Systemic mycoses in children

Systemic Mycoses PART I

"

Children HARRIS D. RILEY, JR.

THE R O L E of mycotic agents in diseases of humans was, until recently, regarded as being confined to superficial infections, and their diagnosis and management was the concern of a limited number of physicians. An increasing interest in fungal diseases has revealed a significant number of patients, including infants and children, suffering from active systemic mycotic disease and a surprisingly high incidence of healthy individuals who show evidence of previous systemic fungal infection. In addition, the increasing concern with the mycotic diseases has been stimulated by the increasingly important pathogenetic influence being played by common saprophytic fungi, which cause serious clinical infection under suitable environmental conditions. 1.7 The acquisition of knowledge concerning the mycology, epidemiology, clinical variations, pathology, pathogenesis, diagnosis, immunology and management of the systemic fungal infections has gathered significant momentum in the past two decades, z These infections deserve calculated consideration in the differential diagnosis of most pulmonary and systemic infections. Because of these reasons, a continuing search for specific chemotherapeutic agents against mycotic disease has taken place with the result that certain effective antifungal drugs are now available for use in treating both topical, superficial and systemic infections. The variable clinical picture presented by fungal infections and the availability of effective therapeutic agents have made it important for clinicians to be familiar with the nature of fungal diseases and their treatment. 1-a NOTE: Some of these studies were supported in part by Grant #FR-26 from the National Institutes of Health supporting the Clinical Research Center, grants to the Pediatric Pharmacology Unit and a grant from The National Foundation to the Clinical Studies Center for Birth Defects, all located at Children's Memorial Hospital.

The first microorganisms to be seen by man were fungi. In 1680, Leeuwenhoek saw yeast cells through his crude microscope. Probably the first occasion a disease was shown to be caused by microorganisms was in 1839, when SchSnlein described the fungus nature of favus. Shortly thereafter, thrush was determined to be of mycotic etiology3 There are more than 200,000 specific names of fungi in the mycologic literature. Depending on his evaluation of minor variations, a mycologist may estimate the total number of valid species of fungi at 50,000 or 500,000. Among fungi and actinomycetes there are at least 20 species that cause systemic and potentially fatal disease, 35 that cause less severe systemic disease or severe localized cutaneous, subcutaneous or lymphatic infections and 45 that cause superficial infections of the skin, its associated keratinized tissues or the mucosa. Fungi of the latter group penetrate only rarely into deeper tissues. 4 In addition to the 100 or more species of fungi that are generally recognized as pathogens of man, it is firmly established that under unusual circumstances of abnormal susceptibility of the patient, or of the traumatic implantation of the fungus, other fungi are capable of causing disease. Some of the fungi that invade tissue under these conditions may be listed as provisional pathogens until the study of additional cases reveals more clearly the frequency and the limits of clinical variability of the mycoses that they cause. 4 With few exceptions, the mycoses are caused by fungi that are essentially free-living saprophytes in nature. These mycoses are not contagious, and infection in man and animals follows inhalation or traumatic implantation of the fungi from their normal saprobic habitats in decaying vegetation, humus, bird or animal excreta, soil or soil enriched by bird or animal excreta. Production of systemic diseases by fungi that are essentially saprobes, and only by accident pathogens of man, is the rule rather than the exception in medical mycology. The fungi that cause systemic and subcutaneous mycoses often have been called "opportunistic fungi" to emphasize the aspect of a normally saprobic fungus that can suddenly become parasitic and pathogenic when it is introduced by various routes into the human body. 4 They are "opportunistic" according to the first definition but not according to the second. To call them "opportunistic" only in those cases in which the mycosis is secondary to another disease is inconsistent and implies a dichotomy among the agents of mycoses that, in most cases, cannot be clearly defined3 Recognition of the saprobic nature of fungi that cause mycoses, of their predilection for specific types of enriched soil or organic debris and of the ecologic (but not parasitic) relationships that some of them bear to specific animals or birds is essential to an understanding of the epidemiology of the mycoses. Associations between coccidioides and rodent burrows and an arid soil of high salinity, between Histoplasma and excreta of chickens, feral birds or bats and between Cryptococcus and pigeon dung are examples, now fully documented, of such ecologic

associations. The associations cited are neither invariable nor essential, but they are so frequent that, since their discoveries, the epidemiologist investigating sources of infection in a patient should first inquire whether he has had such an exposure. 4 Mycotic infections are considerably more frequent than generally appreciated. It has been estimated that in the United States there are some 200,000 cases of acute pulmonary blastomycosis annually, that 20% of the total population ,10 million people--have been infected with H. capstdatttm and that at least 100,000 have coccidioidomycosis. The tables of Vital Statistics of the United States show that within the reporting areas of the country the total number of deaths reported as due to scarlet fever, typhoid, whooping cough, diphtheria, dysentery and malaria fell from 10,165 in 1941 to 267 in 1966. During this 25year period, the number of deaths reported as due to mycoses rose from 324 to 393. 4 Each year there are approximately 75 reported deaths due to each histoplasmosis and to cryptococcosis and about 53 to coccidioidomycosis. Moreover, the number of deaths directly due to opportunistic fungal infections in patients with serious underlying disorders has increased dramatically. For a variety of reasons, the actual incidence of systemic mycoses probably is considerably greater than the reported figures. CLASSIFICATION.--Frequently there has been confusion concerning the terminology and classification of fungus infections. The position of aerobic and anaerobic Actinomycetes and the diseases caused by them is somewhat controversial. The problem whether Actinomycetes, Nocardia and Streptomyces are fungi or not and, consequently, whether the diseases they cause are fungal diseases is not agreed on by all workers. Although Actinomycetes are filamentous bacteria, the clinical diseases they produce are quite similar to some of the true mycoses and, for this reason, are included as mycotic infections, a practice adopted by most medical mycologists. The mycoses can be classified in several different ways. For example, classifying mycoses by geographic distribution has some validity and usefulness. However, a topographic classification is more useful to the clinician. By this classification, and for purposes of convenience, the mycoses generally are divided into four topographic groups: superficial, cutaneous, subcutaneous and systemic or deep infections. However, all workers do not agree on which diseases should be placed in the various categories. For example, some believe that fungal infections involving the dermis and subcutaneous tissues, such as cutaneous chromomycosis and sporotrichosis, should be classified as superficial rather than deep because they involve the skin. Others prefer to consider all the diseases that are caused by fungi invading the subepithelial tissues as "deep" or "systemic," in contrast to superficial infections in which the fungi are present only in the epidermis and its surface appendages (hair and nails) or on the epithelial surface of mucous membranes. In this review, the various forms of tinea and other epidermophytoses, and also

such infections of mucosal surfaces as candida vulvovaginitis and thrush, are classified as superficial fungal infections. The group of systemic or deep fungal infections comprise the mycotic diseases of the dermis and deeper tissues, and include such infections as sporotrichosis, cutaneous chromomycosis and the different forms of mycetoma and the visceral and systemic infections, such as histoplasmosis, cryptococcosis and the various fungal septicemias. 4. 5 This review will be limited to discussion of the systemic or deep m y c o s e s - - t h e infections that constitute the greatest challenge to diagnosis and management because they are the severest threat to life. The more classic pathogenic fungi have been well defined as characteristic clinical entities since before 1900. More recently, certain opportunistic fungi have found hosts susceptible to systemic infection and must now be included in the group of deep mycoses. T h e known systemic mycoses of man and their causative organisms are shown in the accompanying table. However, consideration will be restricted to the following systemic fungal infections: histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis, actinomycosis, nocardiosis, candidiasis, aspergillosis, sporotrichosis and the phycomycoses. TIIE DEEP MYCOSESOF ]~|ANANDTIIEIRCAUSATIVEORGANISMS* I. 2. 3. 4, 5. 6. 7. 8. 9. l 0. 11. 12. 13.

Histoplasmosis: Histoplasma capsulatum Coccidioidomycosis: Coccidioides immitis African histoplasmosis: Histoplasma dttboisii Actinomycosis: Actinomyces israelii~ Candidosis (candidiasis) : Candida albicans b and Candida spp? North American blastomycosis: Blastomyces dermatitidis South American blastomycosis: Paracoccidioides brasiliensis Cryptococcosis: Cryptococctts neo]ormans Lobo's disease: Loboa Iobol Nocardiosis: Nocardia asteroides"' c Aspergillosis: Aspergilhts [umlgatus b and Aspergillus spp? Phycomycosis Rhizopus spp." and Mttcor spp. b Subcutaneous phycomycosis: Basidiobohts meristosportts and Entonzyphthora coronata

14. Mycetoma: Nocardia brasiliensis, N. cariae, Streptomyces spp.; ,411escheria boydii, Cephalosporhtnt spp., Pyrenochaeta ronteroi, Leptosphaeria senagalens(s 15. Sporotrichosls: Sporothrix schenckii 16. Chromoblastomycosis: Phialophora rerrttcosa. Cladosporium carrionii, Fonsecaea spp. 17. Cladosporiosis or cerebral chromoblastomycotic abscess: Cladosporittm trichoides 18..Subcutaneous chromoblastomycotic abscess: Phialophora gougerotti 19. Rhinosporidiosis: Rhbzosporidium seeberi 20. Geotrichosis: Geotrichum candidttnl 2 I. Deep dermatophytosis: Trichophyton rubrttm, T. schoenleini

tFalse fungi. Higher bacteria. ~Opportunistie fungi, I.e., usually nonpathogenlcfungi infecting hosts of lowered resistance. 9Sometimesopportunistic. 9*ModifiedfromBaker.6

REVERENCES---GENERAL

1. Hildick-Smith, G., Blank, H., and Sarkany, I.: Fungus Diseases and Their Treatment (Boston: Little, Brown & Company, 1964). 2. Procknow, J. J.: Fungal infections, Ann. Rev. Med. 13 : 1, 1962. 3. Hughes, W. T.: The Deep Mycoses, in Kelley, V. C. (ed.), Brennemaml's Practice o/ Pediatrics (Hagerstown, Md.: Harper & Row, Publishers, 1970), pp. 1-20. 4. Emmons, C. W., Binford, C. H., and Utz, J. P.: Medical Mycology (2d ed.; Philadelphia: Lea & Febiger, 1970). 5. Wolstenholme, G. E. W., and Porter, R.: Systemic Mycoses (Boston: Little, Brown & Company, 1967). 6. Baker, R. D.: Organ Distribution and Pathogenesis of the Deep Mycoses, in Wolstenholme, G. E. W., and Porter, R. (ed.), Systemic Mycoses (Boston: Little, Brown & Company, 1967), pp. 9-19. 7. Louria, D. B.: Superinfection Due to Fungi, in Proceedings o/the hzternatiotzal Con/erence on Nosocomial ln/ections (Chicago: American Hospital Association, 1971 ), pp. 147-152.

HISTOPLASMOSIS Histoplasmosis, caused by Histoplasma capsulatum, is the most common systemic fungus infection in the United States. It is a pleomorphic disease with a wide variety of manifestations that may occur in acute, subacute or chronic forms, tending in m a n y ways to simulate tuberculosis and often being confused with that infection. It produces a granulomatous type of tissue reaction involving various parts of the reticuloendothelial system, with relatively minimal inflammatory change until advanced stages are reached. Infections vary greatly from relatively inapparent asymptomatic parasitization to overwhelming infection that can be rapidly fatal. 1-3 Until recent years, histoplasmosis was regarded as a rare disease of mysterious origin, which invariably progressed to a fatal outcome. It is now recognized as a relatively common, benign (often clinically inapparent) or moderately severe disease. Infection with Histoplasma capsttlatum is startlingly prevalent. A recent estimate holds that perhaps one-fifth of this country's population is infected, whereas other authorities suggest that as m a n y as 500,000 new infections develop each year. 4 At least 3 0 % of the observed cases have occurred in children. 3 It is quite probable that histoplasmosis constitutes one of the most c o m m o n causes of fever of undetermined origin in childhood in the central portion of the United States. 1. z HISTORICAL NOTE Schwartz and Baum s have published a comprehensive historical review of histoplasmosis, and only certain highlights will be given here. The history of histoplasmosis may be arbitrarily divided into two periods. The first began in 1906 when Darling, G in Panama, described 3 cases of illness caused by Histoplasma capsulatttm, which he thought to be a protozoan. In this period, the disease was regarded as extremely 7

rare and invariably fatal. The first case reported in North America was in 1926, but it remained for DeMonbreum 7 at Vanderbilt University in 1934 to demonstrate conclusively the fungus origin of this disease by brilliant use of transmission and cultural methods. The second period began in 1941 with the development of a specific cutaneous test. The intradermal histoplasmin test opened new channels of investigation that resulted in the discovery that the infection exists commonly as a widespread but subclinical and benign disease. The enigma of pulmonary calcification in tuberculin-negative individuals had stimulated wide interest and caused doubt to be cast on the assumption that only in the very exceptional case would a person previously infected with tuberculosis fail to react to strong concentrations of old tuberculin. The enigma was solved in 1944, when Christie and Peterson 8 demonstrated an immunologic relationship between histoplasmin sensitivity and pulmonary calcification that has been confirmed repeatedly. From these and other studies, evidence has evolved that infections with H. capsulatum may be benign and asymptomatic and rarely recognized clinically. In 1949, Emmons 9 was able to recover Histoplasma capsulatum from soil samples obtained in a run where rats infected with H. capsulatum had been trapped. Subsequently, others were able to cultivate H. capsulatum from samples of soil taken from areas in which people have been infected with H. capsulatum, and to show certain factors that favor its growth in the soil. 1~ Furculow and Grayston 11 were able to obtain soil isolations thought to be significantly related in 11 of 13 examples of small epidemics of histoplasmosis. Since that time, outbreaks in both urban and rural areas have been described, lz These and other studies have served to establish beyond doubt that histoplasmosis is acquired directly from a contaminated environment, from the free growth of H. capstdatum in the soil and is not transmitted from man to man. ETIOLOGY

Histoplasma capsulatum grows in two forms according to its environment. Although it is found free in nature in certain soils, particularly in those that have been exposed to avian excreta, it grows on artificial culture media at room temperature in its myceliai form, producing a cottony white mass and a brownish yellow subsurface growth. Microscopically, there are branching septate hyphae showing numerous small piriform spores or microconidia, 2-3p. in diameter. As the culture matures, and if examined properly, the characteristic tuberculate chlamydospore or "Teutonic war club" will be apparent. This is the identifying feature of the fungus; no other fungi are known to have this feature. Confusion of H. capsulatum with any other pathogenic fungi should not occur. There are strain differences, however, and the

organism produces several antigens, including a complement-fixing and a skin test antigen, z, 13 In tissues, and when grown on certain forms of enriched culture media at 37 ~ C, the fungus appears as a yeast cell, usually 3-5~ in diameter, which multiplies by budding. In pathologic sections with ordinary stains, the yeast cell has a definite border, a capsule and a crescent of deeply stained cytoplasma, which is the descriptive origin of the term H. capstdatttm. H. capsulatmn is not a particularly fastidious organism. Although it grows slowly on any medium, it can be cultivated on Sabouraud's dextrose medium between wide limits of pH. A more complete medium is that enriched with blood or plasma to which antibiotics have been added; colonies usually become apparent in 2-7 days. Originally it was thought that this was necessary to inhibit the growth of pyogenic organisms so that the rather slow-growing fungus could emerge. There now is evidence that adequate amounts of antibiotics and plasma may be necessary for its ideal growth requirements, which has certain therapeutic implications. 3, lz EPIDEMIOLOGY The transmission of H. capsulatum from its natural habitat in the soil apparently is direct without an intermediate host. TM The fungus also has been positively identified in a wide variety of animals. There is no evidence of transmission from animal to man, animal to animal or man to man. Infection of man occurs by inhalation or ingestion, or by both means. 3 Humans frequently become infected by the inhalation of airborne spores or by activity such as digging at a site where the organism is actively growing. The fungus is cultured predominantly from soil frequented by birds and chickens. Shady areas, such as caves, silos, cellars, chicken coops, underneath buildings, pigeon and starling roosts and areas where the soil has high acidity, organic carbon content and moisture-holding capacity are sites where the fungus grows readily. In addition to chickens, pigeons, starlings, grackles, oil birds and bats have been implicated in this relationship but only bats have been found to be naturally infected. However, chicken feathers have been implicated as a source of infection in a case of histoplasmosis in an infant. 14 The exact limits of the geographic distribution of histoplasmosis have not yet been determined, but certain well-defined endemic foei have been outlined. In the United States, the infection is highly prevalent in the central portion of the Mississippi Basin. Some lesser endemic foci exist in the Middle Atlantic States, in the Potomac Valley and in North Carolina. 17 More than half of the recorded disseminated progressive cases have occurred in states that correspond to the area of the western Appalachian slope and those bordering on the tributaries of the Ohio, Missouri and Mississippi rivers. These represent the

FIG. l.--Prevalence of histoplasmin sensitivity in residents of the United States, by state. (Courtesy of Amos Christie.)

endemic areas in this country, as evidenced by sensitivity to histoplasmin (Fig. 1 ). This area has variously been described as avocado- or pear-shaped, the base of which is in Arkansas and Georgia, tapering off along the western Appalachian slope, with the apex in New York State. In addition, endemic loci have been identified in other parts of the country, as far north as Minnesota and central Pennsylvania. 3 It has been estimated that 30 million people in the United States have been infected with H. capsulatttm. Skin-testing studies with histoplasmin have indicated that some regions are almost wholly free from such infections, such as the southeastern seaboard in the United States and the New England states. However, in parts of Illinois, Kentucky, Missouri, Tennessee and adjoining states almost all people are histoplasmin-positive by the time they reach puberty. 13 Wherever the prevalence of histoplasmin sensitivity has been demonstrated, calcification in nonreactors to tuberculin has been shown to be prevalent also. 3 In some areas, a higher incidence of sensitivity to histoplasmin has been demonstrated in urban residents as compared to those who reside in neighboring rural areas. However, the occurrence of histoplasmosis is not limited to the United States, and its distribution is world-wide. There are parts of southern Europe, Africa and Central and South America in which histoplasmin sensitivity is relatively high.S PATHOGENESIS AND PATHOLOGY The infectious form of the fungus has not been clearly determined, but it is known that macroconidia can excite experimental infections, t3 10

Spores of H. capstdatum usually gain entry to the body through the mucous membranes of the respiratory tract or through the intestinal tract; primary skin and genital lesions also have been described. After establishing a local infection, the parasites pass along lymphatics to the regional lymph nodes, where the process may be arrested or where they may multiply and eventually reach the blood stream, with subsequent vascular dissemination. Some degree of dissemination probably occurs quite commonly and does not necessarily result in progressive infection. Clinically, it may be manifest only by moderate hepatosplenomegaly. Regional lymph node involvement usually follows a focal infection, but there rarely is marked generalized lymphadenopathy. 13 After the organism is inhaled into the lung, the characteristic lesion --the primary complex---occurs. It consists of (1) primary focus at the site of penetration, (2) lymphangitis from this site to the regional lymph nodes and (3) regional lymphadenitis with inflammation and tendency toward caseation. The hilar component of the primary complex may be variable in size and sometimes is disproportionate to the size of the parenchymal loci. Large hilar and mediastinal masses may cause symptoms related to their anatomic location. As proliferation continues, the organisms may be dispersed into the blood stream by way of the thoracic duct. Just as in tuberculosis, spread of the organisms is dependent on tissue resistance of the host and the dose (immediate or recurrent) of the inoculum. Hypersensitivity now occurs, and histoplasmin sensitivity is established. The time interval from the primary inoculation to this point usually is 3-6 weeks, similar to that in tuberculosis. 3 In most instances, the primary complex localizes and eventually heals, with calcification. The metastatic lesions within the spleen, regional lymph nodes and liver secondary to hematogenous dissemination also may heal by calcification. In rare instances, the host is unable to mobilize sufficient resistance, localization fails to occur and the organism continues to multiply and is disseminated throughout the body. The infant is more susceptible to severe disseminated disease than is the older child or the adult, s, 1~ The individual lesion of histoplasmosis is a tubercle-like granuloma, sometimes almost indistinguishable from those seen in tuberculosis. In larger lesions, central necrosis with caseation further mimics the lesions of tuberculosis. 13.14 Lesions may occur in any part of the body but primarily in the organs with abundant reticuloendothelial cells, especially the liver, spleen, adrenals, lymph nodes and the mucous membranes of the mouth or gastrointestinal tract. Brain abscesses may occur also. During the active phase, involved areas show granulomatous lesions with large multinuclear epithelioid cells and macrophages, many of which may be filled with the yeast cells of the fungus. In the young infant, the hallmark of the pathologic picture is the presence of large 11

FIG. 2.--Proved primary histoplasmosis with granulomatous lesion in lung. Caseous necrosis and calcification are present. (Courtesy of Amos Christie.) mononuclear phagocytes, which proliferate and contain many conspicuous intracellular parasites. There is little to be seen, grossly or microscopically, in the way of necrosis or nodular granulomatous formation (Fig. 2). In later infancy, childhood or adult life, focal lesions occur that often are marked by caseous necrosis, granulomatous formation and a paucity of organisms, making their identification within tissue sections difficult.3 The bone marrow commonly is involved, and with this there is a proliferation of large mononuclear cells filled with the yeast cells, which may crowd out the normal bone marrow elements and produce severe anemia and, at times, leukopenia and thrombocytopenia. Not infrequently, this clinical aspect of histoplasmosis is mistaken for aleukemic leukemia, even by experienced clinicians. 3 In approximately half of the cases there is ulceration of the skin or mucous membranes. Lesions in the oropharynx occur frequently, particularly in adults. Ulcerative lesions have been described in the bowel and colon, and a picture similar to that of tabes mesenterica of tuberculosis is well documented. 3 Invasion of the adrenal gland with caseous necrosis and adrenal failure produces the signs and symptoms of Addison's disease, another similarity to tuberculosis. Involvement of the nervous system is not common, but the disease process can produce signs, symptoms and laboratory findings indistinguishable from those of tuberculous meningitis. 15 12

CLINICAL MANIFESTATIONS

Histoplasmosis is a protean disease, the clinical spectrum of which ranges from inapparent infection to the fulminating and usually fatal disease. In mild forms, histoplasmosis resembles influenza or viral pneumonia; in the more severe forms it mimics tuberculosis. It is likely that most cases of mild to moderate severity are not recognized as histoplasmosis, since the majority of such patients are ,symptomatic or have symptoms so similar to acute undifferentiated respiratory tract infections that the illnesses cannot be distinguished one from the other. 3 Most cases of histoplasmosis can be classified as one or a combination of five major clinical forms of the disease. ~ INAPPARENT INFECTIONS (ASYMPTOMATIC).--Histoplasmosis is a

benign infection under most circumstances and usually produces lesions of no serious consequence. Most cases of histoplasmosis probably are of the ,symptomatic type. In these patients, the inhalation of spores of H. capstdatt,m does not produce symptoms. The common denominator of this type of lesion is the primary pulmonary infection in which one or two small focal granulomatous lesions develop in the lung, together with a regional lymphadenitis of the hilar glands. These lesions may, as in tuberculosis, be single primary insertions, but histoplasmosis, in contrast to tuberculosis, is associated much more commonly with multiple areas of involvement as a result of the primary infection, and not uncommonly there may be a great many such lesions even when the circumstances leading to the development of the infection are the result of heavy contamination, such as that seen in local epidemics of histoplasmosis. In these instances, a fairly high percentage of the patients are likely to show multiple pulmonary lesions. However, the lesions are more likely to be single or small multiples of the single insertions, especially in childhood.'. 2 In most cases, these lesions go on to heal without the development of recognizable symptoms, and infection is manifest only by the development of a delayed reaction to the histoplasmin skin test several weeks after the exposure. Probably such infections cause minor illnesses that remain either unrecognized or undiagnosed. It is interesting to point out that milder primary infections occurring in laboratory personnel, where the inoculum may be relatively large, are likely to be associated with definite if not severe signs of infection, and symptoms may persist for several weeks before the person feels entirely well again. In some instances, such symptoms might be ignored if the patient is not being scrutinized. Whether primary infection is always associated with significant morbidity is a problem that can be solved only by careful clinical examination of patients during the primary infection, and remains for future studies to elucidate. A significant percentage of these asymptomatic infections result in pulmonary calcifications in the periphery of the lung parenchyma and in the hilar nodes 3, 16 (Fig. 3). 13

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ir

Fro. 3 (above).--A, multiple primary lesions in lungs of a child, simulating miliary tuberculosis. B, note healing within 2 years. (Courtesy of Amos Christie.) Fro. 4 (below).--Primary histoplasmosis in a child. History of malaise, cough, low-grade fever of 3 months' duration, positive histoplasmin skin and complement fixation tests. Note peripheral lesion with mediastinal adenopathy. (Courtesy of Amos Christie.) ACUTE PULMONARY ItlSTOPLASMOSIS.--In this form of the disease, the symptoms may be mild, moderate or severe. Such patients are represented by the more severe cases occurring in laboratory workers who have been observed to have definite illness, but even more exemplary are many of the cases in the groups from naturally occurring epidemics in which some of the patients are more severely ill. In many instances, these cases may have some degree of dissemination of the infection beyond the primary lymph nodes but the host reaction is sufficient to overcome the infection, z In milder illnesses, the symptoms are influenza-like, with low-grade fever, malaise, anorexia and headache lasting for a few days. In the moderately affected individuals, the

14

influenza-like symptoms are of longer duration and of greater intensity, lasting 1-2 weeks. Respiratory symptoms of chest pain, cough and fever are prominent. Physical examination of the lungs usually is not revealing, but pulmonary infiltrates and hilar aden0pathy may be'demonstrated radiographically (Fig. 4). In contrast to tuberculosis, histoplasmosis rarely causes pleural effusion. In the severe form of the acute pulmonary disease, symptoms of an atypical pneumonia may persist for weeks or months. Small disseminated foci of infection may be scattered throughout both lungs or the infiltrates may be more localized but of an extensive nature. Certain nonspecific skin lesions, such as erythema nodosum and erythema multiforme, have been described with pulmonary histoplasmosis. 1 s. 13, 14 CHRONIC HISTOPLASMOSIS.--The patients who fall in this group have chronic lesions that show slow, progressive extension that becomes disseminated from the local area. Such lesions occur much more commonly in adults but a few definite cases have been described in children. This type of disease is more likely to occur in individuals suffering from another illness, such as leukemia, Hodgkin's disease or tuberculosis. The tissues involved most commonly in this form are the oropharynx, the larynx and the gastrointestinal tract, all with indolent ulcerative lesions; the lungs with necrosis and cavitation; the adrenals with caseous necrosis; and, less commonly, other tissues, such as the central nervous system, the genitalia, the osseous system and the skin, which may show ulcerations, papillomatous infiltrations or even tumorlike indurations, z Endocarditis may occur. CHRONIC PUL/~fONARYtlISTOPLASMOSIS.~The discovery of patients showing a positive intracutaneous response to histoplasmin with chronic pulmonary lesions resembling tuberculosis, but free of tuberculous infection, led to the observation that chronic pulmonary histoplasmosis exists as a definite clinical entity. This clinical form resembles chronic pulmonary tuberculosis of the adult and rarely occurs in children. The chronic course is one of exacerbations and remissions of pulmonary disease; infiltrates in the apical areas evolve into cavities and H. caps,latttm may be recovered from the sputum. Cough with productive sputum and fever are common symptoms. Children with cavitary histoplasmosis who presented with hemoptysis and fever have been described, s Pulmonary granulomas--the so-called coin lesion-and fibrosing mediastinitis due to H. capstdatttm have been observed. ACUTE DISSEMINATED IllSTOPLASMOSIS.--The acute disseminated type of histoplasmosis represents an uncommon but overwhelming form of the disease in which H. capstdatum is dispersed throughout the reticuloendothelial system. Although general dissemination of the infection with a fatal outcome may well be the least common type of histoplasmosis, it nevertheless is the one that has been studied most and has been reported most commonly. General dissemination of histoplasmosis occurs in any age group, but most commonly in two 15

groups--those less than 2 years of age and those in the fifth decade or older. In the younger group, the sex incidence is about the same; in groups beyond childhood, males are affected much more commonly than are females, exccpt in the third d e c a d e - - t h e period of childbeari n g - w h e n incidence in females is as high as in males. 2. is This type of histoplasmosis, as indicated, may result from the extension of localized infection but, in most instances, especially in childhood, is more likely to be a generalized invasion due to the host's failure to localize the primary infection, either as a result of poor capacity of the host to respond, as in early infancy, or because the inoculation is massive. Presumably the organisms enter either the respiratory tract or the alimentary tract, and from these sites they are blood-borne to most of the tissues of the body. Such patients commonly show dissemination throughout the lungs, lymph nodes, particularly in the thorax and the abdominal cavity, the bone marrow, the gastrointestinal tract, the liver and spleen, the adrenals, the kidney and the thymus. To a lesser extent, the heart, skin, lymph nodes generally and nervous system may be involved. ~-s, ~3 The presenting signs and symptoms include fever, hepatomegaly, splenomegaly, cough, diarrhea, anorexia, weight loss, pallor, vomiting, dyspnea, purpura and mucocutaneous or cutaneous lesions. There usually is no enlargement of the peripheral lymph nodes. Adenopathy is regional when secondary to an ulcerative lesion. The child may have been ill for several weeks before medical attention was sought; less commonly, the course may be that of an abrupt onset and rapidly fatal outcome. Rarely a patient may be encountered whose signs and symptoms are indistinguishable from tuberculous meningitis.Z, z, 13, 14 The physical findings include fever, obvious illness, wasting and even cachexia in a small number of cases. Enlargement of the spleen and liver is almost uniformly present to a marked degree, especially in younger patients (Fig. 5). Approximately 2 5 % of the patients show involvement of the skin or mucous membranes, with the oral lesions predominant in the youngest group and the skin lesions more common in the older group. Approximately 2 0 % of the infants and 10% of the older children show clinical signs of pulmonary involvement; by x-ray, 3 0 - 4 0 % show infiltrative parenchymal lesions and moderate to marked hilar adenopathy, la Most infants with this picture, particularly if they are cachectic and showing purpuric manifestations, run a rapidly downhill course and die in a few days to a few weeks. The duration of the disease usually is 6 weeks or less. Anemia, sometimes severe, is present in 7 0 % of the younger group and in 25% of the older group; it has no specific character. Approximately half the youngest patients show a leukopenia, sometimes associated with purpura and thrombocytopenia. On the other hand, leuko16

FIG. 5.--Disseminated histoplasmosis in infancy. A, an infant 5V2 months of age with fever, anemia, hepatosplenomegaly and leukopenia, ti. capsulatunl was identified in smears and cultures of the bone marrow. B, chest roentgenogram showing a diffuse pneumonitis and mediastinal mass. Diagnosis was confirmed at autopsy. (Courtesy of Amos Christie.) cytosis of marked degree may be seen in approximately 10% of the patients) a The diagnosis of progressive histoplasmosis should be suspected whenever infants or young children show hepatosplenomegaly together with pulmonary disease, gastroentcritis, ulcerative lesions of the skin or mucous membranes or when there is unexplained anemia or leukopenia in the absence of leukemia. When the condition is suspected, it usually is not difficult to secure cultural confirmation from the blood or bone marrow or from biopsies of ulcers, lymph nodes, liver or spleen. DIAGNOSIS Although a presumptive diagnosis can be made in some instances on the basis of conversion to positive of the histoplasmin skin test and a rise in antibody titers, microscopic or cultural demonstration of H. capsulatton is required for a definitive diagnosis. ~. 3, 7, 1~ On occasion, the parasites can be demonstrated in the white blood cells in the peripheral blood or in bone marrow. The yeast phase of the fungus as it occurs in the cells of the body appears as a small (3--5/.t), encapsulated oval body in the large mononuclear cells. Thick-drop preparations of smears of the peripheral blood and bone marrow should be stained with Wright's or Giemsa's stain. Biopsy material from lymph nodes or from the liver or spleen, as well as bone marrow, sputum or material swabbed from an ulcerative lesion, also can be smeared and stained by one of these methods and cultured. 17

HISTOPLASMIN SKIN TEST.--The histoplasmin skin test resembles the tuberculin test and has proved useful epidemiologically and diagnostically in the individual patient. 4, 17 This test is useful in endemic areas mainly as an exclusion test. Once the test becomes positive, usually it remains so for many years, but the reaction is not as durable as the tuberculin test. 17 A positive histoplasmin reaction indicates past or present infection with H. capsulatum; it does not signify the extent or stage of the infection. TM Patients with blastomycosis or coccidioidomycosis may react to histoplasmin, but differential skin testing usually will distinguish such cross-reactions. The skin test usually becomes positive from 2 to 10 weeks after infection, a time that usually coincides with the onset of illness. A case with conversion from negative to positive in 21 days has been reported. 17 Active cases of histoplasmosis, with the exception of those of the acute disseminated type, almost invariably react positively. Only about half the infants with acute disseminated disease have positive skin tests; however, as the patient recovers, conversion of the skin test to positive occurs. Conversion from a negative to a positive reaction during an acute febrile illness strongly suggests the diagnosis. Transient reversion from a positive to a negative reaction may occur following acute viral infections or following the administration of live viral vaccines, such as those of measles and smallpox. 14 SEROLO6IC TESTS.--Agglutinins, precipitins and complement-fixing antibodies may be demonstrated in the sera from patients with histoplasmosis and have more value diagnostically than the skin test. Serial tests are valuable in observing the reslSonse of the patient. In fulminant infection, these may be a failure of serologic response. Complement-fixing antibodies appear in infected persons from 2 to 4 weeks after the primary infection and can persist for months or years. Both mycelial phase (histoplasmin) and yeast phase antigens are used in the test. A titer of 1:8 or higher with either histoplasmin or yeast phase antigens is considered indicative of infection. Mycelial phase but not yeast phase antibodies sometimes are stimulated by skin testing. This effect does not occur until a week after the skin test; therefore, blood samples for serologic tests should be collected either before or within the week following administration of skin test antigens. 14 The agar gel precipitin test with the soluble mycelial antigen histoplasmin usually demonstrates earlier antibodies, which subside more rapidly than do those that are detected by complement fixation. The agglutination of sensitized collodion or latex particles is useful as a rapid screening test in the initial stage of histoplasmosis. The test becomes positive within 2-3 weeks, rises rapidly to a maximum titer and falls to normal within 3-8 months. 14 MicRoBioLoGY.---Cultivation of the fungus is the only absolute method for establishing the diagnosis. This can be accomplished by plating blood, bone marrow or biopsy tissues on infusion agar en18

riched with plasma or blood; plasma is preferable, since it yields a clear plate easier to examine. If contaminated material, such as stools, ulcer scrapings, gastric washings or sputum is to be cultured, the media should contain inhibitory amounts of penicillin (200~, per nil.) and streptomycin (0.2 rag. per ml.) to prevent the growth of bacterial contaminants. The plates should be sealed with paraffin to prevent drying and incubated at room temperature. The fungus is identified by the appearance after 2---4 days of small white aerial colonies that go on to form typical yeast cells within the large mononuclear phagocytes in aspirated bone marrow, blood smears, or within biopsy sections, which is, in experienced hands, almost as reliable as the demonstration of the fungus by culture. 13 TREATMENT* There is no completely satisfactory fungicidal agent for Histoplasma capstdatum. Drugs that are effective may result in injury to the host. Patients with primary Histoplasma infections rarely require specific therapy. The prognosis usually is excellent and recovery is complete in the majority of cases. However, children with progressive disseminated disease have a poor prognosis, with a fatality rate of approximately 85%.2, s, 13 At present, most investigators believe that amphotericin B, despite its toxicity, is the drug of choice in disseminated histoplasmosis.14, is. 19 Controlled trials lend substance to this belief. Chronic pulmonary histoplasmosis rarely occurs in children; however, in the occasional persistent case, specific therapy may be indicated.3 The sulfonamides have been shown to be protective against H. capstdatttm infection in mice, and Christie 3 has reported good results with a sulfonamide combination in human infections. However, controlled clinical trials have not been reported. Saramycetin and hamycin have chemotherapeutic activity against H. capstdatttnz in experimental infections. A beneficial effect has been observed in some of the small numbers of human patients with histoplasmosis treated with saramycetin. REFERENCES---HISTOPLASMOSIS 1. Christie, A.: The disease spectrum of human histoplasmosis, Tr. A. Am. Physicians 64: 147, 1951. 2. Peterson, J. C., and Christie, A.: .Histoplasmosis, Pediat. Clin. North America 2:127, 1955. 3. Christie, A.: Histoplasmosis, in Kendig, E. L., Jr. (ed.), Disorders o] the Respiratory Tract in Children (Philadelphia: W. B. Saunders Company, 1967), pp. 624-638. *In this and other sections dealing with specific infections, only general reference is made to therapy. The final section of Part II, to be published as the November issue, contains more extensive details of treatment, including dosage schedules.

19

4. Riley, H. D., Jr.: Epidemiologic studies of histoplasmin sensitivity, U.S. Armed Forces M. J. 7:817, 1956. 5. Schwarz, J., and Baum, G. L.: The history of histoplasmosis, 1906-1956, New England J. Med. 256:253, 1957. 6. Darling, S. T.: Protozoon general infection producing pseudotubercles in lungs and focal necrosis in liver, spleen, and lymph nodes, J.A.M.A. 46: 1283, 1906. 7. DeMonbreum, W. A.: Cultivation and cultural characteristics of Darling's Histoplasma capsulatum, Am. J. Trop. Med. 14:93, 1934. 8. Christie, A., and Peterson, J. C.: Pulmonary calcification in negative reactors to tuberculin, Am. J. Pub. ltealth 35: I 13 !, 1945. 9. Emmons, C. W.: Isolation of Histoplasma capsulatum from soil, Pub. Health Rep. 64:892, 1949. I0. Zeidberg, L. D., Avello, L., Dillon, A., and Runyon, L. C.: Isolation of Histoplasma capsulatum from soil, Am. J. Pub. Ilealth 42:930, 1952. 11. Furculow, M. L., and Grayston, J. T.: Occurrence of ltistoplasmosis in epi.; demics; etiologic studies, Am. Rev. Tuberc. 68:307, 1953. 12. Furculow, M. L., Tosh, F. E., Larsh, H. W., Lynch, H. J., Jr., and Shaw, G.: The emerging pattern of urban histoplasmosis, New England J. Med. 264: 1226, 1961. 13. Peterson, J. C.: Histoplasmosis, in Barnett, H. L. (ed.), Pediatrica (14th ed.; New York: Appleton-Century-Crofts, 1968), pp. 765-769. 14. Hughes, W. T.: The Deep Mycoses, in Kelley, V. C. (ed.), Bremlemann's Practice of Pediatrics (Hagerstown, Md.: Itarper & Row, Publishers, 1970), pp. 1-20. 15. Shapiro, J. L., Lux, J. J., and Sprofkin, B.: Histoplasmosis of the central nervous system, Am. J. Path. 31:319, 1955. 16. Silverman, F. N., Schwarz, J., Lahey, M. E., and Carson, R. P.: Histoplasmosis, Am. J. Med. 19:410, 1955. 17. Riley, H. D., Jr.: Epidemiological studies of histoplasmin sensitivity. II. Conversion rates, Am. Pract. 10:1931, 1959. 18. Furcolow, M. L.: Comparison of treated and untreated severe histoplasmosis. A Communicable Disease Center Cooperative Mycoses Study, J.A.M.A. 183:823, 1963. 19. Sarosi, G. A., Voth, D. W., Dahl, B. A., Doto, I. L., and Tosh, F. E.: Disseminated histoplasmosis: Results of long-term follow-up. A Center for Disease Control Cooperative Mycoses Study, Ann. Int. Med. 75:511, 1971.

COCCI DIOI DOMYCOSIS C o c c i d i o i d o m y c o s i s m a y be an i n a p p a r e n t , benign, severe o r fatal mycosis. 1 T h e causative organism, Coccidioides immitis, is a d i m o r phic o r g a n i s m whose free living form inhabits soils of the l o w e r s o n o r a n life zone. 2 Initially, it was c o n s i d e r e d to be an u n c o m m o n infection with a p o o r prognosis until 1936, w h e n it was d e m o n s t r a t e d that the fungus was the etiologic agent of the c o m m o n influenza-like illness k n o w n as the San J o a q u i n Valley disease, o r valley fever, p r e v a l e n t in that a r e a of C a l i f o r n i a P ETIOLOGY

Coccidioides immitis, although a n i m p e r f e c t fungus, has been classified as a h y p h o m y c e t e . ThC~'~'spherule '' o r " p a r a s i t i c " form has a 20

doubly refractile capsule and multiplies by endosporulation. No true budding occurs. Cover-slip preparations are unreliable, however, and even in tissue sections errors occur. Sometimes on the surface of pulmonary coccidioidal cavities, the mycelial "saprophytic" form may be observed. Otherwise, only the sporangia occur in animals and measure 8-100/~ in diameter. On artificial media, the sporangia develop hyphae and the mycelia soon become septate. Characteristically, arthrospores and sometimes chlamydospores form, so that as a culture dries it may consist solely of myriads of these rectangular or cuboidal spores 1.510/~ in size. They are well adapted to being transported through the air either in endemic areas or in laboratories and, once inhaled, being retained in the pulmonary alveoli. Occasionally, they may enter through abrasions, although this is rare. Although some mycologists claim to be able to identify Coccidioides merely by gross and microscopic examination of cultures, the strains of the fungus differ greatly, so that the pitfalls are serious. Differential media also are helpful, but in identification there is no substitute for demonstration of the diphasic nature of the fungus by culture and animal inoculation. ~ How the fungus multiplies in nature still is not determined, but it has been cultured from the soil. 3 Man, dogs, cattle, sheep and rodents are infected in endemic areas, but chickens and presumably birds are resistant to massive inoculation. 1 Although Histoplasma is identifiable in nature by its characteristic tuberculate chlamydospores, the spores of Coccidioides are nondescript and cannot be identified even in soil from which Coccidioides has been recovered, except by culture and animal inoculation. A solution of ammonium acetate can provide nitrogen and carbon for the growth of the fungus, which also can be grown on vegetables or even in heated, moistened soil. ~ EPIDEMIOLOGY In contrast to Histoplasma, which is found in moist areas, Coccidioides is confined to arid and semiarid regions. Occasional human cases have been reported from the Balkans and even the Orient. However, the only endemic areas that have been established definitely are in the Western Hemisphere. The original cases were reported in Argentina. ~ Northward, coccidioidomycosis has been demonstrated in the northern section of Paraguay and may well extend to the arid areas of Peru and Ecuador, for it also is found in the arid province of Lara in Venezuela. t The endemic arid area of northern Mexico adjoins the southwestern states of Texas, New Mexico, Arizona and California. Additionally, the southwestern areas of Utah and Nevada are involved, although lightly. The endemic area in Texas extends all along the Rio Grande River from El Paso to within 100 miles of the Gulf and northward nearly to San Antonio. The area of northern and eastern Texas in which histoplasmosis occurs is free of coccidioidomycosis. The New 21

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22

Mexico area, although ill defined, is in the south and does not extend north as far as Albuquerque or Santa Fe. The northern part of Arizona also appears to be free of the infection. California's endemic area is not confined to the San Joaquin Valley, but also includes adjacent slopes over the crest of the Coast Range mountains, the San Fernando Valley of Los Angeles County and spottily in Riverside, San Bernardino and San Diego counties 1 (Figs. 6 and 7). The disease in a stable endemic area is primarily one of childhood. 4 Gifford5 found that in a highly endemic area more than half of the preschool and school children had positive skin reactions to coccidioidin. Seventeen per cent of children who had lived less than I year in the endemic area had positive skin tests; 77% of those whose residence in the area exceeded 10 years had positive reactions. The highest incidence of infection usually occurs in the dusty and dry summer and fall. Most infections are clinically inapparent. Negroes, Mexicans, Filipinos and American Indians are especially susceptible to the disseminated form of the disease. Rodents, cattle, sheep and dogs also are infected in endemic areas. Animal-to-man and man-to-man transmission does not occur. 4 It has been estimated that in each year 35,000 cases occur in California and that there are 10 million persons in the United States who have been infected with the causative organism3 PATHOLOGY AND PATHOGENESIS Coccidioidomycosis is one of the infectious granulomas. In fact, "coccidioidal granuloma" was the designation for the clinical entity now termed "disseminated" or "progressive" coccidioidomycosis.1 After arthrospores and chlamydospores of C. immitis have been inhaled, they convert to sporangia and reproduce by endosporulation. The endosporcs, after rupturing the wall of the sporangium, may be disseminated by the blood stream or lymphatics but usually remain localized. The large spherical cells of C. hnmitis usually are prominent features in the lesions of coccidioidomycosis. The early lesions of coccidioidomycosis observed in humans are historically indistinguishable from focal pulmonary pyogenic pneumonitis of bacterial origin, but, even in the very early lesion, sporangia with endospores may be observed. 6 In chronic, fibrotic lesions, the epithelioid and Langhans giant cells are indistinguishable from those of tuberculosis; these giant cells frequently contain sporangia. In old lesions, the organisms may be found only after diligent search, t Calcification has been observed in both human and experimental infections. The same histologic structures are found in focalized solitary pulmonary residuals of the infection. In progressive disease, fibrotic and even calcified lesions may be found simultaneously with acute active lesions exhibiting round cell or eosinophilic 23

infiltration and even caseation. These lesions of various anatomic ages have given rise to the belief that dissemination can occur many years after a primary infection. However, in thoroughly focalized infections, such late dissemination is extremely rare.t Because the broad patterns of body reaction to both C. immitis and Mycobacterium tuberctdosis are so similar, a common pathogenetic pattern can be applied to both diseases. The primary disease refers to the first infection; this may resolve or progress, leave residual foci or disseminate to pulmonary and extrapulmonary tissues. In instances of reinfection, disease activity develops some time after the primary infection and its associated hypersensitivity. Reinfection may develop from endogenous or exogenous sources. 4 Most disseminated infections, either pulmonary or extrapulmonary, occur with the primary infection. Lesions may be found in nearly all tissues and viscera. * CLINICAL MANIFESTATIONS Coccidioidal infections are characterized by a spectrum of severity, at one end of which is the completely inapparent infection and at the other is the fatal disseminated variety. The manifestations of the host's response pass almost imperceptibly from one extreme to the other, a The clinical picture that may arise in an individual infected with C. immitis may not only be related to the size of the inoculum and pathogenicity of the infecting organism but is the result of the individual's initial resistance to the infection and the degree of immune response that is provoked. 3 The clinical manifestations of coccidioidomycosis vary from those of an inapparent upper respiratory infection to those of disseminated disease. The majority of infections are subclinical and are detected only by conversion to a positive skin test. Generally, cases may be categorized as primary pulmonary, primary extrapulmonary and disseminated types. 4 PRIMARY PULMONARY COCCIDIOIDOMYCOSIS.--In approximately 60% of the patients with acute pulmonary coccidioidomycosis as characterized by a positive immunologic response to coccidioidin, the disease is asymptomatic; in the remainder, the disease resembles an "influenza-like" illness. The characteristic signs and symptoms in children are fever, sore throat, cough, chest pain and rash. The rash may vary from a diffuse, maculopapular eruption primarily on the trunk and proximal extremities to erythema multiforme, sometimes apparent over the entire body but most frequently on the anterior and inner thighs, lower trunk and over the face and neck. The rash usually follows within 48 hours the first evidence of acute illness. Tile acute symptoms usually last from 1 to 10 days. 1. 3.4 Erythema nodosum, which is :related to marked hypersensitivity to 24

the coccidioidin skin test, also may be a manifestation of the acute disease. The lesions are red, tender and pruritic nodules, usually located over the anterior tibial areas. Within a few days, they bccome purplish, then brown and finally regress. Arthralgia may occur; it usually involves the knees and ankles. Acute tracheal obstruction rarely occurs as a result of coccidioidal granuloma of the trachea. 4 Physical examination of the lungs rarely discloses positive findings, even though roentgenograms may reveal extensive consolidation. Infrequently, dullness, a friction rub, fine rales or evidence of pleural effusion may be present. During the primary infection, roentgenograms of the chest may reveal no pulmonary changes, and those that occur are not diagnostic. Hilar adenopathy occurs frequently, and there may be single or multiple, sharply circumscribed or soft, feathery, small pulmonary densities or larger consolidated areas. Pulmonary cavities, when present, tend to be thin-walled. There may be pleural effusions of variable extent. Multiple pulmonary calcifications occur occasionally. The osseous lesions of the disseminated infection usually are multiple, with a predilection for cancellous bone; the lesions often show considerable proliferation and generally are indistinguishable from those of tuberculosis. Residual ptdmonary disease.---Although the majority of patients suffering from primary pulmonary infection recover completely, in approximately 5% of the cases pulmonary signs and symptoms persist despite the fact that the patient has been able to control the primary infection adequately. The residual pulmonary lesion may consist of parenchymal fibrosis, hilar adenopathy, pleural effusion, bronchiectasis and cavitation, the latter occurring in 0.5-3% of the cases of primary infection; it is the most common pulmonary complication in adults but occurs rarely in children. These lesions must be differentiated from other disease processes, such as tuberculosis, other pulmonary mycoses and sarcoidosisP PRIMARY EXTRAPULMONARY COCClDIOIDOMYCOSIS.----Primarycutaneous infection with C. immitis is rare and usually occurs in individuals such as laboratory and agricultural workers. The portal of entry usually is created by trauma, and dissemination may occur from the primary skin lesion. 4 DISSEMINATED COCClDIOtOOMVCOSIS.--Although a large number of individuals are infected with C. immitis each year, only about 40% of them will show signs or symptoms of clinical disease and only about 1 in each 1,000 cases of clinical primary disease will progress to the disseminated form. z Dissemination of C. immitis may occur acutely or insidiously by hematogenous spread of endospores of the fungus to any or all organs of the body and, in this regard, resembles tuberculosis. The sites of predilection are the lungs, lymph nodes, meninges, bones, joints, visceral organs and skin. Unlike disseminated histoplasmosis, intestinal lesions and peritonitis are uncommon. In children, the bones 25

of the fingers, toes, ankles, vertebrae and ribs are the most frequently involved. Meningitis is more likely to be encountered in children than in adults and is fatal. Invasion of the meninges occurs most often in Caucasians, whereas in dark-skinned persons dissemination occurs without meningeal involvement.L 4 The skin lesion usually is verrucous and may ulcerate. Involvement of lymph nodes and subcutaneous tissues appears as cold abscesses, and sinus tracts often develop. Symptoms and physical findings are related to the organ systems involved. If dissemination does not occur when coccidioidomycosis occurs as a complication in pregnancy, the course of the pregnancy is not affected. In the event of dissemination, maternal mortality is high and the fetal death rate is increased, although the placenta is an effective barrier against infection of the fetus. 5 Coccidioidal meningitis, on the basis of clinical manifestations and cerebrospinal fluid findings, is indistinguishable from tuberculous meningitis. This is the most frequently fatal form in white children and adults, often with no other extrapulmonary involvement. Although recovery may occur in all other forms of dissemination, obstructive hydrocephalus often develops even though the infectious process is arrested. In coccidioidal meningitis, the cerebrospinal fluid may be under variable pressure. The protein content usually is increased and the glucose is Iess than 40 mg./lO0 ml. in approximately 40% of cases and may be as low as 5 mg./100 ml. The white cell count varies, with either lymphocytes or neutrophils predominating, but eosinophils sometimes are present. 4 Most patients with coccidioidal meningitis succumb within a few weeks or months. 1 C. immitis infection occasionally may produce a cyst-like lesion in the central nervous system, with clinical manifestations simulating a brain tumor. 7 DIAGNOSIS The clinical picture and cpidemiologic circumstances may suggest a coccidioidal infection, but definite diagnosis requires laboratory confirmation. COCCIDIOIDIN SKIN TEST.---A recent conversion from a negative to a positive skin test strongly suggests infection. The significance of the test is similar to that of the tuberculin test. There is some degree of cross-reaction with histoplasmosis and blastomycosis. ~ A 1:100 dilution of coccidioidin is employed for routine skin testing. Dilutions of 1 : 1,000 or 1 : 10,000 should be used for children with erythema nodosum or erythema multiforme. Usually by the time clinical manifestations become apparent, most patients react positively to the intradermal test. However, in the first week of symptoms, one-sixth of patients still will not react. 1 Dermal sensitivity antedates the development of circulating antibodies; therefore, it may be used as a guide in performing serologic tests. 4 26

SEROLOGIC TESTS.--Complement fixation and precipitin tests for coccidioidomycosis are reliable and useful in diagnosis. By the use of both tests, 95% or more of the primary infections with symptoms can be confirmed. Approximately 3 - 7 % of patients with asymptomatic primary infections show positive serologic tests. 1 The precipitin test is best for recognizing the early stages, and the complement fixation test is most useful in identifying and following the later stages of the disease. Precipitins have little prognostic value; when complement fixation titers exceed a critical level, the likelihood of dissemination is greater. A progressive increase in titer is cause for concern. The persistence of a low complement fixation titer has no serious prognostic implication. 4 CULTURE.--Pathologic material can be cultured on Sabouraud's agar slants or similar media. Petri dishes should not be used, since viable arthrospores may become dispersed in handling. Cultures are incubated at 25 ~ C and the resulting growth is identified morphologically or after intraperitoneal injection into mice and identification of spherules typical of C. immitis. 4 DIRECT EXAMINATION.--In infected materials, C. immitis appears as a thick-walled spherule, 30-6%t in diameter, filled with endospores. Grocott's methenamine silver stain demonstrates the endospores well. 4 TREATMENT Although the clinical course of coccidioidomycosis is unpredictable, it is fortunate that, in most cases, the infection passes unnoticed or is of such a mild nature that no specific therapy is required. Under certain circumstances, however, the severity of the infection is sufficient to incapacitate or the infection so endangers life that active therapeutic measures are indicated. 3 Innumerable therapeutic agents have been utilized in the treatment of this disease and, although promising therapeutic successes have been reported, they have, in most cases, reflected the unpredictable course of the disease rather than the therapeutic merit of the agent employed. Only the disseminated regularly and the progressive pulmonary forms occasionally require specific drug therapy in infants and children, and amphotericin B is the drug of choice. If meningitis accompanies disseminated coccidioidomycosis,'intrathecal administration of amphotericin B diluted in 5 ml. of water'is injected intrathecaIly every other day, but usually only a few such infections can be tolerated. 4 The appearance of obstructive hydrocephalus in the course of coccidioidal meningitis suggests a poor outcome. This complication, however, may be corrected in some cases by a ventriculovenous shunt. Therapy for the disseminated form of coccidioidomycosis should be maintained for at least 1 month. Relapses may occur many years after apparent cures and require retreatment with alnphotericin B. 4 27

REFERENCES---CoccIDIOIDOMYCOSIS

1. Smith, C. E.: Coccidioidomycosis, Pediat. Clin. North America 2:109, 1955. 2. Seabury, J. H.: The Mycoses (Excluding ttistoplasmosis), in Kendig, E. L., Jr. (ed.), Disorders o/ tile Respiratory Tract in Children (Philadelphia: W. B. Saunders Company, 1967), p. 568. 3. Hildick-Smith, G., Blank, H., and Sarkany, I.: Fungus Diseases and Their Treatment (Boston: Little, Brown & Company, 1964). 4. Hughes, W. T.: The Deep Mycoses, in Kelley, V. C. (ed.), Brennemann's Practice o/Pediatrics (Hagerstown, Md.: Harper & Row, Publishers, 1970), pp. 1-20. 5. Gifford, M. A.: Coccidioidomycosis in Kern County, California, in Proceedings 6th Pacific Science Con[erence (Berkeley, Calif.: University of California Press, 1942), Vol. 5, pp. 791-796. 6. Emmons, C. W., Binford, C. W., and Utz, J. P.: Medical Mycology (2d ed.; Philadelphia: Lea & Febiger, 1970). 7. Ryan, J. M., and Riley, H. D., Jr.: Coccidioidal cerebral cyst simulating a brain tumor. In preparation.

NORTH AMERICAN BLASTOMYCOSIS North American blastomycosis is a chronic granulomatous and suppurative disease that usually originates as a respiratory infection and frequently disseminates, with pulmonary, osseous and cutaneous involvement predominating. It is confined almost exclusively to the North American continent, where the prevalence is greatest in the Mississippi Valley and southeastern states, x,z It occurs more commonly in adults than in children. However, small outbreaks involving primarily children have been described. ETIOLOGY The etiologic agent of North American blastomycosis is B l a s t o m y c e s dermatitidis. This dimorphic fungus grows as the parasitic yeast phase in tissue and when incubated in cultures at 37 ~ C its free-living form is mycelial. In tissues, the organism appears as a large, spherical, thickwalled, budding yeast cell varying in size from 8Ft to 15v in diameter. In the mycelial phase, spherical to piriform spores, 5 - 8 v in diameter, are attached directly to the hyphae or at the ends of short pedicles. In the human host, B. dermatitMis almost invariably appears as the yeast form.Z, 3 The characteristics of the parasitic form are more constant in fresh pus or sputum than in wet preparations of cultures at 37 ~ C. Hydroxide chloride wet mounts of exudates may be supplemented by periodic acid-Schiff stain preparations of the same material in order to study the details of budding and cytology. 4 EPIDEMIOLOGY North American blastomycosis is a disease of man and some domestic animals, chiefly the dog and horse. It is confined almost exclusively 28

to the United States and Canada. However, cases have been reported from Mexico, South America and Africa. 2, 3 Although the majority of cases in the United States occur in the southeastern states and the Mississippi Valley area, sporadic cases have been reported from virtually every section of the country and from certain regions in Canada. s It seems likely that increasing interest in medical mycology in all parts of the world will reveal that the characterization of blastomycosis as North American is inappropriate. ~ The organism has been isolated on occasion from soils and other organic debris from old chicken coops, aging homes and outbuildings. There is a strong possibility that it may occur in association with rotting wood. Recent studies suggest that B. dermatitidis has a limited temporal recoverability from soils known to contain the naturally acquired fungus. Ecologic causes for this are not known. Man-to-man and animal-to-man transmission has not been reported, s It is possible that animal reservoirs are important in bringing about soil inoculation. 4 This disease may occur at any age, but the highest incidence is among adults between the ages of 20 and 50. The infection rarely occurs in children. 5 In reviewing 615 patients with North American blastomycosis, Greer 6 found only 6 under 10 years of age. Approximately 21 cases have been reported in children. 7 Although in adult patients with North American blastomycosis the ratio of males to females is about 6:1, the distribution is nearly equal in children. Whereas in adults the disease occurs more frequently among the white race than among the black race, the reverse is true in children. 3 Although infection of children appears to be relatively infrequent in endemic areas in contrast to the high incidence noted for other soilinhabiting fungi, such as H. capsttlatton and C. immitis, outbreaks of infection involving children have been reported. Of 10 patients with clinical illness due to B. dermatitidis during a 5-month period in a small community, 7 were 16 years of age or younger; 4 of these were under 7 years of age. s Studies by Edwards and co-workers 9 showing only 1 blastomycin skin reactor to every 20 histoplasmin reactors suggest that subclinical infection is relatively infrequent. However, the actual incidence and age distribution of infection in any area must await the development of more satisfactory skin test antigens and serologic methods. 4 PATItOGENESIS AND PATHOLOGY The mycelial form of B. dermatitidis usually gains access to the body through the respiratory tract. The organisms proliferate into the yeast phase as infection develops. Dissemination may occur by hematogenous or lymphatic routes or by direct extension. With the disseminated form, nearly all the organs of the body, with the exception of the intestine, have been involved, a The clinical characteristics and course 29

of blastomycosis from cutaneous inoculation are ditferent from those seen in the usual cutaneous form of blastomycosis, which almost certainly is a manifestation of dissemination from an active or inactive pulmonary focus. The occurrence of self-limited pulmonary blastomycosis lacks the documentation of histoplasmosis and coccidioidomycosis but has been observed in a few patients. 4 Cutaneous blastomycosis has been initiated by accidental laboratory inoculation, a The characteristic tissue response to the organism is a combination of suppuration and epithelioid cell granulomatous reaction with giant cells. The reaction may vary from patient to patient or from one site to another in the same individual. Lesions vary in size from microscopic to grossly visible abscesses, z The histologie diagnosis can be made only on the demonstration of B. dermatitidis, which in tissue sections has the same morphologic characteristics shown in purulent exudate from dermal lesions and sinus tracts. 2 In sections, the fungus is seen as a round structure with thick walls and a double-contoured appearance. Budding from a broad base attachment to the parent cell is seen. In the older portions of the lesion, the reaction is essentially chronic and granulomatous, resembling tuberculosis. Pulmonary lesions are present in 9 5 % of cases studied at autopsy, z CLINICAL MANIFESTATIONS 9The clinical spectrum of blastomycosis is varied, but most cases generally are classified as pulmonary disseminated and cutaneous, although these divisions are arbitrary and represent stages in the pathogenesis and extent of the disease, a In essentially all cases of childhood blastomycosis, the lungs are affected and the clinical spectrum of the pulmonary form is as varied as that of tuberculosis. The presenting symptoms in children usually are those of an acute respiratory infection that persists. Fever and cough, coryza, chest pain and weakness are common. With progression, the symptoms gradually increase in severity. Night sweats, high spiking fever, hemoptysis and weight loss ensue. The chest roentgenogram may reveal a variety of lesions--a segmental pneumonitis, extensive infiltrations, diffuse miliary lesions, nodular or homogeneous areas of consolidation and abscesses of various sizes. In some cases, cavitation develops. Empyema is rare. Pulmonary blastomycosis not only may regress without treatment but also may disappear roentgenographically without evidence of dissemination. It is reasonably certain that primary pulmonary blastomycosis may heal spontaneously, but reliable serologic methods to separate those requiring treatment from those needing observation are not available. 4 A cutaneous lesion may be the first manifestation; it appears as a papule or pustule that ulcerates and discharges purulent material. As 30

the lesion progresses, a large elevated granulomatous mass may develop. Healing occurs first in the central portion of the lesion. 3 Cutaneous blastomycosis may result from direct inoculation of the organism into the skin or from dissemination to the subcutaneous tissues from a pulmonary lesion that may go unrecognized. Erythema nodosum may occur. The symptoms and physical signs are proportionate to the extent of pulmonary involvement and resemble those of tuberculosis. Disseminated blastomycosis begins with pulmonary infection, and the onset, with symptoms of a respiratory infection, is disseminated from the lungs; subsequent signs and symptoms are dependent on the organ affected. The skin, subcutaneous tissues and the musculoskeletal, urogenital and central nervous systems, as well as the abdominal viscera, excepting the gastrointestinal tract, may be involved. Secondary loci may be more obvious than the pulmonary disease. Localized or diffuse osteomyelitis, with destruction of bone and formation of cutaneous sinuses, is common. DIAGNOSIS Clinical diagnosis must be confirmed by laboratory studies. The pulmonary lesions may resemble those of tuberculosis, pneumonia, abscess, sarcoidosis and other mycotic diseases. The cutaneous lesions must be distinguished from those seen in pyoderma, tuberculosis, catscratch disease, bromide intoxication and other fungus infections. Diagnosis is established by demonstration (smear and culture) of the organism. SKIN TESTS.--Only about 25% of the children with blastomycosis react to the blastomycin skin test while suffering from active disease. 7 However, if cross-reactions from histoplasmosis and coccidioidomycosis can be ruled out, a positive intradermal test indicates the possibility of infection.3 Two skin test antigens may be employed--a heat-killed suspension of the yeast phase of B. dermatitidis and a broth filtrate (blastomycin) of the growing organism. Skin tests are administered and interpreted exactly as tuberculin tests. Skin tests of histoplasmin and coccidioidin should be applied simultaneously with the Blastomyces vaccine or blastomycin. Reactions to the blastomycin antigen are more marked in patients with blastomycosis than are their reactions to other antigens. 3 SEROLOGY.--Less than 50% of the proved cases of blastomycosis have a positive complement fixation test. Both complement fixation and agar-gel precipitin tests should be utilized in case evaluations, with an understanding of their shortcomings. Cross-reactions occur with C. albicans and H. capsulatum. 3 BACTERIOLOGY.---A diagnosis of blastomycosis is established by demonstration of the organism in blood, bone marrow, pus, sputum or body tissue. Specimens can be cultured on Sabouraud's glucose agar 31

at room temperature or 30 ~ C. Such a culture shows spherical to piriform spores attached directly to the hyphae or at the ends of short pcdicles. The mycelial form can be converted to the yeast phase by subculturing to blood agar and incubating at 37 ~ C. 2, ~ DIRECT EXAMINATION.--Crusts or exudate from lesions may be placed in a drop of 10% potassium hydroxide under a cover glass and heated gently. The finding of doubly contoured budding cells with granular contents and slightly smaller than leukocytes is highly suggestive of blastomycosis. 3 There are times, however, when no classic budding forms can be seen and cultures are negative. In such situations, fluorescent microscopy, using specific antiglobulins labeled with fluorescein, may be helpful. 4 TREATMENT North American blastomycosis responds well to treatment widl amphotericirt B. All patients with involvement of the central nervous system, those with disease that is severely disseminated and those critically ill should be treated with this agent. 1, 4, 7 If amphotericin is ineffective or cannot be tolerated, 2-hydroxystilbamidine should be tried. Hamycin and saramycetin have shown promise in experimental infections and in limited clinical trials in selected patients. 1~ REFEP,ENCES-----NORTIiAMERICANBLASTOMYCOSIS I. Hildick-Smith, G., Blank, H., and Sarkany, I.: Fltngus Diseases and Their Treatment (Boston: Little, Brown & Company, 1964). 2. Emmons, C. W., Binford, C. H., and U.tz, J. P.: MedicaIMycology (2d ed.; Philadelphia: Lea & Febiger, 1970). 3. Hughes, W. T.: The Deep Mycoses, in Kelley, V. C. (ed.), Brennenlann's Practice of Pediatrics (Hagerstown, Md.: Harper & Row, Publishers, 1970), pp. 1-20. 4. Seabury, J. H.: North American BIastomycosis, in Kendig, E. L., Jr. (ed.), Disorders of the Respirator)" Tract in Children (Philadelphia: W. B. Saunders Company, 1967), p. 586. 5. Hughes, W. T., Franco, S., and Kim, M. H.: Systemic blastomycosis in childhood, Clin. Pediat. 8:597, 1969. 6. Greer, A. E.: Disseminating Fungus Disease of tile Lung (Springfield, 111.: Charles C Thomas, Publisher, 1962), pp. 82-126. 7. Turner, D. J., and Wadlington, W. B.: Blastomycosis in childhood: Treatment with amphotericin B and a review of the literature, J. Pediat. 75:708, 1969. 8. Smith, J. G., Jr., Harris, J. S., Conant, N. F., and Smith, D. T.: An epidemic of North American blastomycosis, J.A.M.A. 158:641, 1955. 9. Edwards, P. Q., Knight, R. A., and Marcus, J.: Skin sensitivity of human being to H. capsulatum and B. dermatitidis polysaccharide antigens, Am. Rev. Resp. Dis. 83:528, 1961. 10. Andriole, V. T.: Treatment of systemic mycosis. Available drugs and promising agents under investigation, Mod. Treatment 7:565, 1970.

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CRYPTOCOCCOSIS Cryptococcosis is a subacute or chronic infection caused by Cryptococcus neo/ormans, a fungus that can invade the lungs, skin, joints and subcutaneous tissues but has a predilection for the central nervous system. It usually is referred to as "European blastomycosis" in the European literature and "torulosis" in the older American literature. The disease, however, occurs sporadically throughout the world, and a defining geographic term, such as "European blastomycosis," is misleading. It occurs at all ages. ETIOLOGY In tissue specimens as well as in culture, Cryptococcus neo/ormans appears as a spherical or oval budding yeast cell 5-20/~ in diameter. It is surrounded by a refractile mucinous capsule of varying thickness, sometimes twice the diameter of the cell. It produces a polysaccharide toxic to laboratory animals. 1 India ink mounts reveal a wide gelatinous capsule surrounding both individual single cells and cells in the process of budding. Growth in culture occurs at room temperature but is more rapid at 37 ~ C. Young colonies are white, wrinkled and granular and become mucoid and tan with maturity. Many old cells in culture are surrounded by a burr-like envelope, z. 3 Identification is facilitated by emulsifying a portion of the colony, pus from abscesses, sputum or the sediment from spinal fluid in a drop of India ink under a cover glass. The presence of the large, gelatinous capsule, seen clearly in such preparations, differentiates this fungus from other yeast-like organisms. EPIDEMIOLOGY Although the recognized incidence of cryptococcus may vary considerably from area to area, it is world-wide in distribution. C. neotormans exists as a saprophyte in nature, and has been isolated from a variety of sources, including normal skin, peach juice, pigeon droppings, soil, the human gastrointestinal tract and the milk of cows suffering from cryptococcal mastitis. ~ Cryptococcosis has been observed in the monkey, ox, goat, sheep, horse, dog, fox, koala bear, guinea pig, ferret, mink, cheetah and cat. There is little evidence, however, to suggest its spread from animal to animal to man. 3 The most common source of C~ neoformans is pigeon excreta. The pigeon is not a host to this organism, but the fungus flourishes as a saprophyte in pigeon feces and frequently can be isolated from droppings under roosting sites, on window ledges, in old pigeon nests and on upper floors of buildings frequented by pigeons. 3 In view of the ubiquity of C. neoformans, it is surprising that human 33

clinical disease is not more frequent. The exact incidence of cryptococcosis is not known, since many infections are believed to cause no clinical symptoms. However, an annual incidence in New York City of 5,000-15,000 cases of subclinical or clinical pulmonary cryptococcosis has been postulated. 3 Certain debilitating diseases predispose the host to cryptococcosis, including leukemia, Hodgkin's disease, various malignant neoplasms, tuberculosis and diabetes mellitus. This fact lends support to the hypothesis that only those persons with defects in immunologic capacity are likely to fall victim to the infection. I There are no outstanding differences in the disease as related to age, sex or race, and the geographic distribution is world-wide. ~ PATHOGENESIS AND PATHOLOGY Comparatively little is known about host-parasite relationships in human cryptococcosis. Normal human serum has been shown to have an inhibitory effect on the growth of cryptococci as well as some other fungi. This inhibitory effect presumably is not related to specific antibodies. The antibody and cellular responses during cryptococcal infections are not striking, which brings into focus the question of a relationship of encapsulation of the organism to virulence and immunity--a matter that still is not settled, s Cryptococctts neo/ormans is inhaled into the lungs, which almost always is the site of the primary lesion, and tubercle-like lesions develop. As the lesion progresses, the organisms are engulfed within the giant cells and eventually fibrosis occurs. The fungus may be spread hematogenously to the central nervous system and cause meningitis. Less frequently, it may spread to other organs. ~ Cryptococcal infection is associated with minimal inflammatory response, and the histologic appearance of a lesion is characterized by the paucity of inflammatory reaction and minimal cellular response. The characteristic lesion consists of an aggregate of encapsulated budding ceils mixed with connective tissue, which enlarges to compress surrounding tissues. The characteristic clusters of cells can occur in most tissues of the body, and are seen commonly in the central nervous system, where the subarachnoid space and areas of the brain often contain gelatinous cysts. I CLINICAL MANIFESTATIONS Cryptococcosis has been described in patient s of all ages, with twothirds of the cases occurring between the ages of 30 and 60 years. Males are affected more commonly than are females, with no specific predilection for race or geographic area being noted. Any tissue of the body may be involved in disseminated cryptococcosis, but it commonly 34

presents with infection of the central nervous system and less commonly with involvement of the lungs, skin and osseous tissue, z A review of 220 published cases shows, in fact, that only 19 patients were free of central nervous system involvement. The incidence of the disease is higher in patients suffering from disease of the reticuloendothelial system or diabetes mellitus; 30% of the cases in some series were associated with Hodgkin's disease or diseases of the reticuloendothelial system, z In 1964, Siewers and Cramblett G reported on 42 cases of cryptococcosis in children from the world literature and added 4 cases from their own experience. In the total of 46 cases, 7 patients did not have central nervous system involvement. The authors concluded that, in view of the difficulty in establishing a diagnosis, the 46 cases did not represent a true picture of the incidence of the disease. Clinical manifestations depend on the organ system affected. This may be primarily the central nervous, the respiratory, the lymphatic or the cardiovascular systems, the skin, the mucous membranes or the bones and joints. Usually, a combination of these organ systems is invaded by C. neo/ormans, with clinical manifestations from one site predominating. Cryptococcal meningitis is the form encountered most frequently in children, although the incidence of this form is greatest in adult men. 3 RESPIRATORY SYSTEM.--The respiratory tract is considered to be the portal of entry in most cases. Dissemination by hematogenous spread to bones, skin, central nervous system and other viscera occurs frequently. Dissemination of infection from the lung to other organs can occur, and isolated lesions may involve lymph nodes, skin, bones and eyes without involving the central nervous system, z The initial pulmonary lesion may be transient and clinically insignificant. Pulmonary cryptococcosis usually is a disease of mild to moderate severity. Symptoms include cough, hemoptysis, fever and pleural pain. Physical findings ai'e those of a pneumonitis, but abscess or cavitation sometimes occurs. The pulmonary lesions frequently are bilateral, are by no means pathognomonic and the disease may closely resemble tuberculosis. The roentgenograms of pulmonary cryptococcosis may show solitary lesions without hilar enlargement, diffuse pneumonic infiltration, extensive peribronchial infiltration or a disseminated form resembling miliary tuberculosis. I Pulmonary cryptococcosis has been reported in the absence of central nervous system involvement, and on rare occasions has been the cause of death, z CENTRAL NERVOUS SYSTEM.--Cryptococcal infection of the central nervous system is the most common form of mycotic meningitis. 1 It may take the form of meningoencephalitis or cryptococcal granuloma localized to the brain or spinal cord. The clinical picture and physical findings observed, therefore, will depend on the nature and location of the cryptococcal lesion. 1 The onset of cryptococcal meningitis may 35

be sudden or insidious. In the acute form, the patient usually has nausea, vomiting, headache, vertigo and fever. Signs of meningeal irritation are common. There is evidence of increased intracranial pressure, as manifested by papilledema and retinal hemorrhages as well as ocular palsies. The infection of the central nervous system frequently is diagnosed as tuberculous meningitis. The disease may progress to stupor, coma and death. Approximately 95% of the patients die within a few days or weeks. 3 If the onset of cryptococcal meningitis is insidious, fever usually is low grade, headache and nuchal rigidity are prominent and meningeal signs usually are present. As the disease progresses, increased intracranial pressure develops, and the course usually is downhill; without treatment, most patients die within 6 months to a year. 3 At least 37 cases of cryptococcal meningitis in children have been reported. 6 The majority of cases of cryptococcal meningitis result from hematogenous dissemination from a pulmonary focus, although the pulmonary lesion may be healed or inapparent at the time manifestation of the central nervous system infection occurs. There is some suggestion that the portal of entry occasionally is the gastrointestinal tract. 3 In the case of meningitis, the condition must be differentiated from tuberculous meningitis, neoplasms and abscess of the brain. Examination of the cerebrospinal fluid will reveal the characteristic yeast organisms often mistaken for mononuclear leukocytes but readily identified by the use of India ink or fluorescent antibodies and cultural means. 1 9LYMPH NODES.--Lymphadenopathy occurs in several types of cryptococcosis and may be coincident with some form of malignancy of Hodgkin's disease. SKIN.--It has been reported that skin manifestations occur in approximately 15% of cases of cryptococcosis. The lesions rarely are caused by direct inoculation. They usually are associated with disseminated disease. 1 Skin lesions appear as acneiform papules; these undergo necrosis, ulcerate, crust and coalesce. Chronic nodular lesions and sinus tracts may develop. CARDIOVASCULAR svs'rEr~t.ICryptococcal endocarditis and thromboembolic phenomena occasionally have been described in the presence of such underlying disease as rheumatic heart disease or diabetes mellitus. 3 BONE AND JOiNTS.---The cryptococcal lesions of bone are similar to those seen with North American blastomycosis and coccidioidomycosis in that they usually are multiple, widely disseminated and discrete, and have a tendency to be destructive and chronic in nature. Osteolytic bone involvement occurs in approximately 10% of cases of cryptococcosis and usually is a part of generalized infection, s VISCERAL CRYPTOCOCCOSIS.---Any organ of the body, including the kidneys, liver and eyes, may be subject to invasion by C. neoformans, a Of particular interest is the generalized disseminated form that has 36

been found in the newborn infant. The symptoms date from birth and include central nervous system manifestations, jaundice, hepatomegaly, splenomegaly, chorioretinitis and intracranial calcifications. Hydrocephalus and cerebral degeneration may occur. 7 The manifestations resemble those of congenital toxoplasmosis and cytomegalie inclusion disease. 8 DIAGNOSIS Diagnosis is established by finding encapsulated budding yeast ceils in the cerebrospinal fluid, sputum or in lesions (biopsy) by direct examination and culture. The fungus appears as a thin-walled budding yeast surrounded by a large gelatinous capsule. Growth on Sabouraud's medium is creamy white, mucoid and glistening. Fungus cells in cerebrospinal fluid may easily be mistaken for iymphocytes unless an India ink preparation is used to demonstrate the capsule. In differential diagnosis, tuberculosis and infections by other fungi must be considered. Laboratory aids to the diagnosis of cryptococcosis include the following. Serology.--Complement fixation, agglutination, hemagglutination methods, the use of antibody-coated latex particles and the direct fluorescent-antibody staining of cryptococcal cells have met with varying degrees of success in different laboratories. It is, therefore, helpful to have more than one determination by more than one method in arriving at a decision from serologic data. a Cultures.--Cryptococcosis neolormans may be difficult to recover from some patients. Cultures of cerebrospinal fluid, blood, sputum, urine, stool, bone marrow and cutaneous and mucosal lesions should be utilized. The organism grows on Sabouraud's dextrose agar at 37 ~ C. Although chloramphenicol can be incorporated into the medium to inhibit growth of bacterial contaminants, Actidione, which frequently is so used, should not be used here, since it inhibits C. neo/ormans. L-forms of C. neolormans have been described. 3 Cerebrospinal fluid.---The cerebrospinal fluid frequently is under increased pressure. The white cell count is elevated but seldom exceeds 700-800/cu. ram., and the cells are predominantly lymphocytes. Protein is increased, chlorides may be low and glucose levels sometimes are as low as 10 mg./100 ml. but may be normal, s Demonstration o~ organisms in cerebrospinal fltdd or tissttes.--It is difficult to identify C. neoIormans in wet preparations, and the organism may be confused with white or red blood cells. It can be identified by the use of the India ink mount, which demonstrates the thick halo-like capsule between the budding yeast and India ink particles. Mucicarmine stains the mucinous capsule intensely and is useful, since other fungi stain poorly with this dye. Fluorescein-labeled antibody to 37

C. neoIormans may be used with some degree of reliability for specific identification.2, a

TREATMENT In localized, nonprogressive pulmonary cryptococcosis, specific therapy is not indicated, since spontaneous recovery is likely. In some cases, localized lesions may be amenable to surgical excision. Cryptococcal meningitis of disseminated forms and acute pneumonic disease that is not localized, however, require treatment with amphotericin B intravenously. Before amphotericin B, no truly effective therapy existed for cryptococcal meningitis and disseminated forms and these forms of the infection were almost universally fatal. The fatality rate of cryptococcal meningitis has been reduced from virtually 100% to approximately 3 0 % . 9 Sulfadiazine also has been used but it is rarely effective for serious infections. A new drug, 5-fluorocytosine, offers some promise for the successful systemic treatment of cryptococeosis. REFERENCES.-.--CRYPTOCOCCOSIS 1. Hildick-Smith, G., Blank, H., and Sarkany, I.: Futlglts Diseases and Their Treatment (Boston: Little, Brown & Company, 1964). 2. Emmons, C. W., Binford, C. H., and Utz, J. P.: Medical Mycology (2d ed.; Philadelphia: Lea & Febiger, 1970). 3. Hughes, W. T.: The Deep Mycoses, in Kelley, V. C. (ed.), Bmmzemamz's Practice of Pediatrics (Hagerstown, Md.: Harper & Row, Publishers, 1970), pp. 1-20. 4. Seabury, J. H.: The Mycoses (Excluding Histoplasmosis), in Kendig, E. L., Jr., (ed.), Disorders o] the Respiratory Tract in Children (Philadelphia: W. B. Saunders Company, 1967), p. 568. 5. Procknow, J. J.: Fungal infections, Ann. Rev. Med. 13:1, 1962. 6. Siewers, C. M. G., and Cramblett, H. G.: Cryptococcosis (torulosis) in children, Pediatrics 34:393, 1964. 7. Nassau, E., and Weinberg-Heiruti, C.: Torulosis of the newborn, Harefuah 35:50, 1948. 8. Neuhauser, E. B. D., and Tucker, A.: The roentgen changes produced by diffuse torulosis in the newborn, Am. J. Roentgenol. 59:805, 1948. 9. Otz, J. P.: Systemic Fungal Infection Amenable to Chemotherapy, Diseasea-month (Chicago: Year Book Medical Publishers, Inc., September, 1963).

Part II will be published as the November issue.

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