6 Infections Due to the Dimorphic Fungi

T.S. HARRISON l and S.M. LEVITZ l

CONTENTS VII. Infections Caused by Penicillium marneffei .. 142 A. Mycology ...... 142 I. Introduction ...... 125 B. Epidemiology and Ecology ...... 142 II. Coccidioidomycosis ...... 125 C. Clinical Manifestations ...... 142 A. Mycology ...... 126 D. Diagnosis ...... 143 B. Epidemiology and Ecology ...... 126 E. Treatment ...... 143 C. Clinical Manifestations ...... 127 VIII. Conclusions ...... 143 1. Primary Coccidioidomycosis ...... 127 References ...... 144 2. Disseminated Disease ...... 128 3. Coccidioidomycosis in HIV Infection ... . 128 D. Diagnosis ...... 128 E. Therapy and Prevention ...... 129 III. Histoplasmosis ...... 130 I. Introduction A. Mycology ...... 130 B. Epidemiology and Ecology ...... 131 C. Clinical Manifestations ...... 131 1. Primary and Thoracic Disease ...... 131 The thermally dimorphic fungi grow as molds in 2. Disseminated Disease ...... 132 the natural environment or in the laboratory at 3. Histoplasmosis in HIV Infection ...... 133 25-30 DC, and as yeasts or spherules in tissue or D. Diagnosis ...... 133 when incubated on enriched media at 37 DC. E. Treatment ...... 133 IV. Blastomycosis ...... 134 They include the agents of the endemic systemic A. Mycology ...... 134 mycoses prevalent in the Western Hemisphere, B. Epidemiology and Ecology ...... 135 i.e., Coccidioides immitis, Histoplasma cap­ C. Clinical Manifestations ...... 135 sulatum, Blastomyces dermatitidis, and Par­ 1. Primary and Pulmonary Disease ...... 135 2. Extrapulmonary Disease ...... 136 acoccidioides brasiliensis. Also discussed here are 3. Blastomycosis in HIV Infection ...... 136 Sporothrix schenckii, which occurs worldwide and D. Diagnosis ...... 136 usually causes cutaneous rather than systemic E. Treatment ...... 137 disease, and Penicillium marneffei, a recently V. Paracoccidioidomycosis ...... 137 A. Mycology ...... 137 recognized cause of systemic mycosis in Southeast B. Epidemiology and Ecology ...... 138 Asia. In recent years, these fungi have become an C. Clinical Manifestations ...... 138 increasing problem due to rising populations in 1. Childhood Disease ...... 138 2. Adult Disease ...... 139 the endemic areas, more travel, and an increasing 3. Paracoccidioidomycosis in HIV Infection 139 number of immunocompromised patients D. Diagnosis ...... 139 (especially those with AIDS). Because of space E. Treatment ...... 139 limitations we have tried to emphasize more VI. Sporotrichosis ...... 140 A. Mycology ...... 140 recent developments in the ecology, epidemiology, B. Epidemiology and Ecology ...... 140 and clinical aspects of these mycoses. Pathogenesis C. Clinical Manifestations ...... 141 and host defense are reviewed in other chapters 1. Cutaneous Sporotrichosis ...... 141 (Chaps. 1,3,4, this Vol.). 2. Systemic Sporotrichosis ...... 141 D. Diagnosis ...... 141 E. Treatment ...... 141 II. Coccidioidomycosis

1 Section of Infectious Diseases, Evans Memorial Department of Clinical Research and Department of The first case of disseminated coccidioidomycosis Medicine, Boston University School of Medicine, Boston was reported in 1892 in Argentina. By 1900 MA 02118, USA Ophiils described the causative organism as a

The Mycota VI Human and Animal Relationships Howard/Miller (Eds.) © Springer-Verlag Berlin Heidelberg 1996 126 T.S. Harrison and S.M. Levitz dimorphic fungus. In the 1930s Dickson and the presence of particular plants (e.g., creosote Gifford recognized the milder self-limiting forms bush, cacti, and yuccas) and animals (Drutz and of primary pulmonary infection. Charles Smith Catanzaro 1978). The highest prevalences are in and his coworkers (1946) defined much of the southern Arizona around Phoenix and Tucson, in epidemiology of the infection in studies during the San Joaquin Valley in southern California, World War II at military installations in the San and in Texas along the Rio Grande around EI Joaquin Valley. The first effective treatment, Paso. Parts of southern Nevada, Utah, and New amphotericin B, was introduced in 1957; and Mexico are also endemic. In Mexico the main from the 1970s azoles also became available. areas are in the north and west along the border with the USA, the Pacific coast, and a more central region. There are smaller endemic areas A. Mycology in Honduras and Guatemala. In South America the highest incidence occurs in northwest Coccidioides immitis is classified with imperfect Venezuela. Endemic disease has also been re­ fungi or deuteromycetes, as no sexual state has ported in the adjacent areas of Columbia, and in yet been described (Kwon-Chung and Bennett Paraguay, Bolivia, and Argentina. Interestingly, 1992). However, analysis of rONA sequence data endemic foci have also been found outside the suggests a close relationship with other dimorphic Lower Sonoran Life Zone, e.g., in the Pacific fungi of medical importance, such as Blastomyces beach area of San Diego, in a woodland area of dermatitidis and Histoplasma capsulatum, whose northern California, and in two tropical areas of sexual forms place them in the Ascomycotina. As Mexico. Within endemic areas, the occurrence of a saprophyte in soil or on agar, C. immitis pro­ C. immitis in the soil is very patchy. The reasons duces septate hyphae. Arthroconidia are formed for this are not fully understood. Soil around by alternate cells which swell and lay down an rodent burrows more often yields fungus. The inner wall, while the intervening cells degenerate. high salinity and alkalinity of most positive When disturbed, the hardy arthroconidia are soils may inhibit the growth of competing released into the air. They may germinate to microorganisms. produce hyphae, but if inhaled by man or a range Within endemic areas, the risk of infection is of animals they enlarge to become multinucleate clearly increased by work outdoors under dusty spherules up to 80.um in diameter within the host conditions. Outbreaks can occur during construc­ tissues. By successive cycles of cleavage, endo­ tion and archeological digs. Larger epidemics spores 2-5.um in diameter with single nuclei are may result from climatic factors. In December formed and released when the spherule wall rup­ 1977, high winds scoured the topsoil from the tures. In the susceptible host, each endospore can southern San Joaquin Valley and deposited dust then form a new spherule. In the laboratory, up to 700 km to the north, well outside the usual conversion to the parasitic form is favored by endemic area. In the first 16 weeks of 1978, 550 increased CO2 tension and a temperature between cases of coccidioidomycosis were reported in 34 and 40°C. Up to one quarter of isolates show California compared to a maximum of 175 in the variations in the color, texture, or form of the same period over the previous 10 years (Flynn et mycelial colonies, or in the pattern of conidiation, al. 1979). From September to December 1991, which can lead to delays in identification. Atypical and again in the latter half of 1992, there was isolates may have differing degrees of virulence in a dramatic increase in the number of cases of mice, but there is no evidence for any clinical coccidioidomycosis in the southern San Joaquin correlation in man. In addition, there is no Valley (Einstein and Johnson 1993). After a pro­ evidence for any significant antigenic variation longed drought, significant rainfall in March 1991 between strains. and in February and March 1992 may have led to mycelial growth and the germination of arth­ roconidia which were dispersed in the subsequent B. Epidemiology and Ecology dry months. In southern California in a normal year, there is not usually such a marked seasonal In the USA the endemic areas largely correspond variation in incidence, but studies from Arizona with the Lower Sonoran Life Zone, characterized have also found an increased incidence in the by an arid climate with short rainy seasons and second half of the year (Kerrick et al. 1985). Dimorphic Fungal Infections 127

Outside the endemic region, cases most often C. Clinical Manifestations result from travel, which may only have been brief within an endemic area. Very rarely fomites 1. Primary Coccidioidomycosis (e.g., cotton and clothes) have led to infections outside the endemic area. Infrequent cases Symptomatic disease occurs in about 40% of those acquired by direct cutaneous inoculation have infected, within 1 to 4 weeks after exposure. The also been described. Under normal circumstances, common manifestations are cough (which is person to person spread does not occur, although usually dry), fever, headache, chest pain (which in one case report, medical staff were infected may be pleuritic), malaise, and myalgia. A fine from arthroconidia produced by a mycelium which erythematous macular rash in the first few days of grew on the plaster cast of a patient with illness may be more common in children. Some osteomyelitis. patients develop a self-limiting complex of Prevalence varies but skin tests are positive in symptoms known as valley fever or desert greater than 50% of residents in some endemic rheumatism consisting of erythema nodosum or areas. Annual incidence of symptomatic disease erythema multiforme, arthritis, and mild con­ (about 40% of those infected) among susceptible junctivitis or episcleritis. Erythema nodosum can persons was 0.43% in one study of students in occur up to 3 weeks after the onset of respiratory Arizona (Kerrick et al. 1985). Skin testing suggests symptoms, coinciding with and probably second­ there is no increased susceptibility to primary ary to the development of a strong delayed hyper­ infection on the basis of age, sex, or race. How­ sensitivity reaction. It is more common in females ever, the risk of disseminated disease is dependent and in Caucasians, occurring in 50% of sympto­ on a number of host factors. From studies of matic cases in Caucasian females in studies by mortality data, the prospective studies of Smith Smith (1946), and is a favorable prognostic sign. and coworkers (1946) among military recruits, Arthritis, most often of the knees or ankles, occurs and more recently from observations following in about a third of these patients. the dust storm-related outbreak, it appears that Hospitalized patients usually have an ab­ African-Americans and Filipinos have the greatest normal chest X-ray. Single or multiple segmental risk, followed by Native Americans and Mexicans, or lobar infiltrates are most frequent. Hilar and then Caucasians. In addition, dissemination adenopathy occurs in about 20%. Occasionally, is more frequent in men, and during the third there may be a large pleural effusion. In these trimester of pregnancy or immediately post­ cases, pleural biopsy is more sensitive than direct partum. Disseminated disease has been associated examination or culture of fluid to confirm the with type B blood group and HLA-A9, although diagnosis. Primary pulmonary coccidioidomycosis whether these factors are independent of race is usually resolves in 2 to 3 weeks without specific not clear. Immunocompromised patients com­ therapy. However persisting and fatal pneumonia monly develop disseminated disease. Of 260 renal is well recognized especially in immunocom­ transplant patients in Arizona, 7% developed promised hosts. Severe pneumonia may also follow coccidioidomycosis over a lO-year period, and intense exposure (Larsen et al. 1985). Patients 75% of these had disseminated disease (Cohen et may deteriorate dramatically due to hemato­ al. 1982). Of nine patients with evidence of sig­ genous spread leading to miliary involvement of nificant infection with C. immitis prior to under­ the lungs, respiratory failure, and a sepsis-like going cardiac or renal transplant, two of four who syndrome. Less than 1 % of cases develop chronic did not receive antifungal prophylaxis developed progressive pneumonia with symptoms and apical active disease, both after treatment for rejection fibrosis and cavitation suggestive of tuberculosis. (Hall et al. 1993). A positive skin test alone Sputum cultures are usually positive for C. immitis. before transplant did not appear to be a risk Common sequelae of pulmonary infection are factor. nodules and cavities, which may present incident­ ally long after a mild initial inrection for which the patient never sought medical attention. Nodules are most often single. Central fibrocaseous material is surrounded by granulomatous inflam­ mation. Calcification can occur. Most contain identifiable spherules; less often viable organisms 128 T.S. Harrison and S.M. Levitz can be recovered by culture (in one study 14% of diagnosis often depends on the CSF complement these patients had a positive sputum culture). fixation (CF) test, which is positive in 75-95% of Often the main problem is to differentiate nodules cases. CT or MRI scanning is useful to detect from malignancy. Bronchoscopy, percutaneous hydrocephalus, which may be communicatng or needle biopsy (Forseth et al. 1986), or fine needle non-communicating and require shunting. Imaging aspiration (Raab et al. 1993) may provide a may also show parenchymal lesions suggestive of positive diagnosis and obviate the need for infarction. Vasculitis in association with meningitis thoracotomy. Ninety percent of cavities are single may be more common than previously recognized and most occur in the upper lung fields. Classically (Williams et al. 1992). Untreated meningitis is they are thin-walled. Hyde (1968) found that half nearly always fatal, usually within 2 years. Patients resolved in a mean of 2 years. Culture of sputum with meningitis as the only site of dissemination or bronchial lavage is usually positive, but pul­ usually survive longer than those with widespread monary spread or dissemination of infection is disease. very rare. Most cavities are asymptomatic but Other sites of dissemination include: lymph complications include bacterial superinfection, nodes; genitourinary tract (urine cultures may mycetoma (usually with Aspergillus but also be positive in the absence of other signs of disse­ hyphae of C. immitis itself may form a fungus minated disease, and may not necessarily indicate ball), hemoptysis, and bronchopleural fistual with severe infection (DeFelice et al. 1982»; liver, pyopneumothorax. Surgery is indicated for the spleen, and adrenal glands (commonly found to latter and some cases with recurrent infection or be infected in autopsy series but not often clinically hemoptysis. significant); larynx; thyroid; and the eyes.

3. Coccidioidomycosis in HIV Infection 2. Disseminated Disease In endemic areas, coccidioidomycosis has emerged Disseminated disease affects about 1 % of symp­ as the third most common opportunistic infection tomatic Caucasian males and usually occurs within after Pneumocystis and esophageal candidiasis. In the first few months after initial infection, most a retrospective study of 77 patients, 31 had diffuse frequently involving skin, subcutaneous tissue, pulmonary involvement with reticular-nodular bones, joints, or the meninges. Skin lesions may infiltrates (Fish et al. 1990). Only 4 had cutaneous be verrucous granulomas, plaques, nodules, or lesions and 7 presented with lymphadenopathy or pustules. Pathologically, there are various degrees liver involvement. Serology by CF was positive in of granuloma or abscess formation, perivascular 74%, with either CF or tube precipitin (TP) tests infiltrate, and tissue eosinophilia. Subcutaneous positive in 83%. In patients with meningitis, the abscesses are often not particularly warm, red, or CSF parameters were not different from those of tender. Osteomyelitis affects particularly the the non-HIV population. CD4 counts were usually vertebrae, metaphyses of the long bones, and the lower than 250. Those with diffuse pulmonary skull. Bone and gallium scans are useful in de­ disease had a median CD4 count of 44 and the tecting early and subclinical lesions. The knee, worst prognosis - a median survival of 1 month. ankle, and wrist are the most frequently affected In a prospective study of HIV patients in Arizona, joints either via hematogenous spread or from the estimated cumulative incidence of coccidioi­ adjacent bone. Subcutaneous or skeletal lesions domycosis by 41 months was 25% (Ampel et al. can give rise to chronic discharging sinuses. 1993). Low CD4 counts were associated with Meningitis usually presents insidiously with infection but not a positive skin test (22% on headache and later lethargy and confusion (Bouza entry), a history of coccidioidomycosis, or long et al. 1981). Fever and signs of meningeal irritation residence in the endemic area. HIV patients may are often not prominent. Cerebro-spinal fluid have an increased susceptibility to new infection (CSF) examination is nearly always abnormal, the in addition to reactivation. usual pattern being lymphocytosis with elevated protein and low glucose. In a recent review of 27 cases, Ragland (1993) found eosinophils in the D. Diagnosis CSF in 19, and recommended a Wright stain of the sedimentated cells in suspected cases. In only Definitive diagnosis is based on culture or the 20-40% of cases is the CSF culture positive, and identification of spherules in clinical specimens. Dimorphic Fungal Infections 129

Specimens may be mounted in 20% potassium E. Therapy and Prevention hydroxide and examined with subdued light. Spherules may be seen on Papanicolaou as well as Most infections are self-limited and do not require PAS or GMS-stained cytology slides. C. immitis therapy. Indications for treatment include severe grows on blood and Sabouraud dextrose agar, or persistent primary infection, risk factors for usually within 3-5 days. Routine blood cultures dissemination (such as ethnic background, will also support the growth of Coccidioides, high complement fixation titers, and immuno­ although lysis centrifugation techniques may be suppression), and disseminated disease. With the superior. Of note, radiometric systems may not availability of safe oral medications there is detect fungal growth reliably (Ampel and Wieden undoubtedly a tendency to treat more patients 1988). The exoantigen or DNA probe tests are with primary disease although there is no evidence used for positive identification of isolates. Proper as yet that this reduces the risk of dissemination precautionary measures should be taken when (Galgiani 1993). handling any mold in view of the risk of infection Amphotericin B is preferred by many experts to laboratory staff. for the treatment of coccidioidomycosis, especially Diagnosis can also be made by serology in patients with extensive disease. However, its (Pappagianis and Zimmer 1990). The tube pre­ many toxicities and the need for parenteral cipitin test, which detect IgM antibody, becomes administration has led to trials with the oral positive after 1-3 weeks of symptoms of primary azoles (ketoconazole, fluconazole, and itracona­ infection, but usually remains positive for only a zole). Unfortunately, as yet there are no com­ short period. IgM antibodies can also be detected parative data. Pulmonary, soft tissue, and skeletal by latex agglutination (which has a high rate of disease usually improved with 400 mg per day of false positives) and immunodiffusion tests. The ketoconazole, although many patients relapsed off­ CF test detects IgG, and becomes positive after treatment (Galgiani 1983). Additional problems 2-6 weeks. High or rising titers are associated with ketoconazole include variable absorption, with dissemination. With recovery, titers should numerous drug interactions, and dose-related fall. The significance of a particular titer will vary side effects (notably nausea and vomiting and between laboratories. The CF test on CSF is the suppression of steroid hormone synthesis). single most useful test to diagnose meningitis. Itraconazole, 400 mg per day, appears to be at Immunodiffusion tests are also widely used to least as effective, although, as with ketoconazole, detect IgG antibodies. In addition, ELISA, improvement often occurs slowly. Itraconazole radioimmunoassay, and counterimmunoelectro­ appears to be better tolerated and in one study phoresis serological tests have been developed as was associated with fewer relapses - 16% well as tests to detect antigen, although none is (Graybill et al. 1990). Similar results have been yet widely used. Development of more purified reported with fluconazole and a trial comparing antigen preparations is underway and will help to itraconazole and fluconazole in nonmeningeal maintain the specificity of more sensitive tests. disease is underway. Skin testing is useful in epidemiologic studies Intrathecal amphotericin B reduces the but rarely helpful in individual cases. Coccidioidin mortality of coccidioidal meningitis. A review of and spherulin are complex antigens prepared published series found survival was correlated from cultures of the mycelial and spherule phases, with total dose of amphotericin B received respectively. In primary disease, positive tests (Labadie and Hamilton 1986). These authors develop from 3 days to 3 weeks after onset. used up to 1.5 mg three times per week (mean Patients with erythema nodosum can develop total dose of 82 mg) combined with 25 - 50 mg of severe reactions and should receive one tenth of hydrocortisone (to reduce inflammatory reactions) the normal dose. A positive test may reflect prior and given primarily by cisternal injection. Among exposure and tests are frequently negative in 11 patients, one death, not attributable to disease, disseminated disease or with residual pulmonary occurred after mean follow-up of 75 months. lesions. Patients with disseminated disease who With improvement, the frequency of injections is maintain or recover delayed hypersensitivity may reduced but the duration of therapy is not well have a better prognosis. defined - CSF CF tests should be negative and CSF glucose normal. Cisternal injection requires technical expertise, and occasional complications 130 T.S. Harrison and S.M. Levitz can be devastating but administration by lumbar outbreaks of disease have been described. The puncture often leads to symptomatic arachnoiditis largest have occurred recently in Indianapolis. and intraventricular catheters may block or be­ come infected. Wrobel and Alksne (1992) recently described retromastoid placement of a reservoir A. Mycology with the catheter in the cisterna magna. In a recent trial, 79% of 47 patients treated with 400 mg Histoplasma capsulatum is classified with Blasto­ fluconazole responded (>40% reduction in base­ myces dermatitidis in the family Onygenaceae of line scoring system within 8 months), although in the Ascomycota following the discovery by 24% some CSF abnormalities persisted (Galgiani Kwon-Chung of the perfect state Ajellomyces et al. 1993). Six of nine HIV-infected patients capsulatus (Kwon-Chung and Bennett 1992). Two responded and four of six non-responders given varieties have been described in human disease: 800 mg improved. In a smaller study, four of five H. capsulatum var. capsulatum and H. capsulatum patients treated with 400 mg itraconazole alone var. duboisii. Primary clinical isolates of var. cap­ responded (Tucker et al. 1990). Because of the sulatum may produce white mycelial colonies with occurrence of frequent relapses off-treatment, thick aerial hyphae or buff to brown colonies with azoles should be continued indefinitely when used fewer aerial hyphae and abundant macroconidia. to treat meningitis. Comparative trials are needed On subculturing, especially on rich media, white to determine which azole is most effective and colonies are formed. Thick-walled macroconidia at what dose, and whether additive effects 8-14,um in diameter and smaller 2-4,um micro­ are obtained by the addition of intrathecal conidia are borne at the tip of short conidiophores amphotericin B. which grow at right angles from the vegetative A vaccine consisting of formaldehyde-killed hyphae. The macroconidia are usually tuberculate, spherules was protective in a mouse model, but being covered in projections arising from the no efficacy was demonstrated in a double blind outer layer of the wall. Some isolates, especially trial involving 2800 susceptible persons in the on primary culture and from patients already on endemic area (Pappagianis et al. 1993). Local antifungal treatment, produce only smooth-walled reactions limited the dose that could be given. conidia. Mycelial colonies can be positively Immunization with subcellular fractions or purified identified by DNA probe, exoantigen tests, or antigen(s) is likely to be better tolerated; such conversion to the yeast form. At 37°C on enriched preparations are under development. media or in host tissues 2-4,um uninucleate oval yeasts with narrow-necked buds are formed. H. capsulatum var. duboisii, which causes disease in III. Histoplasmosis Africa, has indistinguishable mycelial colonies, but the yeasts are 7 -15,um in size, thicker-walled, and often form short chains. When opposite As with coccidioidomycosis, only the disseminated mating strains are paired, cleistothecia are pro­ form of histoplasmosis was initially recognized. duced. Initially, one hypha winds around a hypha The first case was described by Darling in 1904 in of the opposite strain. The cleistothecium is Panama. De Rocha-Lima in 1912 suggested the formed of coiling hyphae which radiate outwards causative organism was a fungus rather than a with a network of peri dial hyphae arising from protozoan and De Monbreun, 30 years later, their proximal ends. At the center, ascogenous described the detailed morphology and dimorphic hyphae give rise to pear-shaped asci containing nature of H. capsulatum. In the 1940s, Christie eight ascospores. Both varieties will form cleisto­ and Peterson recognized that pulmonary calci­ thecia and viable ascospores when opposite mating fications were associated with exposure to the types are paired. Antigenic variation between fungus and subsequent skin test surveys defined isolates of H. capsulatum has allowed their the endemic areas and established the frequency separation into five serotypes. More recently, of mild, self-limiting disease. Emmons in 1949 four classes of isolates have been defined on the was the first to isolate the fungus from soil, and its basis of analysis of restriction fragments of mito­ association with soil enriched with avian guano chondrial and ribosomal DNA (Spitzer et al. was soon realized. Since the late 1940s numerous 1989). Dimorphic Fungal Infections 131

B. Epidemiology and Ecology inoculation has led to spontaneously resolving skin nodules. H. capsulatum has a wide distribution. The highest H. capsulatum var. duboisii occurs in incidence occurs in the United States, Central and equatorial Africa. Most cases have been reported South America, and the Caribbean. Endemic from Senegal, Nigeria, and Zaire, although this disease has also been reported from Southeast may reflect only the distribution of interested Asia, Europe (notably Italy), and Africa, where medical institutions. Var. duboisii has not been H. capsulatum var. duboisii occurs in addition to conclusively isolated from the environment, but H. capsulatum var. capsulatum. Skin testing with cases have been linked to exposure to chickens histoplasmin, a mycelial culture filtrate, has been and bats, suggesting an ecological niche similar to very useful in epidemiological studies, although var. capsulatum. In a review of 56 cases Cockshott some cross-reactions occur (e.g., with C. immitis) and Lucas found a predominance of males and of and reactions wane with time after exposure. older children and young adults (Cockshott and Surveys have established highly endemic areas of Lucas 1964). the central and eastern United States, especially the Mississippi and Ohio River valleys. In these areas, near universal exposure occurs, as suggested C. Clinical Manifestations by rates of positive tests which rise rapidly during childhood to peak at over 80% in 1O-15-year­ 1. Primary and Thoracic Disease olds. A slow decline in the percentage of reactors thereafter reflects a balance between waning Given the extent of exposure, the vast majority of immunity and reexposure, which from longi­ infections are clearly asymptomatic. In studies tudinal studies appears to be common. Overall, it which have followed new residents of endemic has been estimated that approximately 40 million areas, those whose skin tests became positive people in the United States have been exposed. did not have a detectable increased frequency of H. capsulatum has been frequently isolated clinical symptoms. Even in subclinical primary from soil enriched with guano from birds (parti­ infection, however, metastatic foci commonly cularly chickens, starlings, and blackbirds) and develop in liver and spleen and probably also bats. Moderate temperatures and moisture favor other organs prior to the development of cell­ growth of the mycelium. In laboratory experi­ mediated immunity. Development of calcifications ments, dehydration enhances detachment of in the liver, spleen, lung parenchyma, and hilar microconidia, which by virtue of their small size and mediastinal nodes testify to prior infection. (1-5 Jim) are the likely infectious propagules. Occasionally, sporadic symptomatic primary The larger macroconidia are more resistant to disease is recognized in infants and children, adverse environmental conditions. Many out­ and may be responsible for a proportion of un­ breaks of disease have occurred when foci of diagnosed febrile illnesses. Acute histoplasmosis infected material (such as soil and guano in chicken is, however, more commonly diagnosed in the houses, around bird roosts, or in bat-infested setting of an outbreak. The commonest symptoms caves) have been disturbed. Cases have been are malaise and headache with fever, nonproduc­ associated with cutting up decayed wood or the tive cough, shortness of breath, and central or demolition of old houses. Large urban outbreaks pleuritic chest pain (Goodwin et al. 1981). Chest have occurred, such as in 1963 when 42 cases in X-rays usually show patchy or nodular infiltrates Montreal were linked to construction of a subway. and/or hilar or mediastinal adenopathy. The ill­ In 1978-79,435 symptomatic cases were diagnosed ness is self-limiting. Fever lasts from a few days to in Indianapolis (Wheat et al. 1981). Seropre­ over a week, but full recovery may take 1 to 2 valence among young adults in the worst affected months. Severity is related to the intensity of areas rose from 1.5 to 40%. No source of the exposure. Rarely, after intense exposure, patients outbreak was identified, but it is clear that large may present a clinical picture resembling acute urban populations can be at risk from widely respiratory distress syndrome including severe dispersed airborne conidia. hypoxia. As with C. immitis, laboratory infections Lymphadenitis may persist after pneumonitis have occurred. Very rarely, accidental cutaneous resolves. Enlarged lymph nodes may coalesce and 132 T.S. Harrison and S.M. Levitz compress bronchi or mediastinal vessels, although shortness of breath, fever, and weight loss are not not to the degree seen in mediastinal fibrosis. as prominent as in tuberculosis. In 20% of cases Broncholithiasis can result from rupture of a node in Goodwin's series the diagnosis was made in­ through the bronchial wall. Inflammation may cidentally on chest X-ray. Those with cavitary spread to involve the pericardium. In the In­ disease commonly have hemoptysis. The magni­ dianapolis outbreak 24 (5%) patients had peri­ tude of the impact of chronic pulmonary histo­ carditis and 4 required surgery to relieve plasmosis on the progression of COPD is not tamponade. Pericardial fluid is usually bloody, clear. and sterile and pericardial biopsies show scant organisms. Pericarditis is also usually self-limiting, 2. Disseminated Disease although late constriction can occur. Rheumato­ logical manifestations of acute infection including Disseminated disease usually develops in patients arthralgia, arthritis, or erythema nodosum may with some defect in cell-mediated immunity. Of also be seen. sporadic cases prior to the AIDS epidemic, ap­ Late sequelae of infection include histo­ proximately a third occurred in infants less than 1 plasmomas and mediastinal fibrosis. Rarely, year (Goodwin et al. 1980). In adults, there was a primary foci of infection in the peripheral lung predominance of males. In the two outbreaks in slowly enlarge due to continued deposition of Indianapolis in 1978 and 1980, 61 (8.5%) devel­ fibrous tissue leading to a nodule which can oped disseminated disease (Sathapatayavongs resemble a growing neoplasm. Central or con­ et al. 1983). Risk factors were older age and centric layers of calcification may help in distin­ immunocompromised condition. Twenty-one guishing these lesions. The same process can lead percent had no underlying disease, suggesting to mediastinal fibrosis, which can progress to either that large inocula can overcome normal entrap and compress vital mediastinal structures. host defenses or that these patients had some Fibrosis originating in the right paratracheal temporary immune defect. There is a pathological nodes causes superior vena caval obstruction and and clinical spectrum of disease. At one extreme, stenosis of the right main stem bronchus. Carinal in severely immunocompromised infants and node involvement may lead to stenosis of the adults there is unchecked multiplication of main stem bronchi and pulmonary veins, while organisms within macrophages and little host tissue hilar involvement is more likely to affect the reaction. Such patients typically have prominent bronchi and pulmonary arteries. fevers, hepatosplenomegaly, pancytopenia due to Chronic pulmonary histoplasmosis is seen in marrow involvement, diffuse nodular infiltrates those with preexisting chronic lung disease, most on chest X-ray, and a progressive course over often elderly white male smokers with Chronic weeks. Those with a more chronic course on Obstructive Pulmonary Disease (COPD). histology tend to have well-formed granulomata. Goodwin has postulated that disease results from Fever and cytopenias are less prominent. Focal exogenous reinfection of preexisting emphy­ lesions causing, for example, adrenal insufficiency, sematous airspaces in the uppper lobes (Goodwin endocarditis, or intestinal ulceration may dominate et al. 1976). Spillage of antigenic material from the clinical picture. In the most indolent cases, such spaces may result in an area of interstitial fatigue and weight loss may be the only symptoms pneumonitis. This resolves spontaneously al­ for years until an oropharyngeal lesion develops. though recurrent episodes may occur. On chest In Goodwin's series two-thirds of such patients X-ray, areas of necrosis within the pneumonitis had an oropharyngeal lesion which typically pro­ become increasingly dense and then contract into gressed from a nodule to an ulcer with raised fibrotic scars. However, infection is more likely to edges. persist and progress in the 20% of cases in which Infections with var. duboisii in Africa have larger bullous cavities become infected. Goodwin had a different pattern of organ involvement. (1976) found that cavities with a wall thickness Localized skin or bone disease, or disseminated of >4 mm (implying a high degree of hypersen­ infection with multiple skin, subcutaneous, and sitivity) were less likely to heal. Rather, con­ bone lesions and involvement of the reticuloendo­ tinuing deposition of fibrous tissue results in thelial system, are the commonest forms of disease enlargement with destruction of the remaining (Cockshott and Lucas 1964). Osteolytic lesions lung tissue. Symptoms of productive cough, occur, especially in the skull and ribs, but also in Dimorphic Fungal Infections 133 long bones and vertebrae. Pulmonary involve­ sections of node biopsies stained with silver ment has been noted only rarely. Several cases of methenamine. In AIDS patients, cultures of blood disseminated infection have been reported in by lysis centrifugation, marrow, and respiratory HIV-infected patients, but there does not seem to specimens were positive in 91, 90, and 86% of have been a great increase in HIV-associated cases, respectively, in the Indianapolis outbreak. cases as has occurred, for example, with crypto­ Sputum cultures in those with chronic pulmonary cocco sis in Africa. disease are positive in about 60% when three to six early morning specimens are collected. In acute disease, sputum smears or cultures 3. Histoplasmosis in HIV Infection are only rarely positive and diagnosis often de­ Disseminated disease in HIV-infected patients pends on serological methods together with the can occur as a result of either endogenous reac­ epidemiological setting. Complement fixation tivation or exogenous infection. Many cases of (CF) tests with whole yeast antigen are generally presumed reactivation have been diagnosed well more sensitive than immunodiffusion tests which outside the endemic area. The sharp rise in histo­ detect two glycoproteins (M and H); constituents plasmosis cases in HIV patients in Indianapolis in of histoplasmin. By 6 weeks after exposure 70- the fall of 1988 coincident with an epidemic in the 80% of sera are positive by CF while around 50% general population suggests exogenous infection. demonstrate an M band. H bands are seen in only The clinical picture resembles disease seen in 10-20% and last only 3-4 weeks. Antibody tests infants and other profoundly immunocompro­ are also usually positive in chronic pulmonary mised hosts, although it may be more severe and disease. Serology is less useful in disseminated rapidly progressive. Of 72 cases in Indianapolis, disease, especially in the immunocompromised 12% presented with a sepsis-like syndrome that individuals. A radioimmunoassay (RIA) has also included hypotension, coagulopathy, and multiple been developed which is more sensitive but less organ failure (Wheat et al. 1990b). Usually fever, specific. Cross-reactions with other mycoses are a weight loss, and respiratory complaints progress problem with all the serological tests. Wheat et over a couple of months. Hepatomegaly and al. (1989) have developed an RIA to detect poly­ splenomegaly, each in 12-30%, are the com­ saccharide antigen. In AIDS patients with disse­ monest signs. Chest X-rays often show diffuse minated disease, 97% of urine and 79% of serum nodular infiltrates but are normal in around one­ samples were positive. The test also proved useful third. In the Indianapolis series 18% had CNS in monitoring therapy and detecting relapse involvement with encephalopathy, meningitis, or (Wheat et al. 1991). Some cross-reactions, though, focal lesions. Skin or mucosal lesions occur in can still occur. CSF was positive in 5 of 12 patients around 10% of patients. Skin lesions are variable with meningitis. Antibody tests on CSF may also and in order of frequency include papules or be useful in diagnosing meningitis. CSF cultures nodules, macules, and follicular or pustular lesions are often negative unless large volumes are ob­ (Cohen et al. 1990). Occasional patients present tained (Wheat et al. 1990a). with gastrointestinal involvement.

E. Treatment D. Diagnosis Most non-AIDS patients with acute histoplasmosis Direct examination of specimens has the highest do not require specific treatment. Often the pa­ yield in disseminated disease in AIDS patients. tient will be improving by the time the diagnosis is Specimens from skin or mucosal lesions, peri­ made. In cases of severe or prolonged (>2-3 pheral smears or buffy coat preparations, or weeks) illness, or in infants or immunocompro­ marrow aspirates can be stained with Wright's mised hosts, a short course of amphotericin B or or Giemsa stains. In chronic pulmonary disease, ketoconazole has been recommended. With the sedimentated sputum can be used for diagnostic increased experience with itraconazole in other purposes, although the yield is relatively low. In forms of disease, it seems likely this would also be histological sections, organisms are most often effective. For the occasional patient with severe seen in areas of necrosis. In mediastinitis, a posi­ hypoxia after intense exposure, steroids in addition tive diagnosis is most likely by examining multiple to antifungal treatment have been associated with 134 T.S. Harrison and S.M. Levitz

dramatic improvement. Rheumatological mani­ as primary therapy. Nine of 12 patients reported festations of acute disease and pericarditis are by Sharkey-Mathis et al. (1993b) achieved re­ usually treated with nonsteroidal anti-inflam­ mission. There is less experience with fluconazole. matory drugs. Steroids were used in 5 of 16 In the study by Sharkey-Mathis et al. (1993b), six patients with pericarditis without any clear ad­ of ten HIV patients given fluconazole failed ther­ ditional advantage (Picardi et al. 1976). apy. There are a couple of reports of a favorable Antifungal treatment has not been recom­ response to fluconazole in non-HIV patients with mended in mediastinal fibrosis, although favor­ CNS disease. able results were reported with ketoconazole in a small number of patients whose symptoms re­ curred after surgical procedures (Urschel et al. 1990). Surgery may be necessary to relieve ob­ IV. Blastomycosis structions but is often technically very difficult due to the degree of fibrosis. Gilchrist described the first reported case of Patients with chronic pulmonary disease with blastomycosis, involving the skin, in 1894. persistent cavities, cavities with a wall thickness Systemic infection was reported by Walker and of greater than 2 mm, or progressive symptoms Montgomery in 1902. In the 1950s, on the basis of benefit from treatment with amphotericin B. At detailed pathological studies, Swartz and Baum least 35 mg/kg per day or 2 g given over about 10 (1951) postulated that both systemic and cutane­ weeks has been recommended. In a collaborative ous forms of disease resulted from an initial pul­ trial in patients with cavitary disease, treatment monary infection. In 1952, Broc and Haddad with 400-800mg/day of ketoconazole for at least reported cases from Africa. While most cases are 6 months was successful in 84% (National Institute sporadic, about a dozen clusters or outbreaks of Allergy and Infectious Diseases Mycoses Study have been recognized since 1954. B. dermatitidis Group 1985). Other investigators, however, have was first isolated from soil by Denton et al. in had less success with ketoconazole and have re­ 1961, but only in 1986 did Klein and coworkers commended 12 months' treatment, monitoring of manage to culture it from a site, an old beaver cultures, and switching to amphotericin B in those lodge, implicated as the source of an outbreak. who fail to respond. In a recent trial, the success rate was 65% when 200-400 mg/day of itracona­ zole for a median of 9 months was used (Dismukes A. Mycology et al. 1992). Surgery is not advised due to the poor respiratory reserve of most of these patients At 25-30°C, slender septate hyphae form white and the chances of recurrence. to light brown colonies (Kwon-Chung and Bennett Progressive disseminated disease particularly 1992). Smooth spherical or oval conidia 2-1O,um in immunocompromised hosts and in those with in diameter are borne on simple lateral conidi­ meningitis should be treated with amphotericin ophores. At 37°C, hyphae convert within 1-3 B. Azoles have been used successfully in the more weeks into the yeast form seen in host tissues. chronic forms of disseminated disease. Ketocona­ Multinucleated yeast cells are usually between 8 zole, however, has an unacceptably high failure and 15,um and produce broad-based buds which rate in immunocompromised patients. In one trial separate from the mother cell when they are of of itraconazole, all ten patients with non-life­ almost equal size. Yeast colonies are cream­ threatening disseminated disease were cured colored and finely wrinkled. The teleomorph of (Dismukes et al. 1992). For HIV patients in B. dermatitidis, Ajellomyces dermatitidis, was whom the goal is suppression rather than cure, described by McDonough and Lewis in 1967. Wheat et al. (1993) have used amphotericin B When isolates of opposite mating types are paired 50 mg/day (or 1 mg/kg per day in those <50 kg) on soil extract agar fusion leads to production of for 2 weeks followed by 50 mg on alternate days cleistothecia. These consist of radially arranged up to 15 mg/kg, at which point maintenance ther­ spirals of thick-walled hyphae from which arise a apy is started. For maintenance, itraconazole network of thinner peridial hyphae which are 200 mg twice daily has been shown to be as effec­ constricted at each septum to produce diamond­ tive as weekly amphotericin B. A small number of shaped cells. At the center of the cleistothecia, HIV patients have been treated with itraconazole hyphae produce asci with eight uninucleate 1.5- Dimorphic Fungal Infections 135

2,um ascospores which germinate to produce and it had rained in the days immediately prior to mycelial colonies. exposure. Laboratory studies have shown that Some differences have been noted between conidia are released much more readily by air African and North American isolates. African currents when the mycelium has been wetted. strains lack the A exoantigen and have been However, the exact ecological niche of B. der­ difficult to cross with North American strains. matitidis remains unclear. It has only rarely been They are more resistant to conversion into the isolated from soil and then only transiently, sug­ yeast form; and yeast cells more often form gesting that it may have an additional natural clusters due to delayed separation of daughter reservoir. In studies of sporadic disease in hyper­ cells. endemic areas, it has been difficult to link infection to any particular occupation or outdoor activity (Lowry et al. 1989). In Vilas County, Wisconsin, B. Epidemiology and Ecology (annual incidence 40 per 100000) most patients resided within 500 m of the Eagle or Wisconsin Because of the lack of sensitive and specific skin Rivers (Baumgardner et al. 1992). Most dogs with or serological tests, and the difficulty of culturing blastomycosis in Wisconsin were also found to the organism from the environment, the endemic live in close proximity to water. Man and dogs are area for blastomycosis has been defined only by probably exposed to a common source of infec­ the occurrence of cases in man and dogs. In North tion. In the Vilas County study, a third of dog­ America, the distribution of B. dermatitidis owning patients also had a dog diagnosed with includes the Southeastern United States and the blastomycosis. Mississippi, Ohio, and St. Lawrence River valleys. While most cases are presumed to result from States with the highest number of cases are inhalation of conidia, rarely infection can be trans­ Arkansas, Mississippi, Louisiana, Kentucky, mitted by direct cutaneous inoculation (e.g., the Tennessee, North Carolina, and Illinois and bite of an infected dog). Genital tract disease has Wisconsin (annual incidence of approximately 0.5 led to sexual transmission. Most patients are cases per 100000 population). In Canada, in addi­ adults without underlying immunocompromising tion to the St. Lawrence River valley, cases occur conditions. The preponderance of males seen in to the north of Lake Superior and as far west as many studies may reflect differential exposure. Alberta. Blastomycosis is also well documented Some studies have also suggested an increased in Africa, especially in Zimbabwe and South prevalence of disease among African Americans. Africa; and there have been occasional reports of endemic disease from other areas including the Middle East, India, and Mexico. Several cases C. Clinical Manifestations from Europe may have been transmitted via fomites (such as saw dust used in packaging) 1. Primary and Pulmonary Disease originating from endemic areas of the United States. Some understanding of primary disease and the Within the endemic area, there are foci where frequency of subclinical infection has been disease is especially prevalent. These foci are acquired from analysis of outbreaks. In the largest often in forested areas with many waterways, but outbreak at Eagle River in Wisconsin, just over they may also occur in urban settings. Clusters of half of the 95 persons exposed developed infec­ cases have provided clues to the ecology of the tion; of these half were symptomatic (Klein et al. fungus. These have been associated with distur­ 1986). The median incubation period was 45 days bance of soil, such as by construction or children (range 21-106). Commonly, cough, headache, playing, and often have occurred in close pro­ chest pain, weight loss, fever, and sweats are ximity to water. Klein et al. (1986) isolated B. seen. The cough often beco.mes productive of a dermatitidis from two sites implicated as sources little purulent sputum. Chest X-ray findings are of infection, namely, soil and organic debris varied and nonspecific. Alveolar and nodular obtained from an old beaver lodge, and soil from infiltrates are most common. Acute pulmonary a riverbank where seven patients had been fishing disease may resolve spontaneously or lead to prior to developing infection. In both cases, the chronic lung disease and/or dissemination. Cases soil was acidic, moist, and of high organic content, of rapidly progressive pulmonary disease with 136 T.S. Harrison and S.M. Levitz diffuse infiltrates and adult respiratory distress Central nervous system (CNS) involvement is syndrome have also been described (Meyer et a1. seen in 3-10% of cases and includes meningitis, 1993). Compared with outbreaks, in sporadic cases brain abscess or granuloma, and epidural abscess. there is usually a much more insidious onset of In rare cases, isolated CNS disease is seen, which symptoms, and fever is less marked. In a coopera­ can be difficult to diagnosis. CSF cultures from tive study, over half of patients with pulmonary lumbar puncture are most often negative, although involvement also had skin lesions, and over one­ ventricular or cisternal fluid may have a higher third had hemoptysis (Blastomycosis Cooperative yield (Kravitz et a1. 1981). Involvement of many Study of the Veterans Administration 1964). other sites can occur including the mucous mem­ Chest X-ray abnormalities include alveolar infil­ branes, liver, spleen, lymph nodes, esophagus, trates, masses, and nodules, and less often inter­ larynx, and adrenal glands. In African cases, a stitial disease or cavitation (Brown et a1. 1991). high incidence of osteomyelitis and subcutaneous Upper lobe involvement is slightly more common. abscesses with draining sinuses has been noted Hilar adenopathy and pleural effusions are less (Baily et a1. 1991). frequent; calcification is very rare and when present probably usually represents concomitant 3. Blastomycosis in HIV Infection histoplasmosis. Hematogenous spread can result in miliary pulmonary disease, especially in older As opposed to other systemic fungal diseases, or immunocompromised patients. Compared to there does not appear to be a marked increase in acute disease, chronic pulmonary involvement is blastomycosis in immunocompromised patients. more often associated with dissemination and In a recent report of 15 patients with HIV and probably never resolves spontaneously. blastomycosis, 8 had extrapulmonary disease (including 6 and 5 patients with CNS and widely disseminated disease, respectively) (Pappas et a1. 2. Extrapulmonary Disease 1992). Only 3 patients had skin lesions. Of the 11 The most common sites of extrapulmonary disease patients with abnormal chest X-rays, 6 had a are skin, bone, and genitourinary tract. Skin diffuse interstitial or miliary pattern. Most patients lesions, often in association with pulmonary had a CD4 count below 200, and 6 died within 30 disease, have occurred in over half of patients in days secondary to their infection. Four patients most series. They are often on the face and may had not lived in a known endemic area for several be verrucous with a well-demarcated raised border years, suggesting reactivation. In other immuno­ or ulcers with a rolled edge. Central healing with compromised patients, there may also be an fibrosis may occur over time. Lesions show sup­ increased incidence of diffuse pulmonary and purative and granulomatous inflammation. CNS involvement, and an increased mortality Epithelial hyperplasia with downgrowth of rete attributable to infection, although the trends are pegs can lead to confusion with squamous cell not as strong as in the HIV population (Pappas et carcinoma. Primary skin disease from direct a1. 1993). inoculation consists of a nodule or ulcer often with regional lymphadenopathy, which resolves spontaneously. Osteolytic lesions of vertebrae, D. Diagnosis ribs, or long bones are the most common manife­ stations of bone involvement. Lesions are usually Characteristic large thick-walled yeast forms with painless and may present when infection spreads broad-based buds can be seen on wet mounts, causing soft-tissue abscesses and draining sinuses cytology or histology slides. Wet mounts with or arthritis. Vertebral disease often involves the 10% KOH can be prepared from sputum, bron­ intervertebral discs and may be associated with chial washings, aspirates, or sedimentated urine paraspinal, psoas, or epidural abscesses. The or cerebrospinal fluid (CSF). In tissue slides GMS prostate and less often epididymis are the most is excellent for screening due to strong staining of common sites of genitourinary disease. Diagnosis the cell wall, while PAS sections better preserve can be made by examination and culture of urine the morphological details. Variation in morphol­ or secretions obtained after prostatic massage. ogy can cause confusion. Both small forms 2-4,um Urogenital disease in women is less common. A in diameter (resembling H. capsulaturn) , and few sexually transmitted cases have been reported. large forms up to 40,um can occur, although Dimorphic Fungal Infections 137 usually in the presence of more typical yeasts. survival of five of ten patients with ARDS who In these cases, especially if cultures were not received 0.7-1 mg/kg/day of amphotericin B. obtained, direct immunofluorescence may be very Until the introduction of azoles, amphotericin B helpful in confirming the diagnosis. Cultures grow was also the standard treatment for patients with optimally at 30°C and should be held for 4 weeks. less severe disease. Parker et al. (1969) found that The identity of mycelial colonies can be confirmed total doses of less than 1.5 g were associated with by conversion to the yeast form. Goodman (1992) a higher rate of relapse, so that at least 2 g is reports that this can be achieved rapidly by using usually given. Middlebrook's 7HlO medium. Alternatively, the Two trials of ketoconazole have shown this to exoantigen or DNA probe tests can be used. The be a less toxic, oral alternative to amphotericin B latter does not require a mature colony and so can for all but the severest cases. In a Mycoses Study give more rapid results, although recently cross­ Group trial, 89% of 80 patients were cured who hybridization with P. brasiliensis has been reported received 400 or 800 mg/day for 6 months (National (Padhye et al. 1994). Institute of Allergy and Infectious Diseases Skin testing is not used in diagnosis. Serolo­ Mycoses Study Group 1985). Bradsher et al. gical tests have also previously lacked both sensi­ (1985) reported cures in 35 of 44 patients with tivity and specificity. Recently, tests based on the 400mg/day. Relapse was associated with poor A antigen described by Kaufman have shown compliance with the protocol. Ketoconazole does more promise. The enzyme immunoassay (EIA) not cross the blood-brain barrier and is not re­ is most sensitive, but immunodiffusion (ID) is commended for CNS disease; cases have been more specific. In the Eagle River outbreak, sen­ reported of the development of CNS disease sitivities for EIA and ID techniques were 77 and during ketoconazole therapy. Itraconazole seems 28%, respectively (Klein et al. 1987). The ID test to be at least as effective as ketoconazole but with may be more sensitive in chronic and extrapul­ fewer side effects. In a Mycoses Study Group monary disease. Antibodies were detected by trial, 43 of 48 patients were cured (Dismukes et EIA from 2 weeks after onset. The maximum al. 1992). Most received 200 mg/day. In this trial, seroprevalence and peak titers occurred around only 1 of 85 patients treated with itraconazole for 60 days and declined rapidly after 115 days. At blastomycosis or histoplasmosis had therapy low titers, there may be some cross-reactivity stopped due to drug toxicity, involving progressive particularly to histoplasmosis. In the Klein et al. but reversible ankle edema. Bradsher (1992) study (1987), 8% of 89 controls had positive titers reported cure in 37 or 42 patients treated with of 1: 8 or 1: 16. The ID test, which appears to be 200 mg/day of itraconazole including some whose entirely specific, may have a role in confirming disease had progressed on ketoconazole. Limited low positive EIA titers. data with fluconazole have not been encouraging, so that itraconazole is emerging as the drug of choice for non-life-threatening disease outside the E. Treatment CNS. Itraconazole or ketoconazole can also be used in patients with severe disease who have had Some patients with acute blastomycosis may not an initial response to amphotericin B. require treatment. For example, only 9 of 26 symptomatic cases in the Eagle River outbreak received therapy; and in those who were not V. Paracoccidioidomycosis treated there were no instances of complications of reactivation. In those with acute disease confined to the lungs, who are already improving A. Mycology by the time the diagnosis is made, treatment can be withheld, although they should be carefully Like Coccicodioides immitis no sexual stage has followed up. At the opposite end of the clinical been detected for Paracoccidioides brasiliensis spectrum, amphotericin B is indicated for patients and the fungus is classified as a hyphomycete. The with life-threatening disease such as severe mycelial form is slow-growing. Hyphae are thin pneumonia with Acute Respiratory Distress and septate with simple septal pores and on most Syndrome (ARDS), miliary involvement, or CNS laboratory media do not co nidi ate well (Kwon­ disease. Meyer et al. (1993) recently reported Chung and Bennett 1992). A few intercalary 138 T.S. Harrison and S.M. Levitz chlamydoconidia may be seen. Under conditions hood and early adult life. As with clinical disease, of nutritional deprivation isolates co nidi ate more skin tests are more often positive in agricultural freely. Conidia may be formed directly on the workers and cattle farmers. sides of hyphae or on short conidiophores. The lack of any outbreaks or clusters of cases, Arthroconidia, which may bulge to one side, are the long latency of infection, and the tendency for also produced. At 37°C and in host tissues, yeast agricultural workers to migrate have made it dif­ forms (occasionally up to 60l1m in diameter) ficult to determine the precise circumstances in produce multiple narrow-necked buds giving the which infection is acquired. Recently, P. brasili­ characteristic "pilot wheel" appearance. Short ensis has been isolated from the organs of healthy chains of cells may be formed. Yeast colonies are armadillos, but no other instances of naturally cream-colored and wrinkled. Transformation into acquired infection in animals has been found to the yeast form in the laboratory is readily achieved try to help elucidate the ecology of the fungus. In at 37°C on BHI agar. the laboratory the mycelial form grows on soil and vegetation, especially in moist acid conditions, and can survive on very simple media even for a B. Epidemiology and Ecology period in distilled water. P. brasiliensis may be a soil saprophyte like C. immitis but it has been As with blastomycosis, the endemic area is based isolated from soil on only two occasions to date. on reported cases. Paracoccidioidomycosis is Some have suggested that aquatic animals or restricted to Latin America from Mexico to plants may be reservoirs or perhaps that water Argentina. Patients from other parts of the world may act as a vehicle to transport infectious pro­ have all lived in the endemic region, usually for a pagules (Restrepo 1985). A recent case control prolonged period, although they may present study in Columbia found water sources to be one years later. Most cases have been reported from of the factors associated with an increased risk of Brazil, followed by Columbia and Venezuela. a positive skin test (Cadavid and Restrepo 1993). Some countries are spared, notably the Carib­ Infection is presumed to result from inhalation bean, Chile, and Nicaragua. Within endemic of conidia. Person to person transmission has not areas, cases are concentrated in warm, moderately been documented. The lack of laboratory infec­ humid forested areas with plenty of water courses tions may reflect poor sporulation on artificial and acidic soils. Fewer cases are seen in drier media and the high inocula or immunocompro­ prairie regions or the very hot and humid Amazon mised condition usually required to produce basin. experimental infection. Para coccidioidomycosis most often affects adult males between 30 and 50 years from rural areas, from the poorer sectors of society engaged C. Clinical Manifestations in agricultural work. The average male to female ratio is around 13: 1, but skin testing suggests equal exposure of the sexes, and in prepubertal 1. Childhood Disease children there is no gender predominance. Adult females may be protected from disease by fJ­ Infection may be subclinical, as evidenced by skin estradiol, which in physiological concentrations testing or cases in which the diagnosis is incidental. has been shown to inhibit transformation of Symptomatic disease has been divided into a sub­ conidia into the yeast form. There is no clear acute juvenile form and chronic unifocal or multi­ racial predisposition although recent immigrants focal disease seen in adults. Childhood disease seem to have more severe disease. In Brazil, accounts for only 3-5% of cases and progresses HLA B40 was found in an increased proportion over weeks or months. Involvement of the reti­ of patients, while in Columbia, persons with HLA culoendothelial system (i.e., liver, spleen, nodes, A9 and B13 were at greater risk. Skin testing is and bone marrow) usually overshadows pulmonary not entirely sensitive or specific. There is some manifestations (Londero and Melo 1983). Biopsies crossreactivity, especially with histoplasmosis. show many organisms and poor granuloma for­ The percentage of positive reactors varies from mation. Depressed cell-mediated immunity and/ <5% in non endemic areas to 60% in rural areas or poor nutritional status contribute to a high of Rio de Janeiro. Rates increase through child- incidence of secondary infections. Dimorphic Fungal Infections 139

2. Adult Disease one study, sputum cytology after silver methena­ mine staining was more sensitive than wet mounts Adult disease is very indolent. In a recent review, and had the advantage of preserving the specimen Brummer et al. (1993) summarized organ involve­ for later review. The mycelium is not particularly ment in 3 series totalling over 350 patients. The distinctive, and identification is by transformation commonest sites were pulmonary (77%), mucosal into the yeast form or exoantigen test. (63%), lymph nodes (13%), and skin (12%). Serology may also help in diagnosis. CF anti­ About a quarter of cases are unifocal, usually bodies appear later and persist. Higher titers are with pulmonary disease. Pulmonary symptoms seen in disseminated disease and titers should fall include cough, sputum, shortness of breath, and with therapy. Tube precipitin tests are positive hemoptysis. Chest X-ray changes are often more earlier but are less sensitive. Most tests have used extensive than symptoms or signs would suggest, culture filtrates or extracts and have shown cross­ and include bilateral infiltrates with fibrosis and reactivity especially with histoplasmosis. Immu­ cavitation. The lower lung fields are more often nodiffusion (ID) with a yeast culture filtrate is affected. Papular or ulcerating lesions of the oral more specific and useful in monitoring therapy. In mucosa are extremely common. In the skin, a longitudinal study, titers by ID fell in 31 patients plaques, verrucous, or ulcerating lesions occur improving during sulfonamide therapy (Ferreira­ especially around the mouth and nose. Lympha­ da-Cruz et al. 1990). The only patient who denopathy most commonly affects cervical an.d relapsed had a fourfold rise in titer immediately submandibular nodes. As with the other systemIC prior to relapse. However, the test is not specific mycoses, almost any other organ may also be for active disease, as a quarter of patients who affected. In paracoccidioidomycosis, significant remained well still had reactive sera long after adrenal involvement is not uncommon. Del Negro completion of therapy. Much work is going on to et al. (1980) found that 10 of 23 patients had purify suitable antigens for serodiagnosis. A 43- subnormal responses to Adrenocorticotropin kDa glycoprotein isolated from the supernatant (ACTH) stimulation. Even after eradication of of yeast cultures has been found to be very specific the organism healing with fibrosis may lead to by immunodiffusion or immunoblotting. How­ chronic disabilities (e.g., cor pulmonale, micro­ ever, in an ELISA test, cross-reactions to the stomia or dysphonia). carbohydrate moiety occur with sera from patients with other mycoses (Puccia and Travassos 1991). 3. Paracoccidioidomycosis in HIV Infection A second 70-72-kDa antigen from yeast cultures detected on Western blots also appears specific. As yet, less than ten cases of paracoccidioido­ Tests to detect the 43-kDa antigen have recently mycosis in association with HIV infection have been developed (Mendes-Giannini et al. 1989). been reported despite the spread of HIV in the endemic area of Brazil around Rio de Janeiro and Sao Paulo. This may be partly explained by the E. Treatment fact that HIV occurs predominantly in urban centers while paracoccidioidomycosis is more Sulfonamides were the first effective therapy for common in rural areas. Most of the reported paracoccidioidomycosis. About 70% of patients cases have had multifocal involvement, especially respond to sulphadiazine (6 g/day) but up to one­ of the reticuloendothelial system, similar to the third relapse, and the drug needs to be given for juvenile pattern of disease. up to 5 years. Relapse may be due to resistance, and trimethoprim combined with sulphadiazine or sulphamethoxazole has been used. Levels of D. Diagnosis sulphadiazine are affected by acetylator status and renal function. In a small study of cotrimazine As with the other endemic mycoses, definitive (820mg sulphadiazine and 180mg trimethoprim) diagnosis is by identification of characteristic yeast given twice daily, 21 of 22 patients had adequate forms in clinical specimens or culture. The multiple levels of sulphadiazine. The one treatment failure peripheral buds of the yeast form are very char~c­ occurred in the patient with low levels. The teristic, although yeast forms of Mucor speCIes authors recommended assessment of acetylator occasionally may look similar (Cooper 1987). In status and drug levels (Barraviera et al. 1989). 140 T.S. Harrison and S.M. Levitz

Sulpha diazine penetrates the CSF well in rare B. Epidemiology and Ecology cases with CNS involvement. Amphotericin B is used for seriously ill Sporotrichosis occurs worldwide. While most cases patients. Because of frequent relapses, therapy is have been reported from the Americas, the largest continued with sulfonamide or azoles. Admin­ outbreak occurred in South Africa in gold miners istration and monitoring of amphotericin B is in the 1940s and recent large series have been difficult in some endemic areas. Excellent results reported from Japan. Many cases were diagnosed have been obtained with ketoconazole (Restrepo in France at the beginning of the century but it et al. 1985) and itraconazole (Naranjo et al. 1990); appears to have become less common in Europe. 200-400 mg/day ketoconazole or 100-200 mg/day In the United States there is an increased incidence itraconazole have given response rates of over in states bordering the Mississippi and Missouri 90%. Relapse rates have been around 10% for Rivers. ketoconazole and <5% for itraconazole, despite S. schenckii has been isolated from soil, the fact that shorter courses (around 6 mo rather vegetation, and animal excreta. The risk of cut­ than 12) have been used with itraconazole. With aneous disease is increased in those working out­ both drugs, lesions heal slowly over 3-6 months. doors, such as forestry workers, farmers, and Fluconazole also appears to be effective, although gardeners. Outbreaks of disease in the USA have fewer patients have been treated. Unfortunately, been linked to Sphagnum moss [an outbreak in the high cost of the azole drugs preclude their use 1988 involved 84 cases (Coles et al. 1992)], and in many patients. prairie hay. An outbreak in South Africa was caused by contaminated mine timbers. Rose thorns are a commonly associated with sporadic VI. Sporotrichosis cases. Infection can also occur at the site of insect stings and animal bites and scratches. Although sporotrichosis can affect a wide range of animals, A. Mycology infection in these cases probably usually results from contamination of the wound with soil. In Fresh isolates of Sporothrix schenckii at 25-30°C Uruguay, half of the 150 cases described by produce moist flat or wrinkled colonies which MacKinnon were associated with armadillo hunt­ turn from cream to dark brown after 10-14 days ing and were probably acquired in this way with the formation of dark-walled conidia (Kwon­ (MacKinnon et al. 1969). Armadillos need to be Chung and Bennett 1992). The septate hyphae dragged out of their burrows. The fungus was not often occur in strands. Thin-walled and dark thick­ isolated from any of the animals, but was found in walled oval or pyriform conidia are produced in a the dried grass of one of their nests. A number of bouquet at the tip of conidiophores or singly cases, however, have been acquired from infected along the sides of hyphae. Occasionally, secondary cats without any trauma at the site of infection conidia may be formed by budding. With subcul­ (Reed et al. 1993). Cutaneous lesions in cats have turing, the dark coloration is lost and short aerial been found to harbor very large numbers of hyphae are produced. At 37°C, white dry and organisms. In addition, of the few cases of labora­ wrinkled yeast colonies are produced. Most yeast tory-acquired infection that have been reported, forms have a characteristic "cigar shape". Kwon­ several have occurred without any evident skin Chung (1979) found that some isolates from fixed trauma (Cooper et al. 1992). skin lesions grew poorly above 35°C. The yeast In the more common cutaneous form, there is cells from these lesions are often larger and more no gender bias and all ages may be affected. globose. There are also several reports of disease Several series have found an increased incidence due to a variant form, S. schenckii var. luriei. in the cooler months of the year. Pulmonary, Cases have occurred in South Africa, Italy, and osteoarticular, and widely disseminated disease India. In tissue large 15-20 11m thick-walled yeasts affects predominantly men over 40 years of age which multiply by fission as well as budding are and is often associated with some form of host seen in addition to more typical forms. In the immunocompromise. These latter forms of disease mycelial phase the conidia are longer and thinner may be acquired by inhalation. The organism has and dark globose sclerotic bodies may be been cultured from the respiratory tract in the produced. absence of disease and isolated pulmonary disease Dimorphic Fungal Infections 141 is not infrequent, while documented cases of dis­ trichosis in assocIatIOn with HIV have been semination following cutaneous inoculation are reported. Most have had multiple skin lesions, very rare (Lynch et al. 1970). often with additional sites of involvement (Heller and Fuhrer 1991).

C. Clinical Manifestations D. Diagnosis 1. Cutaneous Sporotrichosis Identification of characteristic yeast forms in Cutaneous lesions begin as erythematous papules clinical material may be difficult due to low num­ and usually enlarge over a few weeks into a plaque bers of organisms (especially in primary skin or verrucous or ulcerated lesion. Secondary cut­ lesions and synovial fluid or biopsies) and aneous lesions often occur along the pathway of morphological variation. Characteristic asteroid lymphatic drainage. Alternatively, solitary or bodies formed of eosinophilic material surround­ fixed lesions may develop that remain unchanged ing a yeast cell are not very common: A DFA test for years. Lesions are usually not painful and not can help identify yeast cells but is not widely accompanied by systemic symptoms. Widespread available. As with the other fungi described skin lesions usually result from hematogenous above, inflammation is pyogranulomatous. Diag­ dissemination. nosis often depends on culture. The identity of suspect colonies can be confirmed by conversion to the yeast form on blood glucose cysteine agar 2. Systemic Sporotrichosis at 3rc. In meningitis, however, CSF cultures are often negative and serological tests can provide In a review of 51 patients with pulmonary disease, an earlier diagnosis, which may be vital for therapy most had isolated pulmonary involvement and to be successful. Scott et al. described 7 patients over half had some form of host impairment, in whom CSF and serum were positive by enzyme commonly in the form of alcohol abuse (Pluss and immunoassay with antigen from a yeast culture Opal 1986). Onset was insidious. Common filtrate (Scott et al. 1987). All cases were sub­ symptoms included cough, low-grade fever, sequently confirmed by culture. Among CSF malaise, and weight loss. Hemoptysis occurred in samples from 300 other patients, including 30 18%. The common X-ray abnormalities were with other fungal meningitides, only 2 were posi­ unilateral or less frequently bilateral upper lobe tive (at low titers of 1: 4). The role of serology in cavitary lesions, but parenchymal infiltrates, other forms of disease is less clear. Karlin and adenopathy, and pleural effusions were also Neilsen found the yeast and latex agglutination reported. Those with multifocal disease often had tests to be most sensitive (Karlin and Nielsen linear and nodular changes rather than cavitation. 1970). Titers were higher in extracutaneous The same group of patients appear susceptible to disease. In the 1988 outbreak associated with osteoarticular disease. In a review of 44 reported sphagnum moss the sensitivity and specificity of a cases by Bayer et al. (1979), alcoholism and slide agglutination test at a 1 : 4 titer was 54 and myeloproliferative syndromes were the most fre­ > 97% (Coles et al. 1992). Skin testing is not widely quent underlying disorders. The knee, wrist, used but is positive more often in cutaneous than hand, and elbow were affected most frequently extracutaneous disease. and half the patients had polyarticular involve­ ment. Again the disease was indolent. Most had radiographic changes on X-ray at presentation. In half the cases, infection either spread locally into E. Treatment skin and subcutaneous tissues, or disseminated. Tenosynovitis is also a recognized presentation. Primary cutaneous disease responds to oral potas­ Other rarer sites of involvement include the CNS, sium iodide. Unpleasant side effects are common eye, and genitourinary tract. Multifocal disease and include gastrointestinal disturbance, acnei­ usually involves skin, bone and joints, and less form rash, and parotid swelling. Drops are taken frequently the lungs. Systemic symptoms are three times daily and the dose is gradually incre­ more prominent. Only a few cases of sporo- ased as tolerated. Marked improvement is usually 142 T.S. Harrison and S.M. Levitz seen after 2-3 months Although inexpensive, the A. Mycology side effects and multiple dose adjustments can be problematic. Some patients have responded to P. marneffei is the only known thermally ketoconazole while lesions resolved in all 17 dimorphic Penicillium species. Within a few days, patients treated with itraconazole 100 mg/day for at 25°C, septate branched hyphae form colonies 90-180 days (Restrepo et a1. 1986). Local heat which turn from gray to blue-green (Deng et a1. treatment may also be beneficial in cutaneous 1988). A red pigment is produced which diffuses disease (Hi rum a et a1. 1992). into the medium. Lateral and terminal conidio­ In a review of pulmonary disease, surgery, phores bear 3-5 metulae, each with 4-7 phialides especially when complete resection was possible, giving rise to chains of oval conidia. At 37°C, oval gave the best results. Peri operative medical yeast cells are formed which multiply by fission. therapy was also usually given. Failures were frequent, however, with amphotericin B alone especially in those with isolated cavitary disease. B. Epidemiology and Ecology Bayer et a1. (1979) found that systemic ampho­ tericin B with or without surgery was effective in Infection due to P. marneffei has been reported in 83% of patients with articular disease. Localized Guangxi in southern China, Hong Kong, and amphotericin B has also been used. Results with Thailand, and in persons who have visited ketoconazole have been mixed. At best, Calhoun Southeastern Asia. Reference has been made to et a1. (1991) reported responses in 8 of 12 patients one African patient, who apparently developed with joint or soft tissue disease who had pro­ infection without having ever visited Asia longed treatment, usually more than 1 year, with (Himarsdottir et a1. 1993). The fungus has been 400-800 mg/day. Ketoconazole has generally isolated from the internal organs of over 90% of been ineffective in pulmonary disease. In a bamboo rats examined in Guangxi; and from soil Mycosis Study Group trial, 11 of 15 patients with from around their burrows (Deng et a1. 1988). No osseous or articular disease responded to itracon­ gross pathological lesions were seen in any of the azole 100-600 mg/day, although 4 who received rats. Because people have limited contact with treatment for 6 months or less later relapsed these animals, a common, as yet unidentified, (Sharkey-Mathis et a1. 1993a). Only one of three environmental source for infections in man and patients with pulmonary disease had a satisfactory rats may exist. Of the non-HIV-infected patients, response. Amphotericin B has cured some cases some have been immunocompromised (most of meningitis when therapy has been started early. commonly secondary to steroid therapy) but most Most cases in association with HIV have been had no underlying disease (Deng et a1. 1988). In treated with amphotericin B with some response. HIV-infected patients, penicilliosis was often rapidly followed by AIDS-defining opportunistic infections, and CD4 counts when available were low (Supparatpinyo et a1. 1992). One HIV­ VII. Infections Caused by Penicillium infected patient developed disease 11 years after marneffei visiting China, suggesting reactivation of infection (Jones and See 1992). In both HIV-infected P. marneffei was first isolated from a bamboo rat and uninfected patients, adult males have in 1959 by Segretain, who also inadvertently predominated. pricked his finger with a contaminated needle and developed a nodular lesion and regional lympha­ denopathy. Naturally acquired human infections, C. Clinical Manifestations all originating from Southeast Asia, have been reported since 1973. A larger number of cases in Infection usually involves fever, weight loss, recent years have been associated with HIV anemia, and evidence of disseminated infection. infection. Lymphadenopathy and hepatosplenomegaly, and cough with abnormalities on chest X-ray are common. Lung abscesses may occur but in HI V­ infected patients, focal and diffuse reticulonodular infiltrates are more often seen. Skin lesions and, Dimorphic Fungal Infections 143 in immunocompetent patients, subcutaneous The tissue form of growth of Coccidiodes abscesses are frequent. In HIV-infected patients, immitis, the cause of coccidioidomycosis, is an lesions often resemble molluscum contagiosum endospore-filled spherule, while in nature the and oral and genital ulceration can occur. Other fungus grows as a mycelium comprised of hyphae manifestations include osteolytic bone lesions, that form arthroconidia. The arthroconidia are arthritis, pericardial, intestinal, and renal the infectious elements of the mold. involvement. Histoplasma capsulatum var. capsulatum, the cause of the most commonly encountered form of histoplasmosis, is a facultative intracellular D. Diagnosis parasite of mononuclear phagocytes, where it occurs as a budding yeast. In nature, the fungus P. marneffei is most often cultured from blood, grows as a mycelium composed of hyphae upon bone marrow, and skin lesions. In immunocom­ which two sizes of conidia are produced: micro­ petent hosts, granulomas and suppuration are conidia (the infectious elements of the pathogen) seen. Histiocytes are filled with oval yeast cells. and macroconidia upon whose morphology iden­ Extracellular organisms, more numerous in HIV­ tification of the mold largely rests. infected patients, tend to be longer and sausage­ The causative agent of blastomycosis, shaped with a prominent central septum. Rapid Blastomyces dermatitidis, occurs in the tissues as a diagnosis can be made by Wright's stain of a large yeast cell with a single bud and a very thick marrow aspirate or of specimens from skin lesions. cell wall. The saprobic form in nature is a mycelium Organisms have also been identified in a periph­ comprised of hyphae that produce smooth-walled eral blood smear and in bronchial lavage. Skin or lateral conidia which are the infectious elements serological tests are not available. of the fungus. Multiple-budded yeast cells comprise the tissue phase of Paracoccidiodes brasiliensis, the E. Treatment cause of paracoccidioidomycosis. In nature, the saprobic form consists of a mycelium composed of Without treatment, this form of disease seems to hyphae which form athroconidia and a lateral be progressive and fatal. However, most patients holoblastic form of conidia. Both conidial forms, have responded well to therapy. Response rates blastic and thallic, are potential infectious ele­ with amphotericin Band itraconazole were 77 ments of the fungus. and 75%, respectively, in a recent series of 68 The parasitic form of growth of Sporothrix treated patients from Thailand (Supparatpinyo et schenckii is often difficult to detect in the tissues al. 1993). Only 36% responded to fluconazole. In of an infected host but in disseminated forms of vitro susceptibility data on 30 isolates showed disease the fungus occurs as polymorphic budding itraconazole had the lowest mean MIC of 0.009 yeast cells. The hyphae that comprise the mycelium Jig/ml compared to 7.9 Jig/ml for fluconazole. form conidia arranged in a typical fashion on the Frequent relapses suggest maintenance azole conidiophore. therapy is necessary in HIV-infected patients. Pencillium marneffei occurs in the tissues of an infected host as intracellular yeast cells which reproduce by fission (arthroconidia) rather than VIII. Conclusions budding. The saprobic form of growth is typical for a member of the genus Pencillium. Coccicioidomycosis is essentially a New World Most mycoses discussed in this chapter are usually disease, being found endemically only in North, acquired by inhalation of infectious conidia pro­ Central, and South America. Histoplasmosis duced by saprobic fungi. While pulmonary (common form) is worldwide in distribution but sporotrichosis does occur, the disease is most with a remarkably notable. occurrence in the often a cutaneous affliction acquired by direct United States. The duboisii variety of Histoplasma implantation of infectious conidia of the mold. capsulatum occurs mainly in Africa. The endemic Although rare exceptions are known, the diseases area of occurrence of blastomycosis overlaps that caused by these fungi are not contagious. All of of histoplasmosis in the United States. Paracoc­ the pathogens described are dimorphic. cidioides brasiliensis is found in Central and South 144 T.S. Harrison and S.M. Levitz

America. Sporotrichosis is worldwide in distri­ Brummer E, Castaneda E, Restrepo A (1993) Paracocci­ bution. Sporothrix schenckii occurs on decaying dioidomycosis: an update. Clin Microbiol Rev 6:89-117 Cadavid D, Restrepo A (1993) Factors associated with vegetation or in soil and usually afflicts farmers, Paracoccidioides brasiliensis infection among permanent nurserymen, gardeners, and florists. All the cases residents of three endemic areas in Columbia. Epide­ of Penicillium marneffei infection seem to have miol Infect 111:121-133 originated in eastern and southeastern Asia. Calhoun DL, Was kin H, White MP, Bonner JR, Mulholland JH, Rumans LW, Stevens DA, Galgiani IN Recovery from mycoses caused by dimorphic (1991) Treatment of systemic sporotrichosis with keto­ fungi and the basis of the consequent acquired conazole. Rev Infet Dis 13:47-51 resistance to those infections involves cell­ Cock shott WP, Lucas AO (1964) Histoplasmosis duboisii. mediated immunity. Useful serologic procedures Q J Med N S XXXIII 130:223-241 Cohen 1M, Galgiani IN, Potter D, Ogden DA (1982) are available to assist in the diagnosis of coccidio­ Coccidioidomycosis in renal replacement therapy. Arch idomycosis, histoplasmosis, blastomycosis, and Intern Med 142:489-494 paracoccidioidomycosis. Although serologic Cohen PR, Bank DE, Silvers DN, Grossman ME (1990) adjuncts are also available in sporotrichosis, they Cutaneous lesions of disseminated histoplasmosis in human immunodeficiency virus-infected patients. J Am are not often used. Such tests have not been Acad Dermatol 23:422-428 developed for Penicillium marneffei infections. Coles FB, Schuch at A, Hibbs JR, Kondracki SF, Salkin IF, Dixon DM, Chang HG, Duncan RA, Hurd NJ, Morse DL (1992) A multistate outbreak of sporotricho­ sis associated with sphagnum moss. Am J Epidemiol References 136:475-487 Cooper BH (1987) A case of pseudoparacoccidioidomyco­ sis: detection of the yeast phase of Mucor circinelloides Ampel MN, Wieden MA (1988) Discrepancy between in a clinical specimen. Mycopathologia 97:189-193 growth of Coccidioides immitis in bacterial blood culture Cooper CR, Dixon DM, Salkin IF (1992) Laboratory­ media and a radiometric growht index. Diagn Microbiol acquired sporotrichosis. J Med Vet Mycol 30: 169-171 Infect Dis 9:7-10 DeFelice R, Wi eden MA, Galgiani IN (1982) The incid­ Ampel MN, Dols CL, Galgiani IN (1993) Coccidioidomy­ ence and implications of coccidioidouria. Am Rev cosis during human immunodeficiency virus infection: Respir Dis 125:49-52 results of a prospective study in a coccidioidal endemic Del Negro G, Melo EHL, Rodbard D, Melo MR, Layton area. Am J Med 94:235-240 L, Wachslicht-Rodbard H (1980) Limited adrenal Baily GG, Robertson VJ, Neill P, Garrido P, Levy LF reserve in paracoccidioidomycosis: cortisol and aldo­ (1991) Blastomycosis in Africa: clinical features, diag­ sterone responses to 1-24 ACTH. Clin Endocrinol 13: nosis, and treatment. Rev Infect Dis 13: 1005-1008 553-559 Barraviera B, Pereira PCM, Mendes RP, Machado JM, Deng Z, Ribas JL, Gibson DW, Connor DH (1988) Infec­ Lima CRG, Meira DA (1989) Evaluation of acetylator tions caused by Penicillium marneffei in China and phenotype, renal function and serum sulfadiazine levels Southeast Asia: review of eighteen published cases and in patients with paracoccidioidomycosis treated with report of four more Chinese cases. Rev Infect Dis cotrimazine (a combination of sulfadiazine and trime­ 10:640-652 thoprim). Mycopathologia 108:107-112 Denton JF, McDonough ES, Ajello L, Ausherman RJ Baumgardner DJ, Buggy BP, Mattson BJ, Burdick J, (1961) Isolation of Blastomyces dermatitidis from soil. Ludwig D (1992) Epidemiology of blastomycosis in a Science 133:1126-1127 region of high endemicity in north central Wisconsin. Dismukes WE, Bradsher RW Jr, Cloud GC, Kauffman Clin Infect Dis 15:629-635 CA, Chapman SW, George RB, Stevens DA, Girard Bayer AS, Scott VJ, Guze LB (1979) Fungal arthritis. III. WM, Saag MS, Bowles-Patton C, NIAID Mycoses sporotrichal arthritis. Semin Arthritis Rheum 9:66-74 Study Group (1992) Itraconazole therapy for blasto­ Blastomycosis Cooperative Study of the Veterans Ad­ mycosis and histoplasmosis. Am J Med 93:489-497 ministration (1964) Blastomycosis. I. A review of 198 Drutz DJ, Catanzaro A (1978) Coccidioidomycosis: Part I. collected cases in veterans administration hospitals. Am Am Rev Respir Dis 117:559-585 Rev Respir Dis 889:659-672 Einstein HE, Johnson RH (1993) Coccidioidomycosis: Bouza E, Dreyer JS, Hewitt WL, Meyer RD (1981) Cocci­ new aspects of epidemiology and therapy. Clin Infect dioidal meningitis: an analysis of thirty-one cases and Dis 16:349-356 review of the literature. Medicine 60: 139-172 Ferreira-da-Cruz MF, Francesconi-do-Vale AC, Espinera Bradsher RW (1992) Blastomycosis. Clin Infect Dis 14: MCD, Wanke B, Galvao-Castro B (1990) Study of anti­ S82-S90 bodies in paracoccidioidomycosis: follow-up of patients Bradsher RW, Rice DC, Abernathy RS (1985) Ketocona­ during and after treatment. J Med Vet Mycol 28: zole therapy for endemic blastomycosis. Ann Intern 151-157 Med 103:872-879 Fish DG, Ampel NM, Galgiani IN, Dols CL, Kelly PC, Broc R, Haddad N (1952) Tumeur bronchique a Scopulari­ Johnson CH, Pappagianis D, Edwards JE, Wasserman opsis americana determination prococe d'une mala die de RB, Clark RJ, Antoniskis D, Larsen RA, Englender SJ, Gilchrist. Bull Mem Soc Med Hop (Paris) 68:679-682 Petersen EA (1990) Coccidioidomycosis during human Brown LR, Swensen SJ, Van Scoy RE, Prakash UBS, immunodeficiency virus infection. Medicine 69:384-391 Coles DT, Colby TV (1991) Roentgenologic features of Flynn NM, Hoeprich PD, Kawachi MM, Lee KK, pulmonary blastomycosis. Mayo Clin Proc 66:29-38 Lawrence RM, Goldstein E, Jordan GW, Kundargi RS, Dimorphic Fungal Infections 145

Wong GA (1979) An unusual outbreak of windborne Serological tests for blastomycosis: assessments during a coccidioidomycosis. N Engl J Med 301:358-361 large point-source outbreak in Wisconsin. J Infect Dis Forseth J, Rohwedder JJ, Levine BE, Saubolle MA (1986) 155:262-268 Experience with needle biopsy for coccidioidal lung Kravitz GR, Davies SF, Eckman MR, Sarosi GA (1981) nodules. Arch Intern Med 146:319-320 Chronic blastomycotic meningitis. Am J Med 71: Galgiani IN (1983) Ketoconazole in the treatment of cocci­ 501-505 dioidomycosis. Drugs 26:355-363 Kwon-Chung KJ (1979) Comparison of isolates of Sporo­ Galgiani IN (1993) Coccidioidomycosis. West J Med 159: thrix schenckii obtained from fixed cutaneous lesions 153-171 with isolates from other types of lesions. J Infect Dis Galgiani IN, Catanzaro A, Cloud GA, Higgs J, Friedman 139:424-431 BA, Larsen RA, Graybill JR, The NIAID-Mycoses Kwon-Chung KJ, Bennett JE (1992) Medical mycology. Study Group (1993) Fluconazole therapy for coccidioidal Lea and Febiger, Philadelphia meningitis. Ann Intern Med 119:28-35 Labadie EL, Hamilton RH (1986) Survival improvement Gilchrist TC (1894) Protozoan dermatitidis. J Cutan Geni­ in coccidioidal meningitis by high-dose intrathecal tourin Dis 12:496 amphotericin B. Arch Intern Med 146:2013-2018 Goodman NL (1992) Diagnosis of blastomycosis. In: Al­ Larsen RA, Jacobson JA, Morris AH, Benowitz BA Doory Y, DiSalvo AF (eds) Blastomycosis. Plenum (1985) Acute respiratory failure caused by primary pul­ Press, New York monary coccidioidomycosis: two case reports and a re­ Goodwin RA, Loyd JE, Des Prez RM (1981) Histoplas­ view of the literature. Am Rev Respir Dis 131:797-799 mosis in normal hosts. Medicine 60:231-266 Londero AT, Melo IS (1983) Paracoccidioidomycosis in Goodwin RA Jr, Owens FT, Snell JD, Hubbard WW, childhood. A critical review. Mycopathologia 82:49-55 Buchanan RD, Terry RT, Des Prez RM (1976) Chronic Lowry PW, Kelso KY, McFarland LM (1989) Blastomyco­ pulmonary histoplasmosis. Medicine 55:413-452 sis in Washington Parish, Louisiana, 1976-1985. Am J Goodwin RA Jr, Shapiro JL, Thurman GH, Thurman Epidemiol 130: 151-159 SS, Des Pres RM (1980) Disseminated histoplasmosis: Lynch PJ, Voorhees JJ, Harrell ER (1970) Systemic sporo­ clinical and pathologic correlations. Medicine 59:1-33 trichosis. Ann Intern Med 73:23-30 Graybill JR, Stevens DA, Galgiani IN, Dismukes WE, MacKinnon JE, Conti-Diaz lA, Gezuele E, Civila E, Da Cloud GA, The NAIAD Mycoses Study Group (1990) Luz S (1969) Isolation of Sporothrix schenckii from Itraconazole treatment of coccidioidomycosis. Am J nature and considerations on its pathogenicity and Med 89:282-290 ecology. Sabouraudia 7:38-45 Hall KA, Copeland JG, Zukoski CF, Sethi GK, Galgiani McDonough ES, Lewis AL (1967) Blastomyces dermati­ IN (1993) Markers of coccidioidomycosis before cardiac tidis: production of the sexual stage. Science 156: or renal transplantation and the risk of recurrent infec­ 528-529 tion. Transplantation 55:1422-1442 Mendes-Giannini MJS, Bueno JP, Shikanai-Yasuda MA, Heller HM, Fuhrer J (1991) Disseminated sporotrichosis Ferreira A W, Masuda A (1989) Detection of the 43000- in patients with AIDS: case report and review of the molecular-weight glycoprotein in sera of patients with literature. AIDS 5:1243-1246 paracoccidioidomycosis. J Clin MicrobioI27:2842-2845 Himarsdottir I, Meynard JL, Rogeaux 0, Guermonprez Meyer KC, McManus EJ, Maki DG (1993) Overwhelming G, Datry A, Katlama C, Brucker G, Coutellier A, pulmonary blastomycosis associated with the adult Danis M, Gentilini M (1993) Disseminated Penicillium respiratory distress syndrome. N Engl J Med 329: marneffei infection associated with human immunode­ 1231-1236 ficiency virus: a report of two cases and review of 35 Naranjo MS, Trujillo M, Munera MI, Restrepo P, Gomez published cases. J Acquire Immune Defic Syndr 6: I, Restrepo A (1990) Treatment of paracoccidioido­ 466-471 mycosis with itraconazole. J Med Vet Mycol 28:67-76 Hiruma M, Kawada A, Noguchi H, Ishibashi A, Conti­ National Institute of Allergy and Infectious Diseases Diaz IA (1992) Hyperthermic treatment of sporotri­ Mycoses Study Group (1985) Treatment of blastomyco­ chosis: experimental use of infrared and far infrared sis and histoplasmosis with ketoconazole. Results of a rays. Mycoses 35:293-299 prospective randomized clinical trial. Ann Intern Med Hyde L (1968) Coccidioidal pulmonary cavitation. Dis 103:861-872 Chest 54:273-277 Padhye AA, Smith G, Standard PG, McLaughlin D, Jones PD, See J (1992) Penicillium marneffei infection in Kaufman L (1994) Comparative evaluation of chemilu­ patients infected with human immunodeficiency virus: minescent DNA probe assays and exoantigen tests for late presentation in an area of nonendemicity. Clin rapid identification of Blastomyces dermatitidis and Infect Dis 15:744 Coccidioides immitis. J Clin Microbiol 32:867-870 Karlin JV, Nielsen HS Jr (1970) Serologic aspects of Pappagianis D, The Valley Fever Vaccine Study Group sporotrichosis. J Infect Dis 121:316-327 (1993) Evaluation of the protective efficacy of the killed Kerrick SS, Lundergan LL, Galgiani IN (1985) Coccidioi­ Coccidioides immitis spherule vaccine in humans. Am domycosis at a university health service. Am Rev Respir Rev Respir Dis 148:656-660 Dis 131: 100-102 Pappagianis D, Zimmer BL (1990) Serology of coccidio­ Klein BS, Vergeront JM, Weeks RJ, Kumar UN, Mathai idomycosis. Clin Microbiol Rev 3:247-268 G, Varkey B, Kaufman L, Bradsher RW, Stoebig JF, Pappas PG, Pottage JC, Powderly WG, Fraser VJ, Stratton Davis JP, The Investigation Team (1986) Isolation of CW, McKenzie S, Tapper ML, Chmel H, Bonebrake Blastomyces dermatitidis in soil associated with a large FC, Blum R, Shafer RW, King C, Dismukes WE (1992) outbreak of blastomycosis in Wisconsin. N Engl J Med Blastomycosis in patients with the acquired immuno­ 314:529-534 deficiency syndrome. Ann Intern Med 116:847-853 Klein BS, Vergeront JM, Kaufman L, Bradsher RW, Pappas PG, Threlkeld MG, Bedsole GD, Cleveland KO, Kumar UN, Mathai G, Varkey B, Davis JP (1987) Gelfand MS, Dismukes WE (1993) Blastomycosis in 146 T.S. Harrison and S.M. Levitz

immunocompromised patients. Medicine 72:311- marneffei infection in patients infected with human 325 immunodeficiency virus. Clin Infect Dis 14:871-874 Parker JD, Doto IL, Tosh FE (1969) A decade of experi­ Supparatpinyo K, Nelson KE, Merz WG, Breslin BJ, ence with blastomycosis and its treatment with Cooper CR, Kamwan C, Sirisant T (1993) Response to Amphotericin B. Am Rev Respir Dis 99:895-902 antifungal therapy by human immunodeficiency virus­ Picardi JL, Kauffman CA, Schwarz J, Holmes JC, Phair infected patients with disseminated Penicillium marneffei JP, Fowler NO (1976) Pericarditis caused by Histoplasma infections and in vitro susceptibilities of isolates from capsulatum. Am J Cardiol 37:82-88 clinical specimens. Antimicrob Agents Chemother 37: Pluss JL, Opal SM (1986) Pulmonary sporotrichosis: 2407-2411 review of treatment and outcome. Medicine 65:143-153 Swartz J, Baum GL (1951) Blastomycosis. Am J Clin Puccia R, Travassos LR (1991) 43-Kilodalton glycoprotein Pathol 21 :999-1029 from Para coccidioides brasiliensis: immunochemical Tucker RM, Denning DW, Dupont B, Stevens DA (1990) reactions with sera from patients with paracoccidioido­ Itraconazole therapy for chronic coccidioidal meningitis. mycosis, histoplasmosis, or Jorge Lobo's disease. J Clin Ann Intern Med 112:108-112 Microbiol 29: 1610-1615 Urschel HC Jr, Razzuk MA, Netto GJ, Disiere J, Chung Raab SS, Silverman JF, Zimmerman KG (1993) Fine­ SY (1990) Sclerosing mediastinitis: improved manage­ needle aspiration biopsy of pulmonary coccidioido­ ment with histoplasmosis titer and ketoconazole. Ann mycosis: spectrum of cytologic findings in 73 patients. Thorac Surg 50:215-221 Am J Clin Pathol 99:582-587 Wheat J, Hafner R, Wulfsohn M, Spencer P, Squires K, Ragland AS, Arsura E, Ismail Y, Johnson R (1993) Powderly W, Wong B, Rinaldi M, Saag M, Hamill R, Eosinophilic pleocytosis in coccidioidal meningitis: Murphy R, Connolly-Springfield P, Briggs N, Owens S, frequency and significance. Am J Med 95:254-257 National Institute of Allergy and Infectious Disease Reed KD, Moore FM, Geiger GE, Stemper ME (1993) Clinical Trials and Mycoses Study Group Collaborators Zoonotic transmission of sporotrichosis: case report and (1993) Prevention of relapse of histoplasmosis with review. Clin Infect Dis 16:384-387 itraconazole in patients with acquired immunodeficiency Restrepo A (1985) The ecology of Paracoccidioides brasi­ syndrome. Ann Intern Med 118:61-616 liensis: a puzzle still unsolved. Sabouraudia: J Med Vet Walker JW, Montgomery FH (1902) Further report of a Mycol 23:323-334 previously recorded case of blastomycosis of the skin: Restrepo A, Gomez I, Cano LE, Arango MD, Gutierrez, systemic infection with blastomycoses. Death, autopsy. Sanin As, Robledo MA (1985) Treatment of paracoc­ JAMA 38:867-871 cidioidomycosis with ketoconazole: a 3-year experience. Wheat LJ, Slama TG, Eitzen HE, Kohler RB, French Am J Med 78:48-52 MLV, Biesecker JL (1981) A large urban outbreak of Restrepo A, Robledo J, Gomez I, Tabares AM, Gutierrez histoplasmosis: clinical features. Ann Intern Med 94: R (1986) Itraconazole therapy in lymphangitic and 331-337 cutaneous sporotrichosis. Arch Dermatol 122:413- Wheat LJ, Connolly-Stringfield P, Kohler RB, Frame PT, 417 Gupta MR (1989) Histoplasma capsulatum polysac­ Sathapatayavongs B, Batteiger BE, Wheat J, Slama TG, charide antigen detection in diagnosis and management Wass JL (1983) Clinical and laboratory features of dis­ of disseminated histoplasmosis in patients with acquired seminated histoplasmosis during two large urban out­ immunodeficiency syndrome. Am J Med 87:396-400 breaks. Medicine 62:263-270 Wheat LJ, Batteiger BE, Sathapatayavongs B (1990a) Scott EN, Kaufman L, Brown AC, Muchmore HG (1987) Histoplasma capsulatum infections of the central nervous Serologic studies in the diagnosis and management of system. A clinical review. Medicine 69:244-260 meningitis due to Sporothrix schenckii. N Engl J Med Wheat LJ, Connolly-Stringfield P A, Baker RL, Curfman 317:935-940 MF, Eads ME, Israel KS, Norris SA, Webb DH, Zeckel Sharkey-Mathis PK, Kauffman CA, Graybill JR, Stevens ML (1990b) Disseminated histoplasmosis in the acquired DA, Hosteller JS, Cloud D, Dimukes WE (1993a) immune deficiency syndrome: clinical findings, diagnosis Treatment of sporotrichosis with itraconazole. NIAID and treatment, and review of the literature. Medicine Mycoses Study Group. Am J Med 95:279-285 69:361-374 Sharkey-Mathis P, Velez J, Fetchick R, Graybill JR Wheat LJ, Connolly-Stringfield P, Blair R, Connolly K, (1993b) Histoplasmosis in the acquired immunodefi­ Garringer T, Katz BP (1991) Histoplasmosis relapse in ciency syndrome (AIDS): treatment with itraconazole patients with AIDS: detection using Histoplasma and fluconazole. J Acquire Immune Defic Syndr 6:809- capsulatum variety capsulatum antigen levels. Ann Intern 819 Med 115:936-941 Smith CE, Beard RR, Whiting MEG, Rosenberger MHG Williams PL, Johnson R, Pappagianis D, Einstein H, (1946) Varieties of coccidioidal infection in relation to Slager U, Koster FT, Eron JJ, Morrison J, Aguet J, the epidemiology and control of the diseases. Am J River ME (1992) Vasculitic and encephalitic complica­ Public Health 36: 1394-1402 tions associated with Coccidioides immitis infection of Spitzer ED, Lasker BA, Travis SJ, Kobyashi GS, Medoff the central nervous sytem in humans: report of 10 cases G (1989) Use of mitochondrial and ribosomal DNA and review. Clin Infect Dis 14:673-682 polymorphisms to classify clinical and soil isolates of Wrobel CJ, Alksne JF (1992) Retromastoid cisternal Histoplasma capsulatum. Infect Immun 57:1409-1412 Ommaya reservoir for intrathecal therapy of coccidio­ Supparatpinyo K, Chiewchanvit S, Hirunsri P, Utham­ idomycosis meningitis: technical note. J Neurosurg 77: machai C, Nelson KE, Sirisanthana T (1992) Penicillium 476-477