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Respiratory mycotic infection
PREVENTIVE
MEDICINE
3,517-528
(1974)
Respiratory
Mycotic
CHARLOTTE School
of Medicine, Springfield,
Infection
C. CAMPBELL
Southern Illinois University, lllinois 62708
Clinging to outmoded World War II (when they first came into prominence) concepts of the respiratory mycoses is in this age of concern over air pollution and environment not only paradoxical, but dangerous. The respiratory mycoses are infrequently differentiated from man-to-man transmitted flu-like illnesses. Their incidence and cost in terms of hospitalization and/or productive time lost are, therefore, simply unknown. Arguments are presented that the respiratory mycoses are the “sleeping giants” of all infectious diseases if for no reason other than their continued neglect. Dangers from them increase for compromised hosts. These comprise an ever-increasing number of U. S. citizens. Available drugs are so poor they are rarely used except in advanced disease and life-threatening situations. Suggestions are offered of ways to correct this unfortunate “trend” of overlooking the mycoses until they themselves command attention by long-term, incapacitating illness and death-often negating some of medicine’s most significant and sophisticated advances in other fields.
The mycoses are, with few exceptions, environmental diseases. They are not transmitted from man to man. The respiratory mycoses are acquired by inhalation of particles of certain fungi along with particles of soil. However, mass movements of soil are commonplace in contemporary life. Such fungi may, therefore, be regarded essentially as air pollutants to be inhaled by today’s increasingly aggregating populations. The respiratory mycoses are, in effect, diseases of economic progress. Yet they are still little considered in medicine in this context and do not claim the attention of physicians during the acute flu-like or upper respiratory infection stages. A diagnosis of a respiratory mycosis is usually the last to be entertained in the differential diagnosis of the alarming increase in largely undifferentiated respiratory infection and disease-or their sequelae such as bronchitis or emphysema-particularly in city dwellers. The clinging to outmoded concepts of the respiratory mycoses is indeed paradoxical in our age deeply concerned about air pollutants and environment in general. This report is an effort to update concepts of the respiratory mycoses in physicians and laymen minds alike so that they may receive their proper attention and support (7). INCIDENCE
AND
COST
Information on the incidence and prevalence of the respiratory fungus diseases is essentially lacking. Reporting of these diseases is optional. Thus, the information which is available is unreliable and, therefore, misleading. 517 Copyright @ 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
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One example is that in the 5-yr period between 1964 and 1968, there were 387 reported deaths due to cryptococcosis while only 91 clinical cases were reported to the Center for Disease Control (14). Recently, a group of investigators in the Mycoses Section, Ecological Investigations Program, Center for Disease Control, Kansas City, KS, carried out a study to determine the incidence of hospitalization cases of mycoses throughout the United States (11). Basic data for this study were supplied by the Commission on Professional and Hospital Activities (CPHA), Ann Arbor, MI. These data undoubtedly still represent a low estimate of the systemic mycotic infection and disease which actually occurs, but they are probably the best information yet available. The CPHA compiles limited clinical information on all patients discharged from voluntarily participating, nonfederal, acute-care hospitals throughout the U. S.-the data in this instance were for 1970 in which 33% of such institutions in the U. S. voluntarily participated. Participation by individual states varied from zero to 93%. The discharge diagnoses were tabulated for “systemic mycoses” and included three nonrespiratory mycoses - systemic candidiasis, sporotrichosis, and actinomycosis: however, the number of each of these as primary diagnoses was relatively small. The data can be regarded as generally valid for the respiratory mycoses; histoplasmosis, coccidioidomycosis, aspergillosis, cryptococcosis, and blastomycosis. Projections from the statistical analysis of these data indicated that in the U. S. in 1970 there were 7697 patients hospitalized with these diseases and that the cost of hospitalization was 9.39 million dollars. Hospitalization rates conformed, in general, to the known geographic distribution of the infective agents of histoplasmosis, coccidioidomycosis, and blastomycosis. The geographic distribution of aspergillosis and cryptococcosis is widespread throughout the U. S. In fact, coccidioidomycosis is the only respiratory mycotic disease with a limited geographic distribution. Case fatalities per 100 hospitalized patients ranged from 0.0 for one of the diseases (actinomycosis-not a respiratory disease-nor even a fungus) to 18.0 for cryptococcosis. As noted above, these estimates unquestionably are low. The data on which they are based represent only a third of the nonfederal, acute-care hospitals in the U. S. These hospitals are those in which the respiratory mycoses are least likely to be recognized-particularly as a primary diagnosis. This regrettably is also true for too many in the known endemic areas for coccidioidomycosis and histoplasmosis. Data are not included from any of the hospitals having a major affiliation with a medical school or with more than 300 beds. Nor are data from the Armed Forces-Veterans Administration hospitals or various types of state-supported sanatoria devoted primarily to the care of more chronic types of diseases-at which stage the respiratory mycoses are too frequently first recognized. The estimates may also be considered to be low because of the unavailability of diagnostic reagents for their more rapid diagnosis in large as well as small hospitals, and of the relatively few clinicians and clinical diagnostic
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microbiologists who are trained to recognize the mycotic infections and diseases in the differential diagnosis of acute or chronic pulmonary episodes. THE RESPIRATORY ENVIRONMENTAL
MYCOSES AS DISEASES
The respiratory mycoses have received inadequate attention up to the present time, perhaps because they are not man-to-man transmitted diseases. Man acquires them instead from sources in his environment, most frequently the soil in which the pathogenic fungi live saprophytically. The respiratory mycoses first came into prominence during World War II when a high incidence of both coccidioidomycosis and histoplasmosis was found as acute pulmonary infection in military recruits introduced into the endemic areas for their causative agents for the first time. Only a comparative few developed the extremely disseminated, invariably fatal form of coccidioidomycosis and histoplasmosis, the only form in which these two diseases had theretofore been recognized. They were essentially medical curiosities as late as 1940. Despite the fact that these infections could be quite severe in their primary pulmonary form- requiring days to weeks of hospitalization in many instances-they developed the reputation of being “benign” and spontaneously healing when only a small percentage of healthy young recruits succumbed to these infections. The residues of calcified lesions, fibrosis, cavitation, and other pulmonary pathology obviously were not included in this assessment; merely the clinical recovery from the acute flu-like illness. This reputation of benignity is partially responsible for the loss of interest in the respiratory mycoses in the decades after World War II, particularly in civilian populations. Unfortunately, they also gained reputations of being of interest only to the military because of the closer contacts with soil, generally in nonurban areas. However, in the decade of the 1970’s with its increasingly aggregating populations and continuous upheavals of soils in the massive construction of highways, cities, suburbia, agriculture, and industries to accomodate them, we are ill advised to constrict our thinking of the respiratory mycoses either as rare or benign or as diseases of interest only to the military. The microfoci of cryptococcosis and histoplasmosis are closely associated with birds and bird roosts over a large portion of the U. S. Certain species of birds are as prevalent in cities as in many suburban and rural areas, Certain species of bats, their cloning and hibernating sites (especially caves in the U. S.) are frequently also rich sources of microfoci of Histoplasma capsulatum. The bat is as common as the pigeon and other avian species in many U. S. towns and cities. The bat acquires histoplasmosis presumably in the same way as other mammalians, including man, and is capable of depositing the organism with its feces. This is in contrast to avian species who do not appear to acquire histoplasmosis. These are incapable of introducing new microfoci of the organisms via feces. Moulted feathers, however, have not been excluded as another possible vehicle for introducing new microfoci of this dimorphic fungus into soils.
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The yeast, Cryptococcus neoformans, on the other hand, is carried in the intestinal tracts of pigeons and deposited with their feces (also in those of parakeets, budgerigars, canaries, and other avians increasingly popular as pets frequently with aging high-rise apartment dwellers). These distinctions are important to measures which should be considered in the prevention and/or control of these two most common and widely geographically distributed respiratory mycoses. The microfoci for coccidioidomycosis are not associated with birds or bats but are much more geographically limited in the United States to the arid desert areas of the southwest. These microfoci, too, exist within the densely populated cities of the West Coast as well as the less densely inhabited deserts (15). In fact, the causative organism, Coccidioides immitis, is so easily wafted by wind, it has been estimated that nearly 100% of the population residing in the arid, endemic areas will have been infected within the first or second year of residence and about a fifth of these will have had an illness severe enough to cause temporary incapacity and to warrant medical care (9). Thus, while mortality may be low from the primary infection, morbidity is extremely high and represents a major loss of productive time in the civilian populations of the endemic areas for coccidioidomycosis in the U. S. However, these infections may also occur throughout the U. S. in travellers who jet in and out of the endemic areas; now rarely for reasons of national defense, Nevertheless, this infection also remains a problem to the military, particularly to the Air Force with training bases in these endemic areas. A study at Luke Air Force Base, Glendale, AZ revealed that man-hours lost because of coccidioidomycosis exceeded the loss of training time caused by all other respiratory diseases combined (17). It is not likely the morbidity is less in the surrounding civilian populations. The civilian population merely receives less attention than the expensively trained, medically better cared for Air Force pilots and their supportive personnel. Because of the differences in topography and climate of the endemic areas for coccidioidomycosis from that of a major portion of the rest of the United States it is likely that the attack rate of coccidioidomycosis is more continuous and more constant than for the other respiratory mycoses. Histoplasmosis is known chiefly through “outbreaks” (16). These, not too paradoxically, have been recognized only in smaller rural-type communities having one or two hospitals and better personal communication among the fewer physicians practicing in these areas- or where the outbreaks (or epidemics) of pulmonary infection are so explosive that public health department assistance is sought from the outset to determine the cause. It is unreasonable to assume that these outbreaks do not occur in larger cities. They simply would not be identified in more diffuse city populations with many hospitals and where numerous construction activities are in progress simultaneously. For it is the “isolated” activity by which outbreaks in these smaller communities have been identified as histoplasmosis. For example, there were two successive outbreaks in Mason City, Iowa, an area thought to be nonendemic for histoplasmosis until the first outbreak oc-
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curred. The first derived from felling trees lining a creek which was being widened for the development of a park (8). The trees had been heavily “infested” by large flocks of birds for years-a situation not uncommon in many large cities. However, it was the death of the bulldozer operator who widened the creek which led to further study and to the discovery that there had been an extensive outbreak of histoplasmosis among the townspeople from this single, relatively small but commonplace operation. The bulldozed soil was heavily contaminated with Histoplasma capsdatum whose spores were set free essentially as air pollutants over a large portion of the town and produced active clinical infections in persons who not only were not associated with the park operation but possibly were unaware that it was in progress. The second outbreak occurred when the partially sawed-up trees were removed from the park (21). Aware now that the park was a highly endemic microfocus, all possible precautions were taken. The trees were removed in January when the ground was frozen, on a day when there was no wind, and only men who had experienced the infection in the first outbreak (at least, by positive histoplasmin skin tests) participated in removing the trees. Despite these precautions, there was a second outbreak possibly more extensive than the first. This may be doubtful since the whole medical community was alerted to the second operation and did not mistake the sudden onslaught of flu-like illnesses - some of them quite severe-for bacterial or virus man-to-man transmitted diseases which ordinarily occur at this time of year. The lessons learned from the second outbreak are probably more important to contemporary society than those of the first: (1) It takes little wind to waft the spores of H. capdatum to rather extensive distances. (2) It is not likely that either the first or second outbreak of histoplasmosis identified in Mason City, IA, with only two hospitals would have been identified in Boston, MA or Washington, DC (to name but two major cities in the U. S.), and (3) the movement of soil is commonplace in all our lives. Who yet, however, associates movement of soil with respiratory flu-like illnesses in urban populations ? Still outbreaks of histoplasmosis have been reported from Canada to South Carolina (16), nearly always in “isolated” outbreaks where the etiology could be determined either by differentiation in patients hospitalized in the same hospital or treated by the same physicians or the isolation of the organism from soil, retrospectively, from an identifiable construction activity in the community, shown to have involved a microfocus of this fungus. It is ironic that the largest outbreak of histoplasmosis yet reported occurred on Earth Day, 1970 (3). A f ew children raked leaves in a small courtyard at their school, near the air intakes of the school’s forced-air ventilation system. Clinical illness occurred in 384 (40%) students and faculty with probably an equal number of “subclinical” cases. This outbreak occurred in a state known to be highly endemic for histoplasmosis. The circumstances in the school courtyard were ideal as a microfocus for H. capsulatum. It was a haven for flocks of roosting birds. Yet histoplasmosis was not considered prior to the clean-up activities nor was it remarkably high on the list of possible causes of
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the explosive outbreak of flu-like illnesses beginning IO-14 days later. The water supply and 18 throat-wash specimens were first examined for bacteria and viruses, and the serological screen for antibodies included a battery of antigens for respiratory viruses. It is doubtful histoplasmosis would have been considered at all had the outbreak occurred in less restricted circumstances or in a less captive population than school children, Nevertheless, this outbreak serves to emphasize the importance of population size and density in mycotic infection outbreaks. However, this outbreak points up another hazard of the contemporary age. These are central air conditioning and heating systems which may not only feed in pathogenic fungi from the environment, but because of their engineering design support the growth of thermophilic actinomycetes and other fungi whose spores are disseminated through the air ducts. The development of hypersensitivity alveolitis in office workers, home owners, and others who utilize central air conditioning can be serious and crippling if exposure is repeated or continued. These fungi produce a “Farmers Lung” type of disease in city residents (2). One other respiratory mycosis should be considered in this same general environmental context. As noted above, Cryptococcus neoformans survives in the feces of the ubiquitous pigeon, both in vivo and in vitro. When these excreta dry, the organism also becomes an infectious air pollutant which requires possibly even less disturbance of its microfoci than H. capsulatum or C. immitis. Such microfoci may even be the tops of portable window air conditioners on which pigeons are fed, since in the pigeon fresh feces may also be infectious for C. neoformans (5). The pigeon population is high in most cities throughout the U. S. Feeding them on city streets or in city parks or even on one’s own window sills is a favorite pastime, particuarly of children and senior citizens. New York City and Boston are but two major cities which have tried to quietly reduce their pigeon populations by periodic efforts at extermination for economic reasons; not health of its citizens. Accumulations of droppings are destructive to storefront awnings and canopies of business establishments! The arguments for health have in the main been received with derision. Because of its essentially global distribution, cryptococcosis is possibly the sleeping giant among the pulmonary mycoses (1). Regrettably, it is still seldom considered as a pulmonary infection, but only after it has progressed to the central nervous system disease (cryptococcus meningitis) in which without therapy the case fatality rate in reality more nearly approaches 100%. Because this form of the disease is one of the most easily recognized, it is even more regrettable that at least the reporting of this form of the disease has not been mandatory. In a single State Chest Hospital in Missouri (12) and in the teaching hospitals in Boston, there were 25 and 42 cases of cryptococcosis, respectively, in 1971 (7). The disease has an especially poor prognosis in persons compromised by immunosuppressive and/or chemotherapeutic agents - or those undergoing organ transplantation or cancer chemotherapy. This represents a growing number of U. S. citizens. Therefore, it behooves physicians to begin to recognize the wide clinical spectrum of cryptococcal in-
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fections and not the CNS disease only (13), as well as the prevalence of this organism in nature. It is not the author’s intention to overlook blastomycosis, aspergillosis, or nocardiosis whose causative agents also are acquired from the environment, principally by inhalation. However, hopefully, the point has been made that the respiratory mycotic agents are, in essence, air pollutants because of the changes in man’s living habits. They can no longer be considered as causes of infection or disease associated with isolated identifiable activities in rural communities only. The few cases identified in this way do indeed represent but the tip of “the medical mycological iceberg” (1). PREVENTION
AND
CONTROL
There is no man-to-man chain of transmission to be broken in our daily exposure to air for survival and no realistic way for decontamination of acres and acres of soil. However, there are certain things which are currently possible. 1. Education of the general public about the respiratory mycotic diseases. The public can be advised of the existence of the respiratory mycoses and that their causative agents are airborne; that not all dangers of the air are noxious gases from automobile exhausts or other inanimate pollutants. They should be made particularly aware or the dangers inherent in areas in which large flocks of birds have roosted for long periods of time (16) and that soils around these well-characterized areas, at least, can be decontaminated successfully (22). Decontamination of such areas should be mandatory before the granting of any permit for construction over these areas within city limits or in circumscribed communities. Where no such microfoci are known to exist, there can, at least, be a public demand that dust in any construction project be reduced to a minimum by simple wetting with water if by no other means; and by the enclosing of truck beds transporting soils through densely populated areas. This is particularly important in road construction projects, development of golf courses, or any other project proximate to varying densities of the population. A noted investigator has pointed out that in northern Louisiana where the histoplasmin skin test reactivity rate is about 70% and the primary pulmonary infection of histoplasmosis exceedingly common, there is still an increasing number of outbreaks of histoplasmosis during the course of building roads, particularly superhighways - and that these outbreaks include infants (in whom the disease is especially severe) and children as well as the theoretically already sensitized adults in this highly endemic area (18). These increases occurred particularly during the periods of excavation and grading with no effort to wet the earth prior to either of these major activities. The discovery of an extensive outbreak of histoplasmosis after the development of a golf course adjacent to a densely populated area is well-documented (19). There were an estimated 8000 infections in this outbreak in Greenwood, SC, although only 42 were identified by development of the erythemas (16). The historical association of histoplasmosis with massive movements of soil and economic as well as medical progress was first pointed out by this author in 1967 (4). While there is little likelihood that coccidioidomycosis could be contained
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by these measures, persons expecting to travel to or permanently reside in the known and better circumscribed endemic areas of this mycosis should be advised of the early symptoms of the primary infection and the possibility of acquiring it with no unusual type of exposure. It would be no more exceptional to require application of the coccidioidin skin test prior to arrival in the known endemic areas than to require many vaccines prior to entry into areas known to be “endemic” for many nonmycotic diseases. Coccidioidomycosis can also develop into an extremely severe - even fatal disease - especially for those “meeting” the agent for the first time. If the immigrating mobile general public-much less students on archeological digs (23), farm laborers, or construction workers-are made aware of coccidioidomycosis -they may, in fact, learn to demand a wider use of the coccidioidin skin (and serologic) test(s) in their expected better health care. Similarly the general public can be educated that the pigeon may not be an innocuous bird and thereby discouraged from feeding them or otherwise attracting them to seek refuge in cities. Avians as pets should also be discouraged. This is possible through the mass media. The dangers of cleaning up or playing in areas which are heavily contaminated with bird excreta should be common knowledge to every school child and certainly to every Boy Scout and Girl Scout and their corollaries. This, too, is part of the knowledge of ecology. However, it is evident in the 1970’s that it is not knowledge common even to their teachers or leaders (3). 2. Education of physicians, veterinarians, public health workers, and clinical diagnostic microbiologists in the 1970 concepts of the respiratory mycotic infections. The mandatory reporting of mycotic respiratory mycotic infections will not measurably alter the low status of these infections in terms of numbers of cases reported until physicians, veterinarians, public health workers, and clinical microbiologists themselves learn to consider the mycases in the differentiation of flu-like illnesses with acute onset, The authors of the 1970 Earth Day outbreak of histoplasmosis (3) are worth quoting on this point. “It is worthwhile to emphasize that the clinical illness in most of these cases was mild enough to be considered a nonspecific “flu-like” syndrome. Histoplasmosis is almost never included in the differential diagnosis of mild “flu-like” syndromes, probably because much of the literature on this illness focuses upon the chronic pulmonary or disseminated forms of the disease and not upon the much more common upper respiratory or even subclinical form.” It is of interest that there were 113,661 unclassified respiratory infections optionally reported from only 18 of the 50 states in 1971(14). However, of these 113,661 unclassified respiratory illnesses, 50,841 cases (or nearly 45%) were from the East South Central States- Kentucky, Tennessee, Alabama, Mississippi- known to be endemic for blastomycosis and cryptococcosis as well as histoplasmosis. An additional 13,017 cases (over 10%) were reported from the Mountain states including New Mexico, Arizona, Utah, and Nevada, all recognized as having highly endemic areas for coccidioidomycosis. And from California alone, also part of the known endemic area for coccidioidomycosis, there were 27,704 (or roughly 25%) unclassified respiratory infections. In
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respiratory other words, 91,562 of the 113,661 (or roughly 80%) unclassified infections reported in 1971 were from geographic areas known to be endemic for histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcis. Yet histoplasmosis only was reported separatelywith 190 cases. 3. Mandatory reporting of the respiratoy mycotic diseases. Despite the hazards of still not obtaining a true picture of the incidence of mycotic infection as noted above the reporting of the mycotic disease which is currently recognized should be mandatory. This is essential even to begin to assess the cost in terms of morbidity if not to mortality. 4. Systematic sampling of soils for H. capsulatum and C. neoformans from known bird or bat roosting or hibernating sites and their subsequent decontamination prior to excavation activity in towns or cities throughout the U. S. Since there are no vaccines for the prevention of the mycotic infections and, physicians in any comas yet, very poor drugs for their treatment, munitylarge or small-can, at least, be forewarned that there are active microfoci in the immediate area. It has become clear that the histoplasmin skin test reactivity rate is not a reliable index as to the geographic distribution of this fungus-it pinpoints only those areas in which the microfoci of H. capsulatum have been disturbed. The reported outbreaks have generally occurred in areas of low skin-test hypersensitivity, indicating that microfoci were present. It would, therefore, provide some measure of prevention and control to locate these microfoci and decontaminate them prior to disturbance, at least on surface soils. Microfoci in caves due to the hibernation of birds and/or bats should also be identified prior to superhighway construction projects. Decontamination of these sites should be provided regardless of a high skin-test hypersensitivity rate in any given community. Successive outbreaks can occur even in communities with high histoplasmin sensitivity rates w. of pigeon populations for Cryptococcus neo5. Systematic sampling formans in large and small communities (and of their nesting and roosting places). The accumulation of hard data implicating the pigeon as a real factor in the geographic distribution of Cryptococcus neoformans will be necessary to determine whether efforts should be made toward eradicating the pigeon from large cities at least. 6. Skin testing of certain occupational groups. Skin tests with histoplasmin, coccidioidin, and possibly blastomycin has been neglected in occupational groups in which it would be most useful-for furthering our information about the more precise geographic distribution of these respiratory mycotic agents and for the more rapid differentiation of flu-like illnesses due to them. Such occupational groups include not only construction workers, coal and other types of miners or other laborers having close contact with soil, but also archeologists, entomologists, and other highly skilled persons whose field research brings them into intimate contact with the soil. It definitely includes the clinical diagnostic microbiologist who may be exposed to isolates of these fungi at any time during the course of the days’ work, regardless of geographic location; and as noted earlier, it includes the vacationer to the fairly cir-
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cumscribed endemic areas for coccidioidomycosis and those who indulge in speleology as a hobby or as a profession, anywhere in the U. S. 7. Culture of tissues of domestic unimuls sacrificed for other reasons. Domestic animals or pets, particularly the dog, because of their close contact with soil make excellent sentinel animals for locating microfoci of the respiratory mycotic agents (10). Such programs could be coordinated with rabies control measures already in progress. The mycoses should also be strongly emphasized in the education of veterinarians, as noted above. 8. Wider application of the serologic diagnostic procedures at hand. The serologic procedures for the rapid diagnosis of coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis are essentially the same as those used for any other infectious disease. One need not be a trained medical mycologist to do them. Reasonably satisfactory antigens are available for coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis, either commercially or through the Mycology Unit at the Center for Disease Control, Atlanta. Presumably the reason the tests are not more widely used is because they are rarely requested by physicians to differentiate flu-like or upper respiratory infections (6), a situation due also to antiquated, forgotten, or overlooked knowledge about the respiratory mycoses. However, to assess the real incidence or prevalence of these infections it is essential that the serologic diagnostic tests be used much more extensively. This applies not alone to the flu-like primary syndromes, but also to more chronic type disease, especially the solitary pulmonary nodule. Because of the possibility of lung cancer, these generally are surgically resected. However, in one study of 887 resected nodules, one third were caused by fungi (20). Thus, nearly 300 people in this study alone were subjected to unnecessary surgical risk, in addition to cost in money and productive time lost. 9. Development of pure and homogeneous antigens. Although the antigens currently available are satisfactory for routine screening purposes, much work remains to be done toward their characterization and purification, and toward development of antigens for aspergillosis, mucormycosis, and other mycoses caused by common fungi and yeasts which produce disease generally only in the compromised host. However, as noted earlier, this includes an ever increasing number of citizens in the U. S. and other economically and medically advanced countries. 10. Zmproz;ed chemotherapy. The need for improved chemotherapeutic measures is becoming acute. The principal effective antibiotic currently available is Amphotericin B which is nephrotoxic. Its use is limited essentially to potential life-threatening situations. This problem is compounded today in that patients who must be placed on immunosuppressive or long-term antibacterial therapy are particularly susceptible to fungus infections. This applies not only to the “opportunists” such as species of Candida, Aspergillus, and the Mucors but to the pathogens noted above. Earlier infection with C. immitis, H. capsulatum, and C. neoformans particularly recrudesce with immunosuppression. The problem is serious in kidney transplantation - with the only drug available toxic for the transplanted kidney. A newer
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drug, 5-fluorocytosine, is effective only on yeasts. However, better drugs are needed not only for saving lives, but also for aborting the primary pulmonary infections which cause disability and loss of productive time. This, too, probably is a primary reason why primary pulmonary mycotic infections are not differentiated. There is no safe drug to treat them when they are diagnosed. Yet the many possible delayed effects of untreated primary mycotic infections are simply unknown. 11. Vaccines and immunologic aspects. Population groups at special risk because of occupation or potential environmental exposure would be good candidates for immunizations. The present state of knowledge, however, of fungal antigen specificities and of the mechanisms of host immunity precludes a rational approach to development of a vaccine. Enhancement of cellmediated immunity, for example, as reported in preliminary studies on the use of transfer factor in cutaneous candidiasis offers promising avenues for future exploration of improved treatment, ACKNOWLEDGMENT
Since the writing of this report, the study by Hammerman, Powell and Tosh (11) has been published in its entirety. (Sabouruudiu 12, 33-45, 1974). The author is deeply indebted to these investigators for the use of their material in summary prior to its publication. REFERENCES I. AJELLO, L. The medical mycological iceberg. HSMHA Health Rept. 86, 437-448 (1971). 2. BANASZAK, E. F., THIEDE, W. H., AND FINK, J. ii. Hypersensitivity pneumonitis due to contamination of an air conditioner. N. Engl. ]. Med. 283,3-8 (1970). 3. BRODSKY, A. L., GREGG, M. B., LOWENSTEIN, M. S., KAUF~LIAN, L., AND MALLISON, G. F. Outbreak of histoplasmosis associated with the 1970 Earth Day Activities. Amer. J. Med. 54, 333-342 (1973). 4. CAMPBELL, C. C. Histoplasmosis and other respiratory mycoses in the tropics. lnduvtry and Trot,. Health, VI: (Library Congr. No. 52-34882) 145-152 (1967). 5. CA~~PBELL, C. C. Isolation of C~Y~~OCOCCUSneoformuns from the top of an air conditioner where pigeons are fed. Unpublished data. (1969). 6. CAMPBELL, C. C. The serology of histoplasmosis. Clin. Lab. Forum. June pp. 3 (1972). 7. CAMPBELL, C. C. “The pilot wheel” a change in course. PTOC. 1st Int. Conf. on Paracoccidioidomycosis. Pan American Health Organization Sci. Pub]. 254,306-312 (1972). 8. D’ALESSIO, D. J., HEEREN, R. H., HENDRICKS, S. L., OCILVIE, P., AND FURCOLOW, M. L. A starling roost as the source of urban epidemic histoplasmosis in an area of low incidence. Amer. Reo. Resp. Dis. 92,725-731 (1965). 9. FIESE, M. J. “Coccidioidomycosis,” p. 253. Thomas, Springfield, IL, 1958. 10. FURCOLO~, M. L., BUSEY, J. F., MENGES, R. W., AND CHICK, E. W. Prevalence and incidence studies of human and canine blastomycosis. Amer. 1. Epidemiol. 92, 121-131 (1970). 11. HAMMERMAN, K. J., POWELL, K. E., AND TOSH, F. E. Personal Communication (1973). 12. LARSH, H. W. Personal communications. (1973). 13. LEWIS, J. L., AND RABINOVICH, S. The wide spectrum of cryptococcal infections (A report of 32 patients). Amer. J. Med. 53,315 (1972). 14. Morbidity and Mortality Weekly Report Annual Supplements. Atlanta, Center for Disease Control. (1963 through 1972). B. H. An epidemic ofcoc15. RAhfRAS, D. G., WALCH, H. A., MURRAY, J, P.,.4ND DAVIDSON, cidioidomycosis in the Pacific Beach area of San Diego. Amer. Reo. Rest,. Dis. 101,975-978
(1970).
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16. SAROSI, G. A., PARKER, J. D., AND TOSH, F. E. Histoplasmosis outbreaks, their patterns. “Proc. Second Nat’1 Conf. on Histoplasmosis,” pp. 123-128. Thomas, Springfield, IL., 1969. 17. SCOCINS, J. T. Comparative study of time loss in coccidioidomycosis and other respiratory diseases. Proc. Symp. Coccidioidomycosis. Public Health Service Monogr. 575, 132-135 (1957). 18. SEABURY, J. Personal communication. (1973). 19. SELLERS, T. F., JR., PRICE, W. N., JR., AND NEWBERRY, W. M., JR. An epidemic of erythema multiforme and erythema nodosum caused by histoplasmosis. Amer. J. Intern. Med. 62, 1244 (1964). 20. STEELE, J. D. “The Solitary Pulmonary Nodule,” p. 226. Thomas, Springfield, IL., 1964. 21. TOSH, F. E., DOTO, I. L., D’ALESSIO, D. J,, MEDEIROS, A. A., HENDRICKS, S. L., AND CHIN, T. D. Y. The second of two epidemics of histoplasmosis resulting from work on the same starling roost. Amer. Rev. Resp. Dis. 94,406-413 (1966). 22. WEEKS, II. J., AND TOSH, F. E. Control of epidemic foci of Histoplasma capsulutum. “Proc. Second Nat’1 Conf. Histoplasmosis,” pp. 184-189. Thomas, Springfield, IL., 1968. 23. WERNER, S. B., PAPPAGLANIS, D., HEINDL, I., AND MICKEL, A. An epidemic of coccidioidomycosis among archeology students in Northern California. N. Engl. J. Med. 286, 507-512 (1972).
MEDICINE
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(1974)
Respiratory
Mycotic
CHARLOTTE School
of Medicine, Springfield,
Infection
C. CAMPBELL
Southern Illinois University, lllinois 62708
Clinging to outmoded World War II (when they first came into prominence) concepts of the respiratory mycoses is in this age of concern over air pollution and environment not only paradoxical, but dangerous. The respiratory mycoses are infrequently differentiated from man-to-man transmitted flu-like illnesses. Their incidence and cost in terms of hospitalization and/or productive time lost are, therefore, simply unknown. Arguments are presented that the respiratory mycoses are the “sleeping giants” of all infectious diseases if for no reason other than their continued neglect. Dangers from them increase for compromised hosts. These comprise an ever-increasing number of U. S. citizens. Available drugs are so poor they are rarely used except in advanced disease and life-threatening situations. Suggestions are offered of ways to correct this unfortunate “trend” of overlooking the mycoses until they themselves command attention by long-term, incapacitating illness and death-often negating some of medicine’s most significant and sophisticated advances in other fields.
The mycoses are, with few exceptions, environmental diseases. They are not transmitted from man to man. The respiratory mycoses are acquired by inhalation of particles of certain fungi along with particles of soil. However, mass movements of soil are commonplace in contemporary life. Such fungi may, therefore, be regarded essentially as air pollutants to be inhaled by today’s increasingly aggregating populations. The respiratory mycoses are, in effect, diseases of economic progress. Yet they are still little considered in medicine in this context and do not claim the attention of physicians during the acute flu-like or upper respiratory infection stages. A diagnosis of a respiratory mycosis is usually the last to be entertained in the differential diagnosis of the alarming increase in largely undifferentiated respiratory infection and disease-or their sequelae such as bronchitis or emphysema-particularly in city dwellers. The clinging to outmoded concepts of the respiratory mycoses is indeed paradoxical in our age deeply concerned about air pollutants and environment in general. This report is an effort to update concepts of the respiratory mycoses in physicians and laymen minds alike so that they may receive their proper attention and support (7). INCIDENCE
AND
COST
Information on the incidence and prevalence of the respiratory fungus diseases is essentially lacking. Reporting of these diseases is optional. Thus, the information which is available is unreliable and, therefore, misleading. 517 Copyright @ 1974 by Academic Press, Inc. All rights of reproduction in any form reserved.
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One example is that in the 5-yr period between 1964 and 1968, there were 387 reported deaths due to cryptococcosis while only 91 clinical cases were reported to the Center for Disease Control (14). Recently, a group of investigators in the Mycoses Section, Ecological Investigations Program, Center for Disease Control, Kansas City, KS, carried out a study to determine the incidence of hospitalization cases of mycoses throughout the United States (11). Basic data for this study were supplied by the Commission on Professional and Hospital Activities (CPHA), Ann Arbor, MI. These data undoubtedly still represent a low estimate of the systemic mycotic infection and disease which actually occurs, but they are probably the best information yet available. The CPHA compiles limited clinical information on all patients discharged from voluntarily participating, nonfederal, acute-care hospitals throughout the U. S.-the data in this instance were for 1970 in which 33% of such institutions in the U. S. voluntarily participated. Participation by individual states varied from zero to 93%. The discharge diagnoses were tabulated for “systemic mycoses” and included three nonrespiratory mycoses - systemic candidiasis, sporotrichosis, and actinomycosis: however, the number of each of these as primary diagnoses was relatively small. The data can be regarded as generally valid for the respiratory mycoses; histoplasmosis, coccidioidomycosis, aspergillosis, cryptococcosis, and blastomycosis. Projections from the statistical analysis of these data indicated that in the U. S. in 1970 there were 7697 patients hospitalized with these diseases and that the cost of hospitalization was 9.39 million dollars. Hospitalization rates conformed, in general, to the known geographic distribution of the infective agents of histoplasmosis, coccidioidomycosis, and blastomycosis. The geographic distribution of aspergillosis and cryptococcosis is widespread throughout the U. S. In fact, coccidioidomycosis is the only respiratory mycotic disease with a limited geographic distribution. Case fatalities per 100 hospitalized patients ranged from 0.0 for one of the diseases (actinomycosis-not a respiratory disease-nor even a fungus) to 18.0 for cryptococcosis. As noted above, these estimates unquestionably are low. The data on which they are based represent only a third of the nonfederal, acute-care hospitals in the U. S. These hospitals are those in which the respiratory mycoses are least likely to be recognized-particularly as a primary diagnosis. This regrettably is also true for too many in the known endemic areas for coccidioidomycosis and histoplasmosis. Data are not included from any of the hospitals having a major affiliation with a medical school or with more than 300 beds. Nor are data from the Armed Forces-Veterans Administration hospitals or various types of state-supported sanatoria devoted primarily to the care of more chronic types of diseases-at which stage the respiratory mycoses are too frequently first recognized. The estimates may also be considered to be low because of the unavailability of diagnostic reagents for their more rapid diagnosis in large as well as small hospitals, and of the relatively few clinicians and clinical diagnostic
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microbiologists who are trained to recognize the mycotic infections and diseases in the differential diagnosis of acute or chronic pulmonary episodes. THE RESPIRATORY ENVIRONMENTAL
MYCOSES AS DISEASES
The respiratory mycoses have received inadequate attention up to the present time, perhaps because they are not man-to-man transmitted diseases. Man acquires them instead from sources in his environment, most frequently the soil in which the pathogenic fungi live saprophytically. The respiratory mycoses first came into prominence during World War II when a high incidence of both coccidioidomycosis and histoplasmosis was found as acute pulmonary infection in military recruits introduced into the endemic areas for their causative agents for the first time. Only a comparative few developed the extremely disseminated, invariably fatal form of coccidioidomycosis and histoplasmosis, the only form in which these two diseases had theretofore been recognized. They were essentially medical curiosities as late as 1940. Despite the fact that these infections could be quite severe in their primary pulmonary form- requiring days to weeks of hospitalization in many instances-they developed the reputation of being “benign” and spontaneously healing when only a small percentage of healthy young recruits succumbed to these infections. The residues of calcified lesions, fibrosis, cavitation, and other pulmonary pathology obviously were not included in this assessment; merely the clinical recovery from the acute flu-like illness. This reputation of benignity is partially responsible for the loss of interest in the respiratory mycoses in the decades after World War II, particularly in civilian populations. Unfortunately, they also gained reputations of being of interest only to the military because of the closer contacts with soil, generally in nonurban areas. However, in the decade of the 1970’s with its increasingly aggregating populations and continuous upheavals of soils in the massive construction of highways, cities, suburbia, agriculture, and industries to accomodate them, we are ill advised to constrict our thinking of the respiratory mycoses either as rare or benign or as diseases of interest only to the military. The microfoci of cryptococcosis and histoplasmosis are closely associated with birds and bird roosts over a large portion of the U. S. Certain species of birds are as prevalent in cities as in many suburban and rural areas, Certain species of bats, their cloning and hibernating sites (especially caves in the U. S.) are frequently also rich sources of microfoci of Histoplasma capsulatum. The bat is as common as the pigeon and other avian species in many U. S. towns and cities. The bat acquires histoplasmosis presumably in the same way as other mammalians, including man, and is capable of depositing the organism with its feces. This is in contrast to avian species who do not appear to acquire histoplasmosis. These are incapable of introducing new microfoci of the organisms via feces. Moulted feathers, however, have not been excluded as another possible vehicle for introducing new microfoci of this dimorphic fungus into soils.
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The yeast, Cryptococcus neoformans, on the other hand, is carried in the intestinal tracts of pigeons and deposited with their feces (also in those of parakeets, budgerigars, canaries, and other avians increasingly popular as pets frequently with aging high-rise apartment dwellers). These distinctions are important to measures which should be considered in the prevention and/or control of these two most common and widely geographically distributed respiratory mycoses. The microfoci for coccidioidomycosis are not associated with birds or bats but are much more geographically limited in the United States to the arid desert areas of the southwest. These microfoci, too, exist within the densely populated cities of the West Coast as well as the less densely inhabited deserts (15). In fact, the causative organism, Coccidioides immitis, is so easily wafted by wind, it has been estimated that nearly 100% of the population residing in the arid, endemic areas will have been infected within the first or second year of residence and about a fifth of these will have had an illness severe enough to cause temporary incapacity and to warrant medical care (9). Thus, while mortality may be low from the primary infection, morbidity is extremely high and represents a major loss of productive time in the civilian populations of the endemic areas for coccidioidomycosis in the U. S. However, these infections may also occur throughout the U. S. in travellers who jet in and out of the endemic areas; now rarely for reasons of national defense, Nevertheless, this infection also remains a problem to the military, particularly to the Air Force with training bases in these endemic areas. A study at Luke Air Force Base, Glendale, AZ revealed that man-hours lost because of coccidioidomycosis exceeded the loss of training time caused by all other respiratory diseases combined (17). It is not likely the morbidity is less in the surrounding civilian populations. The civilian population merely receives less attention than the expensively trained, medically better cared for Air Force pilots and their supportive personnel. Because of the differences in topography and climate of the endemic areas for coccidioidomycosis from that of a major portion of the rest of the United States it is likely that the attack rate of coccidioidomycosis is more continuous and more constant than for the other respiratory mycoses. Histoplasmosis is known chiefly through “outbreaks” (16). These, not too paradoxically, have been recognized only in smaller rural-type communities having one or two hospitals and better personal communication among the fewer physicians practicing in these areas- or where the outbreaks (or epidemics) of pulmonary infection are so explosive that public health department assistance is sought from the outset to determine the cause. It is unreasonable to assume that these outbreaks do not occur in larger cities. They simply would not be identified in more diffuse city populations with many hospitals and where numerous construction activities are in progress simultaneously. For it is the “isolated” activity by which outbreaks in these smaller communities have been identified as histoplasmosis. For example, there were two successive outbreaks in Mason City, Iowa, an area thought to be nonendemic for histoplasmosis until the first outbreak oc-
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curred. The first derived from felling trees lining a creek which was being widened for the development of a park (8). The trees had been heavily “infested” by large flocks of birds for years-a situation not uncommon in many large cities. However, it was the death of the bulldozer operator who widened the creek which led to further study and to the discovery that there had been an extensive outbreak of histoplasmosis among the townspeople from this single, relatively small but commonplace operation. The bulldozed soil was heavily contaminated with Histoplasma capsdatum whose spores were set free essentially as air pollutants over a large portion of the town and produced active clinical infections in persons who not only were not associated with the park operation but possibly were unaware that it was in progress. The second outbreak occurred when the partially sawed-up trees were removed from the park (21). Aware now that the park was a highly endemic microfocus, all possible precautions were taken. The trees were removed in January when the ground was frozen, on a day when there was no wind, and only men who had experienced the infection in the first outbreak (at least, by positive histoplasmin skin tests) participated in removing the trees. Despite these precautions, there was a second outbreak possibly more extensive than the first. This may be doubtful since the whole medical community was alerted to the second operation and did not mistake the sudden onslaught of flu-like illnesses - some of them quite severe-for bacterial or virus man-to-man transmitted diseases which ordinarily occur at this time of year. The lessons learned from the second outbreak are probably more important to contemporary society than those of the first: (1) It takes little wind to waft the spores of H. capdatum to rather extensive distances. (2) It is not likely that either the first or second outbreak of histoplasmosis identified in Mason City, IA, with only two hospitals would have been identified in Boston, MA or Washington, DC (to name but two major cities in the U. S.), and (3) the movement of soil is commonplace in all our lives. Who yet, however, associates movement of soil with respiratory flu-like illnesses in urban populations ? Still outbreaks of histoplasmosis have been reported from Canada to South Carolina (16), nearly always in “isolated” outbreaks where the etiology could be determined either by differentiation in patients hospitalized in the same hospital or treated by the same physicians or the isolation of the organism from soil, retrospectively, from an identifiable construction activity in the community, shown to have involved a microfocus of this fungus. It is ironic that the largest outbreak of histoplasmosis yet reported occurred on Earth Day, 1970 (3). A f ew children raked leaves in a small courtyard at their school, near the air intakes of the school’s forced-air ventilation system. Clinical illness occurred in 384 (40%) students and faculty with probably an equal number of “subclinical” cases. This outbreak occurred in a state known to be highly endemic for histoplasmosis. The circumstances in the school courtyard were ideal as a microfocus for H. capsulatum. It was a haven for flocks of roosting birds. Yet histoplasmosis was not considered prior to the clean-up activities nor was it remarkably high on the list of possible causes of
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the explosive outbreak of flu-like illnesses beginning IO-14 days later. The water supply and 18 throat-wash specimens were first examined for bacteria and viruses, and the serological screen for antibodies included a battery of antigens for respiratory viruses. It is doubtful histoplasmosis would have been considered at all had the outbreak occurred in less restricted circumstances or in a less captive population than school children, Nevertheless, this outbreak serves to emphasize the importance of population size and density in mycotic infection outbreaks. However, this outbreak points up another hazard of the contemporary age. These are central air conditioning and heating systems which may not only feed in pathogenic fungi from the environment, but because of their engineering design support the growth of thermophilic actinomycetes and other fungi whose spores are disseminated through the air ducts. The development of hypersensitivity alveolitis in office workers, home owners, and others who utilize central air conditioning can be serious and crippling if exposure is repeated or continued. These fungi produce a “Farmers Lung” type of disease in city residents (2). One other respiratory mycosis should be considered in this same general environmental context. As noted above, Cryptococcus neoformans survives in the feces of the ubiquitous pigeon, both in vivo and in vitro. When these excreta dry, the organism also becomes an infectious air pollutant which requires possibly even less disturbance of its microfoci than H. capsulatum or C. immitis. Such microfoci may even be the tops of portable window air conditioners on which pigeons are fed, since in the pigeon fresh feces may also be infectious for C. neoformans (5). The pigeon population is high in most cities throughout the U. S. Feeding them on city streets or in city parks or even on one’s own window sills is a favorite pastime, particuarly of children and senior citizens. New York City and Boston are but two major cities which have tried to quietly reduce their pigeon populations by periodic efforts at extermination for economic reasons; not health of its citizens. Accumulations of droppings are destructive to storefront awnings and canopies of business establishments! The arguments for health have in the main been received with derision. Because of its essentially global distribution, cryptococcosis is possibly the sleeping giant among the pulmonary mycoses (1). Regrettably, it is still seldom considered as a pulmonary infection, but only after it has progressed to the central nervous system disease (cryptococcus meningitis) in which without therapy the case fatality rate in reality more nearly approaches 100%. Because this form of the disease is one of the most easily recognized, it is even more regrettable that at least the reporting of this form of the disease has not been mandatory. In a single State Chest Hospital in Missouri (12) and in the teaching hospitals in Boston, there were 25 and 42 cases of cryptococcosis, respectively, in 1971 (7). The disease has an especially poor prognosis in persons compromised by immunosuppressive and/or chemotherapeutic agents - or those undergoing organ transplantation or cancer chemotherapy. This represents a growing number of U. S. citizens. Therefore, it behooves physicians to begin to recognize the wide clinical spectrum of cryptococcal in-
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fections and not the CNS disease only (13), as well as the prevalence of this organism in nature. It is not the author’s intention to overlook blastomycosis, aspergillosis, or nocardiosis whose causative agents also are acquired from the environment, principally by inhalation. However, hopefully, the point has been made that the respiratory mycotic agents are, in essence, air pollutants because of the changes in man’s living habits. They can no longer be considered as causes of infection or disease associated with isolated identifiable activities in rural communities only. The few cases identified in this way do indeed represent but the tip of “the medical mycological iceberg” (1). PREVENTION
AND
CONTROL
There is no man-to-man chain of transmission to be broken in our daily exposure to air for survival and no realistic way for decontamination of acres and acres of soil. However, there are certain things which are currently possible. 1. Education of the general public about the respiratory mycotic diseases. The public can be advised of the existence of the respiratory mycoses and that their causative agents are airborne; that not all dangers of the air are noxious gases from automobile exhausts or other inanimate pollutants. They should be made particularly aware or the dangers inherent in areas in which large flocks of birds have roosted for long periods of time (16) and that soils around these well-characterized areas, at least, can be decontaminated successfully (22). Decontamination of such areas should be mandatory before the granting of any permit for construction over these areas within city limits or in circumscribed communities. Where no such microfoci are known to exist, there can, at least, be a public demand that dust in any construction project be reduced to a minimum by simple wetting with water if by no other means; and by the enclosing of truck beds transporting soils through densely populated areas. This is particularly important in road construction projects, development of golf courses, or any other project proximate to varying densities of the population. A noted investigator has pointed out that in northern Louisiana where the histoplasmin skin test reactivity rate is about 70% and the primary pulmonary infection of histoplasmosis exceedingly common, there is still an increasing number of outbreaks of histoplasmosis during the course of building roads, particularly superhighways - and that these outbreaks include infants (in whom the disease is especially severe) and children as well as the theoretically already sensitized adults in this highly endemic area (18). These increases occurred particularly during the periods of excavation and grading with no effort to wet the earth prior to either of these major activities. The discovery of an extensive outbreak of histoplasmosis after the development of a golf course adjacent to a densely populated area is well-documented (19). There were an estimated 8000 infections in this outbreak in Greenwood, SC, although only 42 were identified by development of the erythemas (16). The historical association of histoplasmosis with massive movements of soil and economic as well as medical progress was first pointed out by this author in 1967 (4). While there is little likelihood that coccidioidomycosis could be contained
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by these measures, persons expecting to travel to or permanently reside in the known and better circumscribed endemic areas of this mycosis should be advised of the early symptoms of the primary infection and the possibility of acquiring it with no unusual type of exposure. It would be no more exceptional to require application of the coccidioidin skin test prior to arrival in the known endemic areas than to require many vaccines prior to entry into areas known to be “endemic” for many nonmycotic diseases. Coccidioidomycosis can also develop into an extremely severe - even fatal disease - especially for those “meeting” the agent for the first time. If the immigrating mobile general public-much less students on archeological digs (23), farm laborers, or construction workers-are made aware of coccidioidomycosis -they may, in fact, learn to demand a wider use of the coccidioidin skin (and serologic) test(s) in their expected better health care. Similarly the general public can be educated that the pigeon may not be an innocuous bird and thereby discouraged from feeding them or otherwise attracting them to seek refuge in cities. Avians as pets should also be discouraged. This is possible through the mass media. The dangers of cleaning up or playing in areas which are heavily contaminated with bird excreta should be common knowledge to every school child and certainly to every Boy Scout and Girl Scout and their corollaries. This, too, is part of the knowledge of ecology. However, it is evident in the 1970’s that it is not knowledge common even to their teachers or leaders (3). 2. Education of physicians, veterinarians, public health workers, and clinical diagnostic microbiologists in the 1970 concepts of the respiratory mycotic infections. The mandatory reporting of mycotic respiratory mycotic infections will not measurably alter the low status of these infections in terms of numbers of cases reported until physicians, veterinarians, public health workers, and clinical microbiologists themselves learn to consider the mycases in the differentiation of flu-like illnesses with acute onset, The authors of the 1970 Earth Day outbreak of histoplasmosis (3) are worth quoting on this point. “It is worthwhile to emphasize that the clinical illness in most of these cases was mild enough to be considered a nonspecific “flu-like” syndrome. Histoplasmosis is almost never included in the differential diagnosis of mild “flu-like” syndromes, probably because much of the literature on this illness focuses upon the chronic pulmonary or disseminated forms of the disease and not upon the much more common upper respiratory or even subclinical form.” It is of interest that there were 113,661 unclassified respiratory infections optionally reported from only 18 of the 50 states in 1971(14). However, of these 113,661 unclassified respiratory illnesses, 50,841 cases (or nearly 45%) were from the East South Central States- Kentucky, Tennessee, Alabama, Mississippi- known to be endemic for blastomycosis and cryptococcosis as well as histoplasmosis. An additional 13,017 cases (over 10%) were reported from the Mountain states including New Mexico, Arizona, Utah, and Nevada, all recognized as having highly endemic areas for coccidioidomycosis. And from California alone, also part of the known endemic area for coccidioidomycosis, there were 27,704 (or roughly 25%) unclassified respiratory infections. In
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respiratory other words, 91,562 of the 113,661 (or roughly 80%) unclassified infections reported in 1971 were from geographic areas known to be endemic for histoplasmosis, blastomycosis, coccidioidomycosis, and cryptococcis. Yet histoplasmosis only was reported separatelywith 190 cases. 3. Mandatory reporting of the respiratoy mycotic diseases. Despite the hazards of still not obtaining a true picture of the incidence of mycotic infection as noted above the reporting of the mycotic disease which is currently recognized should be mandatory. This is essential even to begin to assess the cost in terms of morbidity if not to mortality. 4. Systematic sampling of soils for H. capsulatum and C. neoformans from known bird or bat roosting or hibernating sites and their subsequent decontamination prior to excavation activity in towns or cities throughout the U. S. Since there are no vaccines for the prevention of the mycotic infections and, physicians in any comas yet, very poor drugs for their treatment, munitylarge or small-can, at least, be forewarned that there are active microfoci in the immediate area. It has become clear that the histoplasmin skin test reactivity rate is not a reliable index as to the geographic distribution of this fungus-it pinpoints only those areas in which the microfoci of H. capsulatum have been disturbed. The reported outbreaks have generally occurred in areas of low skin-test hypersensitivity, indicating that microfoci were present. It would, therefore, provide some measure of prevention and control to locate these microfoci and decontaminate them prior to disturbance, at least on surface soils. Microfoci in caves due to the hibernation of birds and/or bats should also be identified prior to superhighway construction projects. Decontamination of these sites should be provided regardless of a high skin-test hypersensitivity rate in any given community. Successive outbreaks can occur even in communities with high histoplasmin sensitivity rates w. of pigeon populations for Cryptococcus neo5. Systematic sampling formans in large and small communities (and of their nesting and roosting places). The accumulation of hard data implicating the pigeon as a real factor in the geographic distribution of Cryptococcus neoformans will be necessary to determine whether efforts should be made toward eradicating the pigeon from large cities at least. 6. Skin testing of certain occupational groups. Skin tests with histoplasmin, coccidioidin, and possibly blastomycin has been neglected in occupational groups in which it would be most useful-for furthering our information about the more precise geographic distribution of these respiratory mycotic agents and for the more rapid differentiation of flu-like illnesses due to them. Such occupational groups include not only construction workers, coal and other types of miners or other laborers having close contact with soil, but also archeologists, entomologists, and other highly skilled persons whose field research brings them into intimate contact with the soil. It definitely includes the clinical diagnostic microbiologist who may be exposed to isolates of these fungi at any time during the course of the days’ work, regardless of geographic location; and as noted earlier, it includes the vacationer to the fairly cir-
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cumscribed endemic areas for coccidioidomycosis and those who indulge in speleology as a hobby or as a profession, anywhere in the U. S. 7. Culture of tissues of domestic unimuls sacrificed for other reasons. Domestic animals or pets, particularly the dog, because of their close contact with soil make excellent sentinel animals for locating microfoci of the respiratory mycotic agents (10). Such programs could be coordinated with rabies control measures already in progress. The mycoses should also be strongly emphasized in the education of veterinarians, as noted above. 8. Wider application of the serologic diagnostic procedures at hand. The serologic procedures for the rapid diagnosis of coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis are essentially the same as those used for any other infectious disease. One need not be a trained medical mycologist to do them. Reasonably satisfactory antigens are available for coccidioidomycosis, histoplasmosis, blastomycosis, and cryptococcosis, either commercially or through the Mycology Unit at the Center for Disease Control, Atlanta. Presumably the reason the tests are not more widely used is because they are rarely requested by physicians to differentiate flu-like or upper respiratory infections (6), a situation due also to antiquated, forgotten, or overlooked knowledge about the respiratory mycoses. However, to assess the real incidence or prevalence of these infections it is essential that the serologic diagnostic tests be used much more extensively. This applies not alone to the flu-like primary syndromes, but also to more chronic type disease, especially the solitary pulmonary nodule. Because of the possibility of lung cancer, these generally are surgically resected. However, in one study of 887 resected nodules, one third were caused by fungi (20). Thus, nearly 300 people in this study alone were subjected to unnecessary surgical risk, in addition to cost in money and productive time lost. 9. Development of pure and homogeneous antigens. Although the antigens currently available are satisfactory for routine screening purposes, much work remains to be done toward their characterization and purification, and toward development of antigens for aspergillosis, mucormycosis, and other mycoses caused by common fungi and yeasts which produce disease generally only in the compromised host. However, as noted earlier, this includes an ever increasing number of citizens in the U. S. and other economically and medically advanced countries. 10. Zmproz;ed chemotherapy. The need for improved chemotherapeutic measures is becoming acute. The principal effective antibiotic currently available is Amphotericin B which is nephrotoxic. Its use is limited essentially to potential life-threatening situations. This problem is compounded today in that patients who must be placed on immunosuppressive or long-term antibacterial therapy are particularly susceptible to fungus infections. This applies not only to the “opportunists” such as species of Candida, Aspergillus, and the Mucors but to the pathogens noted above. Earlier infection with C. immitis, H. capsulatum, and C. neoformans particularly recrudesce with immunosuppression. The problem is serious in kidney transplantation - with the only drug available toxic for the transplanted kidney. A newer
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drug, 5-fluorocytosine, is effective only on yeasts. However, better drugs are needed not only for saving lives, but also for aborting the primary pulmonary infections which cause disability and loss of productive time. This, too, probably is a primary reason why primary pulmonary mycotic infections are not differentiated. There is no safe drug to treat them when they are diagnosed. Yet the many possible delayed effects of untreated primary mycotic infections are simply unknown. 11. Vaccines and immunologic aspects. Population groups at special risk because of occupation or potential environmental exposure would be good candidates for immunizations. The present state of knowledge, however, of fungal antigen specificities and of the mechanisms of host immunity precludes a rational approach to development of a vaccine. Enhancement of cellmediated immunity, for example, as reported in preliminary studies on the use of transfer factor in cutaneous candidiasis offers promising avenues for future exploration of improved treatment, ACKNOWLEDGMENT
Since the writing of this report, the study by Hammerman, Powell and Tosh (11) has been published in its entirety. (Sabouruudiu 12, 33-45, 1974). The author is deeply indebted to these investigators for the use of their material in summary prior to its publication. REFERENCES I. AJELLO, L. The medical mycological iceberg. HSMHA Health Rept. 86, 437-448 (1971). 2. BANASZAK, E. F., THIEDE, W. H., AND FINK, J. ii. Hypersensitivity pneumonitis due to contamination of an air conditioner. N. Engl. ]. Med. 283,3-8 (1970). 3. BRODSKY, A. L., GREGG, M. B., LOWENSTEIN, M. S., KAUF~LIAN, L., AND MALLISON, G. F. Outbreak of histoplasmosis associated with the 1970 Earth Day Activities. Amer. J. Med. 54, 333-342 (1973). 4. CAMPBELL, C. C. Histoplasmosis and other respiratory mycoses in the tropics. lnduvtry and Trot,. Health, VI: (Library Congr. No. 52-34882) 145-152 (1967). 5. CA~~PBELL, C. C. Isolation of C~Y~~OCOCCUSneoformuns from the top of an air conditioner where pigeons are fed. Unpublished data. (1969). 6. CAMPBELL, C. C. The serology of histoplasmosis. Clin. Lab. Forum. June pp. 3 (1972). 7. CAMPBELL, C. C. “The pilot wheel” a change in course. PTOC. 1st Int. Conf. on Paracoccidioidomycosis. Pan American Health Organization Sci. Pub]. 254,306-312 (1972). 8. D’ALESSIO, D. J., HEEREN, R. H., HENDRICKS, S. L., OCILVIE, P., AND FURCOLOW, M. L. A starling roost as the source of urban epidemic histoplasmosis in an area of low incidence. Amer. Reo. Resp. Dis. 92,725-731 (1965). 9. FIESE, M. J. “Coccidioidomycosis,” p. 253. Thomas, Springfield, IL, 1958. 10. FURCOLO~, M. L., BUSEY, J. F., MENGES, R. W., AND CHICK, E. W. Prevalence and incidence studies of human and canine blastomycosis. Amer. 1. Epidemiol. 92, 121-131 (1970). 11. HAMMERMAN, K. J., POWELL, K. E., AND TOSH, F. E. Personal Communication (1973). 12. LARSH, H. W. Personal communications. (1973). 13. LEWIS, J. L., AND RABINOVICH, S. The wide spectrum of cryptococcal infections (A report of 32 patients). Amer. J. Med. 53,315 (1972). 14. Morbidity and Mortality Weekly Report Annual Supplements. Atlanta, Center for Disease Control. (1963 through 1972). B. H. An epidemic ofcoc15. RAhfRAS, D. G., WALCH, H. A., MURRAY, J, P.,.4ND DAVIDSON, cidioidomycosis in the Pacific Beach area of San Diego. Amer. Reo. Rest,. Dis. 101,975-978
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