Opportunistic fungal infections in immunocompromised hosts

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Continuing medical education Opportunistic fungal infections in immunocompromised hosts William H. Radentz, MAJ, MC, USA Fort Sam Houston, Texas Fungal infections in immunocompromisedhosts cause major morbidity and mortality. The Candida and Aspergillus species are the most common causes, but many rarer organisms, once considered "contaminants," are being reported. The number of patients who receive immunosuppressive agents for the treatment of malignancy or for organ transplantation is increasing as well as the potential for local or disseminated fungal infections. The diagnosis of these infections is often difficult and the existing methods for treatment are often ineffective. A high degree of suspicion to identify fungal infections and to prompt initiation of treatment must be maintained if the survivalrate of these patients is expected to improve. (J AM ACAD DERMATOL 1989;20:989-1003.)

Fungal infections are a significant cause of death among immunocompromised patients and accounted for 21% of the fatal infections in a group of patients with leukemia. 1 The mortality rate associated with disseminated fungal infections can be attributed to the underlying dysfunction of the patient's immune system, delay in diagnosis, failure to initiate treatment, or ineffective antifungal therapy. The onset of fungal infections is usually between 1 and 6 months after irnmunosuppression.2 The most common opportunistic fungal infections are caused by the Candida and Aspergillus species,3-6but rarer organisms, previously considered to be "contaminants" or saprophytes, are becoming increasingly pathogenic and even fatal in immunocompromised patients. The skin may be involved as a result of primary inoculation or by seeding of the skin from a systemic infection. If caused by a systemic infection, From the Dermatology Service, Department of Medicine, Brooke Army Medical Center. The opinions or assertions herein are the private views of the author and are not to be construed as reflecting the views of the Department of the Army or the Department of Defense. Reprint requests: William H. Radentz, MD, Dermatology Service, Department of Medicine, Madigan Army Medical Center, Fort Lewis, WA 98431.

the cutaneous lesions may be the initial sign of the underlying infection and may provide a convenient source of tissue for diagnosis. The purpose of this article is to review opportunistic fungal infections in immunocompromised hosts. The taxonomy and terminology of fungal infections can be confusing, partly because of the frequently changing names of organisms and because of the lack of a simple method to classify them. The categorization of fungi used in this article is based on the morphology of the organism (Table I). Yeasts are single-celled, round to oval organisms that multiply asexually by budding. The most common organisms that infect immunocompromised hosts are members of the Candida species. Other organisms include Cryptococcus, Torulopsis, Rhodotorula, Saccharornyces, Geotrichum, and Trichosporon species. Molds have hyphae that are elongated, tubular, branching structures with multiple nuclei. Asexual reproduction is accomplished by spore production or by fragmentation of hyphae. The determination of whether these hyphae have cross walls or not is the first step in their classifications. Aseptate hyphae lack cross walls and include organisms in the Zygomycetes class. Older terms used 989

Journal of the American Academy of Dermatology

990 Radentz Table I. Categorization of fungi on the basis of

morphology 1. Yeasts 2. Molds A. Aseptate B. Septate 1. Dematiaeeous 2. Hyaline

a. Aspergillus and the hyalohyphornycosis organisms b. Dermatophytes c. Dimorphicfungi

for infections with such organisms include mucormycosis and phycomycosis. Zygomycosis encompasses infections caused by Rhizopus and Mucor species most commonly but also includes Syn-

cephalastrum, Circinella, Cunninghamella, Absidia, Saksenaea, and Basidiobolus. Septate hyphae are found in a broad range of fungi that have hyphae with cross walls. This group is further categorized by the coloration of the hyphae in tissue: either brown, (also referred to as dematiaceous) or nonpigrnented, (referred to as hyaline). The dematiaceous organisms can be divided into two major groups: those that cause chromoblastomycosis and those that cause phaeohyphomycosis. The ehromoblastomycosis organisms have muriform cells or sclerotic bodies in tissue that are dark brown, thick-walled cells with cross walls in two directions but without budding. The organisms that cause chromoblastomycosis include Cladosporium

carrionii, Fonsecaeapedrosoi, Fonsecaea compacturn, Phialophora verrucosa, and Rhinocladiella aquaspersa.7 The phaeohyphomycosis organisms have brown, yeast-like cells, pseudohyphal-Iike illarnents, or hyphae that may be regular, distorted, or swollen in shape. 8 This diverse category includes Alternaria, Curvularia, Drechslera(now called Exserohilum), Cladosporium,Exophiala, Phoma, and Bipolaris genera. The hyaline fungi have nonpigmented hyphae in tissue and comprise a heterogeneous group that can be subdivided into three major categories: (1) Aspergillus and hyalohyphomycotic organisms, (2) dermatophytes, and (3) the dimorphic fungi. Hyalohyphomycosis includes infections caused by primarily opportunistic pathogens such as the Pseu-

dallescheria, Fusarium, Paecilomyces,Penicillium, Scopulariopsis, Acremonium, Chrysosporium, and

Sepedonium genera. The dermatophytes include organisms in the Microsporum, Trichophyton, and Epidermophyton genera. The dimorphic fungi demonstrate yeastlike structures in tissue when cultured at 37 ~ C but show hyphae when grown at 25 ~ C. These organisms are primary as well as opportunistic pathogens. Included in this group are Blastomy-

ces dermatitidis, Histoplasma capsulatum, Coccidioides immitis, Paracoccidioides brasiliensis, and Sporothrix schenckii. The most commonly used culture media for the detection and identification of fungal organisms are Sabouraud's dextrose agar and Mycosel. Sabouraud's agar will promote the growth of most fungi. Mycosel is merely Sabouraud's agar with the addition of cyclohexamide to inhibit the growth of saprophytic fungi (i.e., Aspergillus, zygomycosis) but Mycosel may also inhibit the growth of certain pathogenic fungi, such as Cryptococcus neoformans (use bird seed agar), Candida tropicalis (use cornmeal agar), Trichosporon beigelii, and the yeast forms of Blastornyces and Histoplasma (use brainheart infusion blood agar). In the evaluation of a fungal infection in an immunocompromised host, culture media without an antifungal agent should be used in addition to standard media to allow the growth of saprophytic fungi. Cultures should be observed for 4 to 6 weeks to identify slowly growing organisms. YEASTS

Candida species are the most common cause of systemic fungal infections in the immunocompromised patient.4-7 Common predisposing factors include neutropenia (most common), corticosteroid therapy, hyperglycemia, broad-spectrum antibiotic therapy, and intravenous catheters. The classic triad of fever, myalgias, and erythematous skin lesions in a patient with sepsis, who is not responding to antibiotic therapy, is highly suggestive of disseminated candidiasis. 9 In a review of 200 episodes of candidiasis occurring at the Sloan-Kettering Cancer Center, Candida albicans infection occurred most frequently, followed by C. tropicalis, C. parapsilosis, C glabrata (Torulopsis glabrata), and C krusei, in decreasing order. 1~ C. tropicalis and C. krusei tended to occur in neutropenic leukemia or lymphoma patients whereas C parapsilosis affected patients with intravenous hyperalimentation. C. tropicalis had the greatest proportion of disseminated infections that have skin lesions (23%) versus

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Opportunistic fungal infections in immunocompromised hosts 991

infections of C. albicans (3.4%) or C. parapsilosis (4.4%). The overall mortality rate associated with systemic candidal infections in immunocomproraised patients varies from 71.5% to 74% (with the exception of C. parapsilosis that has only a 30% mortality rate).1~ a1 Bodey and Luna 12 reported a 13% incidence of cutaneous involvement in disseminated candidiasis. The skin lesions are discrete, firm, raised, pink to red nodules. A biopsy specimen of the skin lesion was diagnostic in each patient and 66% of patients had a positive culture from aspiration biopsy of the skin lesion. The biopsy specimens showed a minimal, mononuclear infiltrate around blood vessels with yeastlike bodies and pseudohyphae within the blood vessels and surrounding dermis. Other reports of disseminated candidiasis have described the cutaneous manifestations as asymptomatic, erythematous macules that became purpuric and pustularl3; pustules, purpuric papules, and nodules with pale centers14; and painless, nodulopustular lesions with central necrosis and seropurulent drainageis (Fig. 1). In addition to skin involvement, disseminated candidiasis can cause myositis, meningitis, endocarditis, pneumonitis, cerebritis, esophagitis, bursitis, osteomyelitis, arthritis, and endophthalmitis. 4 Candidal cerebritis with abscess formation is the most common form of central nervous system involvement and presents with confusion or lethargy. Candidal osteomyelitis16 usually is the result of hematogenous spread (and may appear as late as several weeks or months after candidemia) and usually presents with local pain. The most commonly involved sites are vertebrae, long bones, and the sternum. Candidal ophthalmitis also results from hematogenous dissemination and may present as an anterior chamber hypopyon, iritis, uveitis, or Roth's spots. 4 Two reports from Europe 17,18 describe an unusual candidal septicemia, caused by C. albicans, in persons addicted to heroin. The patients had fever, myalgias, and hepatitis followed by skin, eye, and joint involvement. The skin lesions consisted of nodules and follicular pustules that involved the hairy areas of the body (primarily the scalp, beard, axillae, and pubis). The eyes demonstrated a posterior uveifis, turbid aqueous humor, and decreased vision (permanent vision loss developed in one third of the patients). The milder cases of septicemia resolved without treatment, but amphoteficin B and flucy-

tosine were given to the patients with more severe cases; results were excellent. Cases of disseminated candidiasis caused by some of the rarer species of Candida--C. rugosa, 19 C. guilliermondiL 2~ C. lusitaniae, zl and C. pseudotropicalis22--are appearing in the literature. C rugosa was isolated from two patients with leukemia, one of whom had erythematous papules on the trunk and back. t9 Cryptococcosis caused by C neoformans is a relatively common pathogen in immunocompromised patients with a predilection to infect those with deficiencies in cell-mediated immunity. Present in soil, dust, and pigeon excreta, this encapsulated yeast enters the lungs and then may spread hematogenously to the central nervous system, skin, and other organs. The most common initial presentation in patients with acquired immunodeficiency syndrome (AIDS) is meningitis or encephalitis.23 In these patients the cerebrospinal fluid (CSF) frequently shows normal levels of protein and glucose and normal blood cell count; however, culture, cryptococcal antigen, and reaction to the India ink capsule stain are usually positive. Treatment with amphotericin B alone or with flucytosine has been reported to improve only 3 of 28 patients. In cryptococcosis, involvement of the skin is usually indicative of disseminated disease. Cutaneous manifestations of disseminated cryptococcal infections include cellulitis, 24-26 cutaneous ulcers,27 molluscum contagiosum-like lesions, 28 herpetiform lesions, 29 panniculitis, vasculitic ulceration,z4 acneiform papules and pustules, subcutaneous abscesses, vegetating plaques, and an indurated oral ulcer. 3~Schupback24 reported five immunocompromised patients (leukemia, myeloma, and lupus erythematosus) in whom disseminated eryptococcosis developed. The cutaneous lesions were described as ceUulitis-like with erythema, warmth, and tenderness, but two of the patients also had superficial blisters that were clinically suggestive of herpes zoster or simplex. The Tzanek preparation of a blister has been reported to reveal the encapsulated organisms. 29 A patient with an asymptomatic and undiscovered T cell lymphopenia had an indurated, ulcerated nodule on the chin from C. neoformans infection.31 Because the systemic evaluation did not indicate infection, this was thought to represent primary inoculation and not disseminated infection. The lesion responded to treatment with amphotericin B and flucytosine.

Journal of the American Academy of Dermatology

992 Radentz Other less well-knownyeasts, T. beigelii, Kluyveromyces fragilis, 32 S. cerevisiae, 33 and Geotrichum cutaneum, 34 have also been reported to cause infections in immunocompromised hosts. T. beigelii (cutaneum), which causes white piedra in normal hosts, caused a fatal disseminated infection in a patient with leukemia who was receiving chemotherapy.35 Widespread indurated, tender, erythematous papules with small, central ulcerations developed as well as a solitary black, necrotic ulcer in the palate. Autopsy revealed microscopic infarctions in the heart, kidneys, lungs, and lymph nodes. Other cutaneous manifestations of disseminated T. beigelii include purpuric papules and nodules with hemorrhagic bullae36 and numerous purpuric, ulcerated papules. 37 ZYGOMYCOSIS Zygomycosis organisms are common opportunistic pathogens that infect patients with diabetic ketoacidosis, leukemia or lymphoma, therapeutic immunosuppression, neutropenia, and corticosteroid use. 38 A review of 361 cases of zygomycosis showed that Rhizopus was the most common pathogen, followed by Basidiobolus, Mucor, Cunninghamella, Saksenaea, and Absidia in decreasing order) 9 The histopathologic hallmarks are invasion of blood vessel wails by broad, nonseptate hyphae with branching at right angles, thrombus formation, infarction of surrounding tissue, and the production of black, necrotic debris, s8 Rhinocerebral zygomycosis is the best recognized and the most common form of zygomycosis that occurs most frequently in diabetic patients. 4~ Other clinical manifestations of zygomycosis include pulmonary, gastrointestinal, cutaneous, disseminated, and osteomyelitic forms. Meyer et al. 41 reported 26 patients with leukemia or lymphoma who died of systemic zygomycosis. In each patient the diagnosis was made after death, and the autopsy findings consisted of widespread vascular invasion by hyphae with infarctions in the lungs, heart, muscle, meninges, liver, and bone. The rhinocerebral form of zygomycosis typically demonstrates facial swelling, bloody nasal discharge, ulceration of the palate or nasal septum, black necrotic tissue over mucosal surfaces, headache, focal neurologic deficits, exophthalmos, or altered vision.42 Acute sinusitis and facial cellulitis may occur. 38Morduchowitz et al. 42reported two patients with kidney transplants in whom rhinocerebral zygomycosis developed. One presented with facial swelling and nasal discharge that progressed to exophthalmos, cranial nerve palsy, and seizures. Corn-

puted tomography revealed an infiltrate in the ethmoid sinus and an abscess in the frontal lobe. The second patient initially had eye pain; facial swelling and exophthalmos then developed. The infection progressed to cause blindness and cranial nerve paralysis. Cultures from both patients grew R. arrhizus, but the patients died despite antifungal therapy. In a review of 13 patients with rhinocerebral zygomycosis, surgical debridement and amphotericin B resulted in a survival rate of 46%. 40 In primary cutaneous zygomycosis, the skin lesions usually present either as superficial, vesicopustules or as gangrenous, deeply ulcerating lesions.43 Another reported pattern of cutaneous zygomycosis is an erythematous plaque with superficial pustules at the site of application of elastic (Elastoplast) dressings. 44 Zygomycosis disseminated to the skin produces painful, indurated, dusky nodules with ecchymotic centers,45 ecthyma gangrenosum-like lesions,46 or solitary, erythematous plaques with a dark, purple center47 (Fig. 2). Less well-known zygomycotic organisms are being reported to infect immunocompromised patients. A diabetic man developed typical clinical signs of rhinocerebral zygomycosis with facial cellulitis and sinusitis caused by C. bertholettiae. 48 He died despite antifungal therapy. Disseminated S. vasiformis has been reported to cause tender, erythematous nodules with central black necrosis in a patient receiving chemotherapy.49 A patient receiving high-dose corticosteroids developed a dusky area at the site of an arterial line caused by S. vasiformis that showed cheesy yellow necrosis of the skin, tendon, and fascia9 A painless, palatal ulcer from B. haptosporus developed in a diabetic patient, with involvementof the maxillary sinus and orbit that responded to surgical debridement and amphotericin B.st DEMATIACEOUS FUNGI The dematiaceous fungi have brown hyphae and pseudohyphae and yeastlike cells in tissue; they produce dark colonies on culture. These organisms are common causes of fungal infections in populations of underdeveloped countries and are becoming more frequent pathogens in immunocompromised hosts. Primary inoculation phaeohyphomycosis may present as necrotic ulcer52; subcutaneous cyst53; verrucous plaque54; crusted, erythematous, nodule studded with pustules55; red papulonodule; or superficial, brown keratotic papules that resemble seborrheic keratoses56 (Fig. 3). Estes et al. s2 reported a patient with leukemia in whom an erythematous

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Opportunistic fungal infections in immunocompromised hosts 993

Fig. 1. Disseminated candidiasis in a patient with leukemia shows erythematous macules and small papules. (Courtesy James H. Keeling, MD, Fort Sam Houston, Tex.) Fig. 2. Large purpuric plaque with central necrotic ulceration in patient with disseminated zygomycosis. (Courtesy William Sausker, MD) Fig. 3. Localized cutaneous phaeohyphomycosis in patient receiving heart transplant. Pig. 4. Disseminated aspergillosis in patient with leukemia. (Courtesy Larry E. Becket, MD, Fort Sam Houston, Tex.) Fig. 5. Widespread dermatophytosis from Trichophytonrubrum immunocompromised patient. Fig. 6. Localized dermatophytosis caused by Trichophytonrubrum presenting as indurated, red nodule.

994 Radentz macule developed at the site of previously applied tape that progressed to a necrotic ulcer. The biopsy specimen showed a lymphohistiocytic reaction and numerous septate hyphae with acute angle branching; D. spicifera was isolated from culture. The patient responded to a combination of amphoteficin B therapy and surgical excision. A similar patient with leukemia presented with a dark blue macule with surrounding erythema on the leg, caused by E. rostratum, at the site at which tape had been applied. 57 The lesion progressed to a 2 cm ulcer surrounded by concentric rings of erythema before heating with a regimen of amphotericin B and flucytosine. Noel et al.58 reported resolution of a primary cutaneous phaeohyphomycosis to treatment with ketoconazole, 200 mg daily. Cutaneous lesions that are a result of disseminated phaeohyphomycosis may be subcutaneous nodules,59 ulcerated papules, 6~ hemorrhagic pustules,61 or scaly, hyperpigmented plaques. 62 Adam et al.59 reported a patient with dysmyelopoieric syndrome who presented with numerous, widespread, I to 5 cm, erythematous, tender nodules. The biopsy specimen revealed a subcutaneous abscess with a leukocytoclasticvasculitis; Bipolaris spielfern was isolated from culture. The patient was treated with amphotericin B and, after initial improvement, died of disseminated disease. A patient with lymphoma who was receiving chemotherapy had several erythematous macules on the extremities caused by Ahernaria alternata that progressed into umbilicated, ulcerated papules before causing his death. 6~ Other forms of dematiaceous fungal infection in immunocompromised hosts include keratitis, 63 destructive nasal infection,64 peritonitis, 65 olecranon bursitis,66 and infection of the tongue. 67 Mycotic keratitis, caused by D. spicifera, occurred in a patient who was treating his irritated eye with topical corticosteroids.63 At the time of this patient's evaluation, the eye had a large corneal ulcer and hypopyon. The patient was treated with topical pimaricin ointment, but after the resolution of the infection, he had significant residual visual impairment. HYALINE HYPHAE

Aspergillus is the second most common opportunisticfungalinfection in immunocornpromisedhosts. A. fumigatus causes most of the infections; A. flavus, A. niger, A. terreus, and ,4. nidulans infections occur less frequently. A. fumigatus is the most corn-

Journal of the American Academy of Dermatology

mort cause of disseminated aspergillosis whereas A.

flavus is most commonly associated with primary cutaneous aspergillosis. 68 These organisms are present in soil, water, and plants and have been historically considered saprophytes or contaminants. In tissue Aspergillus and the hyalohyphomycosis organisms have nonpigrnented hyphae that are 3 to 4 gm in diameter, septate, and branching at acute angles. Aspergillus infections occur most commonly in patients with hematologic or lymphoreticular malignancies5 but also may occur in patients with solid tumors or who are receiving immunosuppressive therapy after organ transplantation. Meyer et al.69 in a report of 9 3 patients with Aspergillus found a striking predilection for infection in patients with leukemia versus those with lymphoma or solid tumors. Disseminated aspergillosis often presents as a rapidly fulminating disease that almost invariably results in death. 7~A mortality rate of 9 8.4% has been reported among patients with systemic aspergillosis, and often the patients are receiving amphotericin B at the time of dissemination. 4 Predisposing factors include neutropenia or neutrophil dysfunction, longterm corticosteroid therapy, cytotoxic chemotherapy, hyperglycemia, and localized tissue damage. 6 The most common clinical pattern for Aspergillus infections is an unremitting fever with the development of pulmonary infiltrates despite broad-spectrum antibiotic therapy. 69 Because cultures of sputum, blood, and cerebrospinal fluid are often negative despite widespread disease, the best method for diagnosis of aspergiUosis is direct tissue examination (i.e., skin biopsy) and culture. 71 Pulmonary infection is the most common form of aspergillosis in immunocompromised patients and is characterized by necrotizing bronchopneumonia, hemorrhagic infarction, and abscess and cavity form~ition.5 Patients may present with fever, cough, dyspnea, and pieuritie chest pain. Frequently, Aspergillus will disseminate from the primary focus in the lungs to the central nervous system, heart, kidney, gastrointestinal tract, and skin. Aspergillus has the propensity to invade and thrombose vessels that cause infarction of the surrounding tissue (similar to zygomycosis). Involvement of the central nervous system can produce brain abscesses, cerebral infarction, or focal meningitis, but isolation of Aspergillus from the cerebrospinal fluid in these cases is rare. In the study by Atkinson et al. 3 of cardiac fungal infections, 18% were caused by Aspergillus

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Opportunistic fungal infections in immunocompromised hosts 995

that resulted in myocarditis with microabscesses and necrosis of the myocardium. Primary inoculation aspergillosis with A. fumigatus in a patient with leukemia presented as an enlarging, 2 cm, tender, erythematous nodule with central necrosis at the site of taping for intravenous administration. 72 The patient responded to treatment with amphotericin B and granulocyte transfusion. Six other cases of primary cutaneous aspergillosis, caused by A. flavus, appeared as erythematous to violaceous, edematous, indurated plaques with an overlying necrotic ulcer and black eschar. All occurred at sites of trauma caused by intravenous administration of the transfusion. Grossman et al. 73 reported six cases of primary cutaneous aspergillosis that were also related to intravenous administration. The lesions were described as hemorrhagic bullae, purpuric nodules, or cellulitis. Examination of the blister roof with potassium hydroxide provided an immediate presumptive diagnosis by showing septate hyphae within the stratum comeum. Aspergillus spp. that were isolated included A. flavus (three cases), A. fumigatus (two cases), and A. niger (one case); all patients responded to amphotericin B therapy. In contrast, Prystowsky et al.68 reported two patients who had the characteristic ulcers of primary, cutaneous Aspergillus infection but subsequently died of systemic aspergillosis that disseminated from the primary skin infection. Both patients were receiving amphotericin B and had blood cultures negative for Aspergillus. Invasive aspergillosis has also presented as painless induration and erythema of the perinasal area but was not associated with tape or intravenous trauma. 71 Skin involvement from disseminated aspergillosis is usually caused by A. fumigatus. The lesions have been described as (1) maculopapular, (2) subcutaneous abscesses, and (3) confluent granulomas74,75 (Fig. 4). The maculopapular form usuaUy begins as subtle macules on the trunk that are misinterpreted as a drug or viral eruption. The macules develop into 2 to 15 mm, red-purple papules that may become pustular or undergo central necrosis with crusting. The subcutaneous form presents as numerous deep, subcutaneous abscesses. The confluent form was reported in a patient who had a mass of confluent papules and nodules with overlying scaling, crusting, and necrotic ulceration of the face and scalp. The hyalohyphomycosis organisms are rarer causes of infection in immunocompromised hosts than Aspergillus but are being reported more fre-

quently. Pseudallescheria, also known as Scedosporium (previously Monosporium), is a soil fungus that is the most common cause of mycetoma in the United States. In the immunocompromised patient, this fungus has been reported to cause disseminated disease, meningitis, brain abscesses, sinusitis, osteomyelitis, endophthalmitis, pneumonia, and endoearditis. Smith et al. 76 reported a patient with leukemia who presented with a necrotic nasal ulcer in whom an erythematous maculopapular eruption developed. In tissue the hyphae were indistinguishable from Aspergillus. Cultures of the nasal lesion, a skin biopsy specimen, and blood revealed P. boydii, but the patient died despite amphotericin B therapy. P. boydii is characteristically resistant to amphotericin B and ketoconazole, so intravenous miconazole, up to 3 gm daily, has been used. 77 Another patient with P. boydii had painless loss of vision in the right eye.7s Physical examination showed ptosis and exophthalmos, and x-ray films revealed opacification of the right maxillary and ethmoid sinuses with erosion of the medial orbital wall. Surgical debridement and amphotericin B halted the progression of the infection, but the patient died of unrelated causes 4 months later. Disseminated Fusarium moniliforme was reported in a patient with leukemia who had numerous, discrete, erythematous, purpuric papules, some with necrotic centers, on the trunk and extremities. 79 Another case of disseminated F. moniliforme occurred in a bone marrow transplant recipient who had multiple tender papules with central necrosis on the distal extremities,s~ Autopsy findings revealed microabscesses with angioinvasion by septate, branching hyphae in the heart, lungs, liver, spleen, and kidneys that also showed widespread angioinvasion of hyphae. Disseminated infections with F. solani have cutaneous manifestations described as multiple hemorrhagic pustules with necrosis81 and erythematous plaques with central, flaccid pustules, s2 A patient with disseminated F. oxysporum presented with a black, necrotic ulcer of the hard palate and numerous cutaneous and subcutaneous nodules. 83 Paecilomyces organisms have been reported to cause primary cutaneous mycosis,84 pneumonia,85 cellulitis, endocarditis, endophthalmitis, 86 and an infected corneal transplant. 87 Jade et al. 88 reported a patient with leukemia who had an area in the hand that resembled bacterial ceUulitis with tender fluctuant areas and sanguinopurulent drainage from si-

996

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Radentz

9 Fig. 7. Erythematous follicular papules of pityrosporum folliculitis. Fig. 8. Widespread papules and ulcers of disseminated co~idioidomycosis. Fig. 9. Fungal elements viewed under fluorescent microscopy after addition of 1% calcofluor white. nus tracts. The culture revealed P. lilacinus, and the patient responded to a combination of amphotericin B and flucytosine. Another case of Paecilomyces cellulitis was reported in a kidney transplant recipient who had an erythematous, ulcerated area on the leg that healed with intravenous miconazole therapy. 89 DERMATOPHYTES The dermatophytes commonly infest normal hosts and typically cause superficial, scaling plaques. However, immunocompromised patients may have widespread cutaneous infestations resistant to topical therapy (Fig. 5). Wolfson et al. 9~ reported five patients receiving kidney transplants in whom severe local dermatophyte infestations of the soles, groin, extremities, or nails developed. All patients failed to respond to topical agents or griseofulvin, but four of the five had dramatic improvement with oral ketoconazole therapy. The lesions often recurred after

treatment was stopped. A transplant recipient with a long history of chronic, superficial dermatophytosis had intractable pruritus and six dusky, redpurple, tender, fluctuant nodules on the right arm and leg91 (Fig. 6). The biopsy specimen showed suppurative abscesses in the dermis surrounded by granulation tissue with scattered hyphae that proved to be 7". rubrurn in culture. All lesions and the pruritus resolved with griseofulvin and topical econazole therapy. A patient with lupus erythematosus who received immunosuppressive therapy had a large, erythematous, fluctuant plaque with superficial scaling and numerous sinus tracts on the forearm caused by M. canis.92 After an initially favorable response to oral ketoconazole, the plaque began to enlarge and subsequently healed with intralesional miconazole therapy. Pityrosporum orbiculare (Malasseziafurfur) is a common cutaneous inhabitant that causes tinea versicolor. Redline et al. 9a described seven patients,

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Opportunistic fungal infections in immunocompromised hosts 997

all receiving intravenous Intralipid, who had a systemic infection with P. orbiculare manifested by fever, pulmonary infiltrates, and occasionally thrombocytopenia. Wurtz and Knospe94reported a case of disseminated M. furfur in a patient with hairy cell leukemia who was not receiving intralipid. More commonly, P. orbiculare has been reported to cause a folliculitis, consisting of 2 to 4 ram, erythematous follicular papules and pustules that occur mostly on the shoulders, chest, upper back, and arms 95(Fig. 7). The biopsy specimen shows an occluded hair follicle admixed with budding yeast and follicular disruption with surrounding abscess formation. Patients usually respond to treatment with a topical 2.5% selenium sulfide suspension. Folliculitis from Candida or steroids can easily be confused with this disease. DIMORPHIC FUNGI The dimorphic fungi exhibit a mold phase when grown at 25 ~ C but change into yeast when grown at 37 ~ C. The dimorphic fungi (H. capsulatum, B. dermatitidis, C. immitis, P. braziliensis and S. schenckii) are true pathogens and most often infect the lungs after inhalation of the microconidia. Most normal hosts have a subclinical pulmonary infection that establishes lifelong immunity. Immunocompromised patients, however, are more susceptible to the development of disseminated infections, most of which represent reactivation of previously existing infections96

Histoplasmosis In a study of histoplasmosis in immunocompromised patients, the most common underlying conditions were leukemia (46%), lymphoma (34%), and lupus erythematosus (9%). 97 The lungs were most commonly involved and evidence of dissemination was present in 88% of the patients, involving the bone marrow, spleen, liver, lymph nodes, genitourinary tract, adrenal, oropharynx, gastrointestinal tract, and heart (in decreasing order). The oropharyngeal lesions were described as ulcerative, vegetative, or nodular and occurred in 22% of patients. Cutaneous manifestations of disseminated histoplasmosis have been described as a painful, erythematous rash; cellulitis; indurated, erythematous plaques on the arms; a painless, subcutaneous, axillary nodule; and widespread, erythematous nodules that resemble erythema nodosum. 98,99 The best method for timely diagnosis of disseminated histoplasmosis is direct examination of tissue because the

organism grows very slowly in culture. 97 The bone marrow biopsy was found to be the most useful method of antemortem diagnosis to demonstrate the characteristic pseudoencapsulated, 2 to 4 lzm, yeast within macrophages. Results of biopsy examination of the skin or oropharynx were diagnostic in 12% of patients. All patients who did not receive antifungal therapy, as well as those who received less than 1 gm of amphotericin B, died; whereas the patients who were diagnosed early and survived long enough to receive more than 1 gm of amphotericin B had a mortality rate of only 6%. Histoplasmosis in patients with AIDS is being commonly reported. Hazelhurst and Vismer t~176 described a patient with systemic histoplasmosis who had three different types of skin lesions: pustules that coalesced into indurated, erythematous plaques; discrete, necrotic papules with red halos; and perianal ulcers. Kalter et al. loi reported an AIDS patient with disseminated histoplasmosis who had a widespread, erythematous, blanchable, maculopapular eruption. Both patients died despite treatment with amphotericin B and oral ketoconazole.

Coccidioldomyeosis Cutaneous manifestations of disseminated coccidioidomycosis include small papules, scattered papulopustules, verrucous granulomas, nodules, subcutaneous abscesses, and ulcers with sinus tracts 1~ (Fig. 8). Biopsy specimens have shown numerous thick-walled sporangia with enclosed sporangiospores and a paucity of epithelial and giant cells.

Sporotrichosis Manhart et al. 1o3reported an immunosuppressed patient who presented with skin lesions and joint swelling. The skin lesions appeared as painless, fluctuant swelling with areas of ulceration and drainage of purulent fluid located on the left elbow, wrist, and third finger. The left knee was enlarged with several fluctuant, saclike protrusions, and the proximal interphalangealjoint of the third finger was swollen, warm, erythematous, and tender with decreased range of motion. S. schenckii was cultured from the scrapings of an ulcer, the synovium of the involved finger, and aspiration of the knee fluid. After a poor response to saturated solution of potassium iodine, the patient responded to treatment with amphotericin B. Other reports of cutaneous involvement with sporotrichosis in immunocompromised hosts have

998 Radentz included numerous, erythematous papules and nodules1~ and a 5 cm sternal nodule,los Some patients with extracutaneous sporotrichosis have a history of excessive alcohol consumption. Disseminated sporotrichosis developed in a patient with chronic alcoholism who had end-stage cirrhosis; the disease presented as widespread, erythematous nodules, some crusted and others that drained a sanguinopurulent material, a~ The patient also had deep, necrotic ulcers on several digits and the left elbow. The Gram-stained scrapings from the lesions contained cigar-shaped, budding organisms. S. schenckff was isolated from the skin biopsy specimen, bone marrow, and urine. Therapy with amphotericin B produced an improvement, but he eventually died of complications of the cirrhosis. Other reports of sporotrichosis in patients with alcoholism have described facial swelling with ethmoid sinusitis 1~ and severe eye pain with periorbital swelling and ecchymosis,a~ OTHER ORGANISMS

Protothecosis represents an infection with nonchlorophyll-containingalgae that reproduce by endosporulation, not by budding. In tissue the organism is ovoid or spherical and its size ranges from 3 to 30 tzm. The cells divide by septation to form internal spores and the wall eventually ruptures, thereby releasing the spores. Of the 30 known cases of human protothecosis, two general forms exist. Patients with suppressed immunity usually have a papular or eczematoid dermatitis, 1~ although two eases of disseminated protothecosis have also been reported.a~~Patients with an intact immune system usually have a localized infection of the subcutaneous tissue (most commonly the olecranon bursa). Venezio et al. 11l described a patient with widespread, indurated, scaly plaques that covered more than half of the body surface that was caused by Prototheca wickerhamii. The patient demonstrated a specific neutrophil dysfunction against the organism, and treatment with amphotericin B and tetracycline cleared the infection. A patient receiving a kidney transplant had an ulcerating cellulitis of the fingers, probably caused by prolonged immersion of the hands in water. 9~Because of a poor response to antibiotic therapy, a partial amputation was done; prototheeal organisms were found in the deep tissue. The infection c/eared with local debridement and amphotericin B.

Journal of the American Academyof Dermatology EVALUATION AND TREATMENT In immunocompromised patients with fever, an infection is the most likely cause. 6 The majority respond to empirical antibacterial therapy, so it is presumed that the underlying cause is bacterial. If the fever fails to respond to antibiotics, other diagnostic considerations should include resistant bacterial infection, viral infection, fungal infection, drug fever, or the underlying disease (tumor fever). To identify the cause of the fever, cultures of potential sources of infection should be done (cerebrospinal fluid, blood, urine, and sputum). If the patient has a skin lesion, a biopsy and culture of the skin lesion provides an easily accessible and minimally invasive method for diagnosis. A large excisional biopsy specimen can be divided into two halves (or two 3 ram punch biopsies can be obtained): one portion for staining and one for culture. Instructions tbr staining should include special stains to identify the considerable array of potential organisms: (1) tissue Gram stain for bacteria, (2) acid-fast stains for mycobacteria, and (3) periodic acid-Schiff or GroeottGomori methenamine-silver nitrate stain for fungus. The second portion of the biopsy specimen should be sent (in sterile saline solution) for culture (bacterial, mycobacterial, and fungal). A rapid diagnosis may be obtained by direct examination of material collected from the skin lesions with Gram's stain, Tzanck, and potassium hydroxide preparations. If vesicles or pustules are present, the roofs should be examined for hyphae and the base should be scraped to identify bacteria, fungal structures, or viral changes. Cultures can be made directly of a vesicle, pustule, or ulcer in addition to the biopsy specimen. A new technique to make fungal elements easily visible and allow for an immediate presumptive diagnosis is the addition of 1% calcofluor white solution to the preparation of the specimen and viewing with a fluorescent microscopej 12 (Fig. 9). Serologic methods to diagnose fungal infections, detecting either the fungal antigen or the host's antibody response, are generally unrewarding. Tests for the antibodies often give false-negative results (such as with Aspergillus and Candida infections) because the immunocompromisedhost has not been able to generate an antibody response. Tests for the fungal antigen offer a more reliable method to diagnose fungal infections. The latex agglutination test for candidal antigens has been shown to improve the early detection of invasive candidiasis compared

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Opportun&ticfungal infections in immunocompromised hosts 999

with blood cultures alone. 96 The detection of cryptococcal antigens in the cerebrospinal fluid is a reliable antigen test to diagnose fungal infections.

THERAPY Amphoteriein B Amphotericin B is the drug of choice for most systemic fungal infections (Table II), but concern exists about suboptimal efficacy in the treatment of cryptococcosis, disseminated candidiasis, and aspergillosis. 96 It has not proved effective in treating the rarer forms of opportunistic infections (i.e., P. boydii)) 13The addition of ftucytosine may be synergistic and indicated for certain fungal infections (see later discussion). The mode of action of amphotericin B is its binding to cell membrane sterols (most commonly ergosterol). This increases cell permeability and leads to cell death)14 A major inconvenience of amphotericin B is that it must be given intravenously, although it can also be given intrathecally, intraarticularly, and intraperitoneally. Side effects include fever and chills (almost all), headache (40%), nausea and vomiting (20%), hemolytic anemia, nephrotoxicity, and phlebitis. Nephrotoxicity is the most important side effect and is generally dose related. Some degree of azotemia occurs in every patient but permanent renal damage is unlikely if the total dose is less than 2 gm. Modification of the delivery (i.e., liposomal amphotericin B) may be less toxic and more effective than cor~ventional methods.96 A test dose (usually 1 rag) should always be administered before therapy is begun to assess any allergic reactions or untoward side effects. 115The dose of amphoteriein B should be individualized to take into consideration the patient's overall condition. Monitoring serum levels may be useful in patients with decreased renal function. The standard dose (0.6 mg/kg of body weight daily) has been modified in some cases to 1.0 to 1.5 mg/kg of body weight daily with better results.

Flucytosine Flucytosine (5-fluorocytosine) acts as an antimetabolite and interferes with fungal nucleic acid synthesis.1:4, ::5 The indications for flucytosine are usually as an adjuvant to amphotericin B because organisms may frequently become resistant if the latter is used as the only therapy. Flucytosine is most efficacious if used with amphotericin B to treat disseminated cryptococcosis and candidiasis but can be

Table II. Fungal infections for which amphotericin B is the drug of choice Systemic aspergillosis Blastomycosis Systemic candidiasis Coccidioidiomycosis Cryptococcosis Histoplasmosis Zygomycosis Disseminated sporotrichosis

used as a single therapy for chromoblastomycosis. It is relatively nontoxic and can be given orally. Side effects include diarrhea, liver function abnormalities, and myelosuppression.

Ketoconazole Ketoconazole has been given primarily to treat dermatophytosis, certain forms of candidiasis, and paracoccidioidomycosis. Recently, to take advantage of its low toxicity, trials have been conducted to expand the indications for ketoconazole. It was proved effective to treat with 400 mg daily a group of patients with non-life-threatening and nonmeningeal forms of histoplasmosis and blastomycosis. :16 Goodpasture et al. 117 reported two patients with fungal involvementof the central nervous system (coccidioidomycosis or histoplasmosis) who responded to ketoconazole, 200 mg daily. Other fungal infections treated with ketoconazole include aspergillosis, pseudalleseheriosis, chromoblastomycosis, sporotrichosis, and cryptococcosis. 1:5 Ketoconazole inhibits ergosterol synthesis in fungal cell membranes and interferes with oxidative enzymes. Because amphotericin B must bind to ergosterol to be effective, the addition of ketoconazole is antagonistic, and they should not be used concurrently. Side effects of ketoconazole include nausea or vomiting, pruritus, and headache, but the most important are hepatitis (rarely fatal) and inhibition of adrenal or sex hormone production (may cause adrenal insufficiency, impotence and gynecomastia). Ketoconazole is given orally and depends on gastric acid for absorption so concurrent use of antacids may decrease absorption. Ketoconazole may interfere with warfarin metabolism, may cause a disulfiram-like reaction with ethanol ingestion, may increase serum cyclosporine levels, and may have serum levels decreased by concurrent use of rifampin

Journal of the American Academy of Dermatology

1000 Radentz or isoniazid.115 Newer azole antifungal agents, itraconazole and fluconazole, may be more effective and have a broader spectrum with less toxicity. In general, the prognosis for disseminated fungal infections in immunocompromised patients is poor. This can be attributed to several factors: (1) underlying immunocompromise of the patient, (2) delay in diagnosis, (3) delay in initiating treatment, and (4) failure of the antifungal regimen. The factors that make immunocompromised patients susceptible to opportunistic fungal infections preclude them from mounting an effective defense to eliminate them. The underlying neutropenia, debilitation, leukemia, acidosis, or immunosuppressive medications so impair the host's resistance that recovery from a systemic fungal infection is almost impossible despite early and aggressive treatment. A cure rate of 38% was achieved in patients with systemic candidiasis in whom the neutrophil count was greater than 1000/ram3; however, in those patients with neutrophil counts less than lO00/mm 3, none survived.1 So, whenever possible, every effort should be made to improve the underlying factors although they are often insurmountable. Delays in diagnosing fungal infections may result from a low level of suspicion and the lack of easily recognizable signs and symptoms of a fungal infection. 118 A higher level of suspicion should increase the proportion of fungal infections detected. Delays in initiating antifungal therapy in the course of the infection may be the result of withholding treatment pending the growth of the fungus in culture (which may require several weeks) or failure to recognize the "contaminant" that grew from the specimen as the pathogenic organism. 119 The poor response to antifungal therapy may be due to lack of sensitivity Of the fungus to the antifungal agents, development of resistant organisms, or inability of patients to tolerate the toxicity of the drugs. The empirical use of antifungal agents in immunocompromised patients seems to be justified if the patient has persistent fever while receiving antibacterial therapy. 6 The aggressive use of prophylactic amphotericin B has been shown to reduce fungal infection rates and increase survival. It has reduced the incidence of disseminated candidiasis in patients with fever, neutropenia, and mucosal candidiasis.9 Ketoconazole, however, seems to be effective in reducing local fungal infections but does not appear to reduce the frequency of systemic infections.6 In one study that used ketoconazole as prophylaxis in

patients with leukemia, there was no reduction in systemic or localized fungal infections. 12~Oral clotrimazole trouches were shown to reduce the incidence of oral candidiasis and may be a safe and effective method to prevent colonization and possibly dissemination. 121 Prasad et al. 122 reported a low incidence of candidiasis (13.3%) and only a 1% mortalky rate associated with candidemia in burn patients. Their approach included oral nystatin to reduce candidal colonization, wound debridement, weekly changes of central venous lines and bladder catheters, limited use of parenteral nutrition, vaginal nystatin for female patients, and limited use of broad-spectrum antibiotics. As soon as Candida sepsis is detected, amphotericin B is given in a dose of 5 mg every 8 hours, and, if no clinical response is evident, this is increased to 10 mg every 8 hours. In summary, fungal infections in immunocompromised hosts represent a major source of morbidity and mortality. The number of patients receiving immunosuppressive agents for the treatment of malignancies or for organ transplantation is increasing as well as the potential for local and disseminated fungal infections. The diagnosis of these infections is often difficult and present methods for treatment are commonly ineffective. A high degree of suspicion to identify fungal infections and prompt initiation of treatment must be maintained if the survival of these patients is expected to improve. REFERENCES

1. Bodey GP. Candidiasis in cancer patients. Am J Med 1984;77:I3-9. 2. Rubin RH, Wolfson JS, Cosimi AB. Infection in the renal transplant recipient. Am J Med 1981;70:405-11. 3. Atkinson JB, Connor DH, Robinowitz M. Cardiac fungal infections. Hum Pathol 1984;15:935-42. 4. Wajszczuk CP, Dummer JS, I-1o M. Fungal infections in liver transplant recipients. Transplantation 1985;40:34753. 5. Hawkins C, Armstrong D. Fungal infections in the immunocompromised host. Clin Hematol 1984;13:599-630. 6. Bodey GP. Fungal infection and fever of unknown origin in neutropenic patients. Am J Meal 1986;80(Suppl 5C):1129. 7. McGinnis MR. Chromoblastomycosis and phaeohyphamycosis: new concepts, diagnosis, and mycology. J AM ACAD DERMATOL 1983;8:1-16. 8. McGinnis MR, Ajello L, Schell WA. Mycotic diseases. Int J Dermatol 1985;24:9-15. 9. Arena FP, Perlin M, Brahman H, et at. Fever, rash, and myalgias of disseminated candidiasis during antifungal therapy. Arch Int Med 1981;141:1233. 10. Horn R, Wong B, Kiehn TE. Fungemia in a cancer hospital. Rev Infect Dis 1985;7:646-55. 11. Maksymiuk AW. Systemic candidiasis in cancer patients. Am J Med 1984;77:20-7.

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12. Bodey GP, Luna M. Skin lesions associated with disseminated candidiasis. JAMA 1974;229:1466-8. 13. Tom D. Disseminated candidiasis. Arch Dermatol 1984;120:1618-20. 14. Grossman ME, Silvers DN, Walther RR. Cutaneous manifestations of disseminated candidiasis. J AM ACADDERMATOL 1980;2:111-6. 15. Bardwell A, Hill DW, Runyon B. Disseminated macronodular cutaneous candidiasis in chronic alcoholism. Arch Int Med 1986;146:385-6. 16. Gathe JC, Harris RL, Garland B. Candida osteomyelitis. Am J Med 1987;82:927-37. 17. CoUingnon PJ, Sorrell TC. Disseminated candidiasis: evidence of a distinctive syndrome in heroin abusers. Br Med J 1983;287:861-2. 18. Darcis JM, Etienne M, Demonty J. Candida albicans septicemia with folliculitis in heroin addicts. Am J Dermatopathol 1986;8:501-4. 19. Sugar AM, Stevens DA. Candida rugosa in immunocompromised infection. Cancer 1985;56:318-20. 20. Dick JD, Rosengard BR, Mertz WG. Fatal disseminated candidiasis due to amphotericin B-resistant C. guillierrnondii. Ann Int Med 1985;102:67-8. 21. Guinet R, Chanas J, Goullier A. Fatal septicemia due to amphotericin B-resistant Candida lusitaniae. J Clin Microbiol 1983;18:443-4. 22. Morgan MA, Wilkowske CJ, Roberts GD. C. pseudotropicalis fungemia and invasive disease in an immunocompromised patient. J Clin Microbiol 1984;20:1006-7. 23. Kovacs JA, Kovacs AA, Polis M. Cryptococcosisin AIDS. Ann Int Med 1985;103:533-8. 24. Schupback CW. Cutancous manifestations of disseminated cryptococcosis. Arch Dermatol 1976;112:1734-40. 25. Berhardt MJ, Ward WQ, Sams WM. Cryptococcalcellulitis. Cutis 1984;34:359-61. 26. Carlson KC, Mehlmauer M, Evans S, etal. Cryptoooccal celtulitis in renal transplant recipients. J AM ACADDERMATOL 1987;17:469-72. 27. Sarosi GA, Silberfarb PM, Tosh FE. Cutaneous cryptococcosis. Arch Dermatol 1971;104:1-3. 28. Rico J, Penneys NS. Cutaneous cryptococcosisresembling molluscum contagiosum in a patient with AIDS. Arch Dermatol 1985;121:901-2. 29. Borton LK, Wintroub BU. Disseminated cryptococcosis presenting as herpetiform lesions. J AM ACADDERMATOL 1984;10:387-90. 30. Lynch DP, Naftolin LZ. Oral Cryptococeus neoformans infection in AIDS. Oral Surg Oral Med Oral Pathol 1987;64:449-53. 31. Geyer SJ, Werber JC. Localized cutaneous cryptococcosis in an immunosuppressed man. Int J Dermatol 1984;23:6735. 32. Lutwick LI, Phaff H J, Stevens DA. Kluyveromycesfragilis as an opportunistic fungal pathogen. Sabouraudia 1980;18:69-73. 33. Eng RH, Drehmel R, Smith SM. Saccharomyces cerevisiae infections in man. Sabouraudia 1984;22:403-7. 34. Chang WL. Disseminated geotrichosis. Arch Int Med 1964;113:356-60. 35. Gold JWM, Poston W, Mertelsmann R. Systemicinfection with Trichosporon cutaneum. Cancer 1981;48:2163-7. 36. Yung CW, Hanauer SB, Fretzin D. Disseminated Trichosporon beigelii. Cancer 1981;48:2107-11. 37. Leblond V, Saint Jean O, Dtary A. Systemicinfectionswith Trichosporon beigelii. Cancer 1986;58:2399-2405. 38. K.line MW. Mucormycosis in children: review of the liter-

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dated with immunologic hyporeaetivity. Int J Dermatol 1978;17:323-30. Forster RK, RebeU G, Wilson LA. Dematiaceous fungal keratitis. Br J Ophthalmol 1975;59:372-6. Body BA, Sabio H, Oneson Rt-I. Alternaria infection in a patient with leukemia. Pediatr Infect Dis J 1987;6:418-9. O'Sullivan FX, Stuewe BR, Lynch JM. Peritonitis due to Drechslera spicifera. Ann Int Med 1981;94:213-4. Kwon-Chung K J, Droller DD. Infection of the olecranon bursa by Anthopsis deltoidea. J Clin Microbiol 1984;20:271-3. Rippon JW, Arnow PM, Larson RA. Golden tongue syndrome caused by Ramichloridium schulzeri. Arch Dermatol 1985;121:892-4. Prystowsky SD, Vogelstein B, Ettinger DS. Invasive aspergillosis. N Engl J Med 1976;295:655-8. Meyer RD, Young LS, Armstrong D. Aspergillosis complicating neoplastic disease. Am J Meal 1973;54:6-15. Rinaldi MG. Invasive asporgillosis. Rev Infect Dis 1983;5:1061-77. Weingarten JS, Crockett DM, Lusk RP. Fulminant aspergillosis: early cutaneous manifestations and the disease process in the immunocompromised host. Otolaryngol Head Neck Surg 1987;97:495-9. Estes SA, Hendricks AA, Merz WG, et al. Primary cutaneous aspergiUosis. J AM Ae~d~ DEPdVfATOL1980;3:397400. Grossman ME, Fithian EC, Behrens C, et al. Primary cutaneous aspergillosis in six leukemic children. J AM ACAD DF..RMATOL1985;12:313-8. Findlay GH, Roux HF, Simson IW. Skin manifestation in disseminated aspergillosis. Br J Dermatol 1971; 85(Suppl):94-7. Schneiderrnan H. Purple spot with bleak chest film. Chest 1986;90:607-8. Smith AG, Crain SM, Dejongh C. Systemic pseudallescheriasis in a patient with acute myeloeytie leukemia. Mycopathologia 1985;90:85-9. Rippon J. Medical mycology. 2nd ed. Philadelphia: WB Saunders, 1982:598. Gluckman SJ. Allescheria boydii sinusitis in a compromised h~t, J Clin Mierobiol 1977;5:481-4. Veglia KS, Marks VJ. Fusarium as a pathogen. J AM A c ~ D ~ h T O L 1987;16:260. June CH, Beatty PG, Shulman HM. Disseminated Fusarium moniliforme infection after allogenic marrow transplantation. South Med J 1986;79:513-5. Chaulk CP, Smith PW, Feagler JR. Fungemia due t~, Fusarium solaniin an immunocompromised child. Pediatr Infect Dis J 1986;5:363-5. Matsuda T, Matsumoto T. Disseminated hyalohyphomycosis in a leukemia patient. Arch Dermatol 1986;122: 1171-5. Anaissie E, Kantarjian H, Jones P. Fusarium: a newly recognized fungal pathogen in immunosuppressed patients. Cancer 1986;57:2141-5. Takayasu S, Akagi M, Shimizu Y. Cutaneous mycosis caused by Paecilomyces lilacinus. Arch Dermatol 1977; 113:1687-90. Dharmasena FMC, Davies GSR, Catovsky D. Paecilomyces varioti pneumonia complicating hairy cell leukemia. Br Med J 1985;290:967-8. ODay DM. Fungal endophthalmitis caused by Paecilomyces lilacinus after intraoeular lens implantation. Am J Ophthalmol 1977;83:130-1. Gordon MA, Norton SW. Corneal transplant infection by Paecilomyces lilaciinus. Sabouraudia 1985;23:295-301.

Journal of the American Academy of Dermatology

88. Jade KB, Lyons MF, Gnann JW. Paecilomyces lilacinus cellulitis in an immunocompromised patient. Arch Dermatol 1986;122:l 169-70. 89. Harris LF, Dan BM, Lefkowitz LB. Paecilomyces cellulitis in a renal transplant patient. South Med J 1979;72: 897-8. 90. Wolfson JS, Sober A J, Rubin RH. Dermatologic manifestations of infections in immunocompromised patients. Medicine 1985;64:115-33. 91. Novick NL, Tapia L, Bottone EJ. Invasive Trichophyton rubrum infection in an immunocompromised host. Am J Meal 1987;82:321-5. 92. Barson WJ. Granuloma and pseudogranuloma of the skin due t~ Microsporum canis. Arch Dermatol 1985;121: 95-7. 93. Redline RW, Redline SS, Boxerbaum B. Systemic Malasseziafi~rfur infection in patients receiving Intralipid therapy. Hum Pathol 1985;16:815-22. 94. Wurtz RM, Knospe WN. Malasseziafurfur fungemia in a patient without the usual risk factors. Ann Int Med 1988;109:432-3. 95. Yohn J J, Lucas J, Camisa C. Malassezia folliculitis in immunocompromised patients. Cutis 1985;536-8. 96. Holmberg K. Diagnosis and therapy for systemic mycoses: abstracts from a satellite meeting of the Fourth International Conference on AIDS. J Acquired Immun Def Syn 1988;1:198. 97. Kauffman CA, Israel KS, Smith JW. Histoplasmosis in immunosuppressed patients. Am J Med 1978;64:923-32. 98. Davies SF, Sarosi GA, Peterson PK. Disseminated histoplasmosis in renal transplant recipients. Am J Surg 1979;137:686-91. 99. Abildgaard WH, Hargrove RH, Kalivas J. Histoplasma panniculitis. Arch Dermatol 1985;121:914-6. 100. Hazelhurst JA, Vismer HF. Histoplasmosis presenting with unusual skin lesions in AIDS. Br J Dermatol 1985;113:345-8. 101. Kalter DC, Tschen JA, Klima M. Maculopapular rash in a patient with AIDS. Arch Dermatol 1987;121:1455-6. 102. Prichard JG, Sorotzkin RA, James RE. Cutaneous manifestations of disseminated coccidioidiomycosis in AIDS. Cutis 1987;39:203-5. 103. Manhart JW, Wilson JA, Korbitz BC. Articular and cutaneous sporotrichosis. JAMA 1970;214:365-7. 104. Wilson DE, Mann J J, Bennett JE. Clinical features ofextracutaneous sporotrichosis. Medicine 1967;46:265-79. 105. Lynch PJ, Voorhees J J, HarrelI ER. Systemic sporotrichosis. Ann Int Med 1970;73:23-30. 106. SatterwhiteTK, Kageler WV, Conklin RH. Disseminated sporotrichosis. JAMA 1978;240:771-2. 107. Morgan MA, Wilson WR, Neel HB. Fungal sinusitis in healthy and immunocompromised individuals. Am J Clin Pathol 1984;82:597-601. 108. Agger WA, Caplan WA, Mald DG. Ocular sporotrich.osis mimicking mucormycosis in a diabetic. Ann Ophthaltool 1978;10:767-71. 109. McAnally T, Parry EL. Cutaneous protothecosis presenting as recurrent chromomycosis. Arch Dermatol 1985; 121:1066-9. 110. Cox GE, Wilson JD, Brown P. Protothecosis: a case of disseminated algal infection. Lancet 1974;2:379-81. 111. Venezio FR, Lavoo E, Williams JE. Progressive cutaneous protothecosis. Am J Clin Pathol 1982;77:485-93. 112. Finegold SM, Baron EJ. Bailey and Scott's diagnostic microbiology. 7th ed. St Louis: CV Mosby, 1986:81-3. 113. Rippon J. Medical mycology. 2nd ed. Philadelphia: WB Saunders, 1982:727-8.

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114. Cohen L. Antifungal chemotherapy. Lancet 1982:532-7. 115. Lesher JL, Smith JG. Antifungal agents in dermatology. J AM ACAD DERMATOL 1987;17:383-94. 116. Disukes W. Treatment of hlastomycosis and histoplasmosis with ketoconazole. Ann Int Med 1985;103:861-7. 117. Goodpasture HC, Hershberger RE, Barnett AM. Treatment of central nervous system fungal infection with ketoconazole. Arch [nt Med 1985;t45:879-80. 118. Degregorio MW, Lee WM, Linker CS. Fungat infections in patients, with acute leukemia. Am J Med 1982;73: 543-8.

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119. Zarabi MC, Salmassi S. Antemortem diagnosis of systemic aspergillosis. South Med J 1984;77:584-8. 120. Hansen RM, Renerio N, Sohnle PG. Ketoconazole in the prevention of candidiasis in patients with cancer, Arch Int Med 1987;147:710-2. 121. Quintiliani R, Owens N J, Quercia RA. Treatment and prevention of oropharyngeal candidiasis. Am J Med 1984;77(40):44-7. 122. Prasad JK, Feller I, Thompson PD. A ten-year review of Candidasepsis and mortality in burn patients. Surgery 1987;101:213-6.