence in such diverse regions as the (223) noted that in Williamson County, Tenn., H. Americas and Africa. Further studies should be capsulatum was recovered primarily from acidic directed not only toward a search for B. dermatiti- soils. in as a Goodman found that such chemical factors as dis wide variety of habitats as possible but nitrogen, phosphorous, potassium, and organic also toward its possible association with plants content did not seem to have a significant influ- and lower animals. ence on the growth of H. capsulatum. It was not Ecological studies directed toward C. immitis, possible to determine on the basis of such analy- C. neoformans, and H. capsulatum have been ses why some soils did not support the growth of quite fruitful. These three fungi are adapted to H. capsulatum whereas others of apparently simi- life in specific habitats that give them survival lar composition did. and competitive advantages over other microor- In 1954, Zeidberg (224) suggested that red-yel- ganisms. low podzolic soils provide the best natural habitat C. immitis is restricted to the desert areas of for H. capsulatum. This theory was based on the North, Central, and South America. There, adap- observation that the geographic distribution of tation to high temperatures, low rainfall, and high histoplasmin sensitivity coincides to a remarkable concentrations of salt enables it to thrive. Outside degree with that of the red-yellow podzolic soils. of the arid regions of the Americas, this fungus More recently, Stotzky (201) proposed another evidently cannot establish itself and survive. It soil theory. This investigator holds that clay would appear that, without drastic climatic minerals are important determinants of the changes, the coccidioidomycosis endemic areas "ecology and population dynamics of micro- will not change appreciably. organisms in soil." Mineralogic analysis of soil Although the absence of C. immitis from the samples positive for H. capsulatum from widely arid regions of Africa, Asia, and Australia has not scattered geographic areas revealed that the soils, been conclusively established, all available evi- with two exceptions, did not contain swelling dence indicates that this fungus does not exist three-layer silicates (montmorillonite). Stotzky outside of the American deserts. Bates (23) points suggested that the distribution of H. capsulatum out that there has been relatively little opportu- is influenced by the types of clay minerals present nity for the interchange of desert-adapted plants and animals from one continental desert area to in the soil. Although many of the positive soils another. This is a consequence of formidable that he tested were not red-yellow podzolics, he oceanic barriers that separate the great desert noted that one of the characteristics of red-yellow regions of the world from one another. podzolic soils is the absence of montmorillonite- Habitats that favor the growth of C. neoformans type clay minerals. and H. capsulatum occur throughout the world. None of the proposed theories satisfactorily The oceans do not appear to have barred their accounts for the indisputable association of H. spread. But their occurrence in the several con- capsulatum with bat and bird habitats and its tinents is not haphazard. Each of these two species pattern of geographic distribution. The factors is confined to specific habitats that give them sur- involved must be complex, and much work re- vival advantages. 18 AJELLO BACrERIOL. REV. C. neoformans flourishes in bird manures, es- of Coccidioides immitis from the air. Sabou- pecially that of pigeons. Staib has shown that raudia 4:92-95. this association may be governed by the presence 13. AK1BA, T., AND K. IWATA. 1954. On the de- of creatinine, which is utilizable as a nitrogen structive invasion of a new species, "Bacterium candidodestruens" into Candida cells. Japan. source by C. neoformans but not by competing J. Exptl. Med. 24:159-167. microorganisms. 14. ALARCON, D. G. 1957. Histoplasmosis pulmo- " It has been established that H. capsulatum has a nary epidemica. Gac. Med. Mex. 87:745-750. predilection for bat and bird habitats, but the 15. ALBERT, B. L., AND T. F. SELLERS. 1963. Coc- basis for this association has yet to be determined. cidioidomycosis from formites. Report of a The role of soil types and climate also bears fur- case and review of the literature. Arch. In- ther investigation. ternal Med. 112:253-261. In the coming decades, ecologically oriented 16. ANDLEIGH, H. 1951. Blastomycosis in India. coupled with microbiological and Report of a case. Indian J. Med. Sci. 5:59-62. investigations 17. ARAVIISKII, A. N. 1958. Deep blastomycosis sui biochemical studies promise to cast new and fresh generis similar to American coccidioidomyco- light on the natural history of the fungi that cause sis. Vestn. Dermatol. i Venerol. 32:3-10. human respiratory diseases. 18. ARAVI1SKII, A. N., AND P. N. KAsHIN. 1962. Coccidioidomycosis. State Publishing House LITERATURE CITED for Medical Literature, Medgiz, Leningrad. 1. AGUIRRE PEQUENO, E. 1959. Aislamiento de 19. ARIAS LuZARDO, J. J. 1962. Micosis profundas Histoplasma capsulatum del guano de mur- mas frecuentes en Mexico. Thesis, Universidad cielago en cuevas del noreste de Mexico. Gac. Nacional Autonoma de Mexico, Escuela Med. Mex. 99:243-253. Nacional de Medicina, Mexico, D.F. 2. AJELLO, L. 1956. Soil as natural reservoir for 20. ARIEVICH, A. M., AND Z. G. STEPANISCHEVA. human pathogenic fungi. Science 123:876-879. 1964. First cases of histoplasmosis in the 3. AJELLO, L. 1958. Occurrence of Cryptococcus U.S.S.R. Klin. Med. (Moskva) 1:85-91. neoformans in soils. Am. J. Hyg. 67:72-77. 21. ARTAGAVEYTIA-ALLENDE, R. C. 1949. Estudio de 4. AJELLO, L. 1960. Histoplasma capsulatum soil algunas propiedades biologicas de varias studies. Mykosen 3:43-48. cepas de Coccidioides immitis Stiles, 1896. 5. AJELLO, L. 1960. Geographic distribution of Mycopathologia 4:375-378. Histoplasma capsulatum, p. 88-98. In H. C. 22. BACKHOUSE, T. C., AND A. BOLLIGER. 1960. Sweany [ed.], Histoplasmosis. Charles C Cryptococcosis in the Koala (Phascolarctos Thomas, Publisher, Springfield, Ill. cinereus). Australian J. Sci. 23:86-87. 6. AJELLO, L. 1961. Observations on the epidemi- 23. BATES, M. 1960. The forest and the sea. Random ology of histoplasmosis. Mycopathol. Mycol. House, New York. Appl. 15:231-237. 24. BENBROOK, E. A., J. B. BRYANT, AND L. Z. 7. AJELLO, L., R. E. REED, K. T. MADDY, A. A. SAUNDERS. 1948. A case of blastomycosis in BUDURIN, AND J. C. MOORE. 1956. Ecological the horse. J. Am. Vet. Med. Assoc. 112:475- and epizootiological studies on canine cocci- 478. dioidomycosis. J. Am. Vet. Med. Assoc. 25. BENNETr, J. E., H. F. HASENCLEVER, AND G. L. 129:485-490. BAUM. 1965. Evaluation of a skin test for 8. AJELLO, L., T. BmIcE&O-MAAz, H. CAMPINS, cryptococcosis. Am. Rev. Respirat. Diseases AND J. C. MOORE. 1960. Isolation of Histo- 91:616. plasma capsulatum from an oil bird (Steatornis 26. BERGMAN, F. 1963. Occurrence of Cryptococcus caripensis) cave in Venezuela. Mycopathol. neoformans in Sweden. Acta Med. Scand. Mycol. Appl. 12:199-206. 174:651-655. 9. AJELLO, L., P. E. C. MANSON-BAHR, AND J. C. 27. BINFoRD, C. H. 1941. Torulosis of the central MOORE. 1960. Amboni caves, Tanganyika, a nervous system. Review of recent literature new endemic area for Histoplasma capsulatum. and report of a case. Am. J. Clin. Pathol. Am. J. Trop. Med. Hyg. 9:633-638. 11-.242-251. 10. AJELLO, L., D. W. SNOW, W. G. DOWNS, AND 28. BOLLIGER, A., AND E. S. FiNCKH. 1962. The J. C. MOORE. 1962. Occurrence of Histo- prevalence of cryptococcosis in the Koala plasma capsulatum on the Island of Trinidad, (Phascolarctos cinereus). Med. J. Australia B.W.I. I. Survey of Steatornis caripensis (oil 1:545-547. bird) habitats. Am. J. Trop. Med. Hyg. 11: 29. BOLLiGER, A., AND E. S. F1NCKH. 1962. Crypto- 245-248. coccosis in the Koala (Phascolarctos cinereus). 11. AJELLo, L., A. M. GREENHALL, AND J. C. MooRE. Further observations. Australian J. Sci. 24:325- 1962. Occurrence of Histoplasma capsulatum 326. on the Island of Trinidad, B.W.I. II. Survey 30. BRADY, M. 1947. Blastomycosis, North Ameri- of Chiropteran habitats. Am. J. Trop. Med. can type. A proved case from the European Hyg. 11:249-254. continent. Arch. Dermatol. Syphilol. 56:529- 12. AJELLO, L., K. MADDY, G. CRECELIUS, P. G. 531. HUGENHOLTz, AND L. B. HALL. 1965. Recovery 31. BROC, R., AND N. HADDAD. 1952. Tumeur VOL. 31, 1967 RESPIRATORY MYCOTIC DISEASE AGENTS 19

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