Fungal and Mycobacterial Skin Infections ANNE
M. ANGELES,
MD
he manifestations of opportunistic infections in AIDS patients are dependent upon the nature and severity of the patients’ immunologic defects. AIDS patients have, primarily, a cell-mediated immunodeficiency and are subsequently at increased risk for developing fungal infections. Fungal infections can be divided into two categories: superficial and systemic.
T
Superficial Superficial infections are generally less aggressive and do not usually produce disseminated disease, even in the most severely compromised cases. Candida species are a common cause of superficial infection in the AIDS patient, and Candida ulbicuns is one of the most commonly isolated pathogens. C. ulbicans is a 4-6 ,uM oval budding cell which forms hyphae and pseudo-hyphae and is isolated in over 80% of AIDS cases.’ The most common candidal lesion is the buccal or lingual plaque (thrush) (Plate 24), which may extend to involve the oropharynx. This is frequently an incidental finding that may prompt an HIV work-up. The presence of unexplained oral candidiasis in a prospective study of IV drug abusers and homosexual men predated the diagnosis of AIDS in 59% of the patients.* In AIDS patients, the pattern of infection caused by Candida is similar to that seen in other immunocompromised hosts, except that the lesions may be more extensive and may require prolonged therapy. Paronychia and onycholysis secondary to Cundidu have also been reported in HIV patients, and Kaplan and colleagues3 suggest that there is a correlation between decreased numbers of T-helper cells and severity of disease. Candida may also cause chronic infection of vulva, From the Department of Dermatology, Jefferson Medical College, Thomas jefferson University, Philadelphia, Pennsylvania. Address correspondence to: Anne M. Angeles, MD, 509 Prescott Road, Merion, PA 19066.
0
1991
by Elsevier
Science Publishing Co., Inc. 0738-081x/91/$3.50 l
groin or glabrous skin. 4 Candidemia is a rare occurrence in AIDS patients, which may be due to relatively intact phagocytes and B-cell immunity. Candidemia is most often found in patients with an indwelling catheter.5 The diagnosis of candidal infection may be made by biopsy or scraping of a lesion and demonstrating budding yeast with pseudohyphae on potassium hydroxide (KOH) preparation Culture of the lesions is often useful on the skin, but may yield misleading data when mucosae are cultured, because the yeast may be present in normal individuals. The treatment of mucocutaneous candidosis usually requires topical or systemic ketoconazole (200 - 400 mg/ day) or clotrimazole (30 -50 mg/day). Amphotericin B IV may be used for severe pharyngitis. Recurrences are common and maintenance therapy is often required.6 Dermatophyte infections are very common in AIDS patients and are reported to affect 30 - 56% of this population.3*4*7,8These infections have atypical morphologies and may be widespread and in unusual locations. The most common dermatophytoses are tinea pedis and onychomycosis causing deformity and discoloration.4 Tinea corporis and cruris have the typical clinical appearance, but are usually more extensive and somewhat less exuberant than when seen in the normal host (Plates 25 and 26). Tinea faciale resembling erythema multiforme and discrete flat-topped papules has been reported.9 As in the noncompromised form, Trichophyfon rubrum is a frequent isolate. The diagnosis of dermatophytosis is made by KOH preparation and cultures of scrapings or biopsies. Often, biopsy is required to demonstrate a fungal element. Dermatophyte infections may be treated successfully with newer antifungal creams such as griseofulvin or ketoconazole in usual doses.
Systemic Cutaneous manifestations of systemic fungal infections are also noted in AIDS patients. The clinical cutaneous
65
66
ANGELES
involvement may be subtle and a high index of suspicion together with appropriate biopsies for pathologic and microbiologic evaluation will permit early and accurate diagnosis of these diseases. Cyptococcus neofOrmans is a pathogen in patients with immune suppression other than AIDS, including transplant recipients, and patients with lymphoreticular malignancies, diabetes mellitus and systemic lupus erythematosus. Infections are also seen in normal hosts. In AIDS patients, C. neoformans is reported to be the fourth most commonly recognized cause of life-threatening infection.‘O The organism, a soil saprophyte, is also found in pigeon excreta and is a round budding yeast with a prominant capsule. C. neoformuns infections are acquired by inhalation of the spores into the lungs with subsequent dissemination. The central nervous system and skin are the most commonly involved extrapulmonary sites.” Cutaneous involvement is seen in 10 - 20% of disseminated disease in AIDS patients.” There is no typical lesion morphology. A fungal etiology is often unsuspected since the lesions may appear very nonspecific. Reported presentations include subcutaneous nodules, nonhealing ulcers, cellulitus and acneiform lesions. In addition, symptoms may include atypical, polymorphic umbillicated papules (resembling molluscum contagiosum),12 violacious papules and plaques simulating Kaposi’s sarcornal and herpetiform lesions.14 Since cutaneous signs may be the first manifestations of systemic disease, early diagnosis may be lifesaving and a high index of suspicion is required. The diagnosis of infection is made by visualization of the organism in smears from involved tissue on india ink or Tzank preparations. On skin biopsy, the organism stains red with PAS and mucicarmine. The treatment of disseminated cryptococcosis is IV amphotericin B (0.4-0.6 mg/kg/day), with a total dose of 1.5 - 2 g. Therapy with amphotericin B is not curative and relapses occur in over 50% of patients6 One study demonstrated that maintenance therapy of amphotericin B (100 mg/week) prevented relapse.6 Efficacy of treatment with ketoconazole (800 - 1000 mg/day), fluconozole and itraconozole remains to be studied. Histoplasma capsulutum is a dimorphic fungus endemic to the river valleys of the eastern and central United States, the Caribbean and South America. The organism is virulent and will infect exposed normal individuals, but the illness is usually asymptomatic or causes only very mild upper respiratory tract symptoms. With moderate exposure, symptomatic respiratory illness may be noted. Reinfection with dissemination may be seen in the heavily-exposed normal host or in the immunocompromised host.15 The organism is 3 - 4 PM, oval, budding, uninucleated, intracellular, and surrounded by a halo resem-
Clinics in Dermatology 1991;9:65-69 bling a capsule, but which is actually an artifact of the staining technique. AIDS patients develop a disseminated, more aggressive infection than the normal host. The typical clinical presentation is that of a prolonged, febrile course with hypotension, hypoxia, renal, and hepatic insufficiency.16*17 Fungemia is reported in 2 - 37% of infected AIDS patients.5J7 Cutaneous lesions are reported in approximately 10% of patients with disseminated disease and are rarely the presenting symptom.16 Like cryptococcosis, disseminated histoplasmosis has protein cutaneous manifestations. Oral ulcerations or nodules,23 papules and plaques with or without keratinous plugs,19,22 deep ulcers,24 exfoliative erythroderma,*l and pustules20 all have been reported. The diagnosis may be confirmed by the presence of the budding yeast in biopsied tissues on stained smears. The organism is small, intracellular and budding, and found within macrophages. It may be detected using PAS stain, but it does not stain with mucicarmine. The treatment of disseminated histoplasmosis with amphotericin B (0.6 mg/kg/day) in the non-AIDS patient shows a cure rate of approximately 90%. In the AIDS patients, amphotericin B is much less effective and a high relapse rate is reported. Maintenance therapy with ketoconozole (400 mg/day) is recommended.25 Coccidioidomycosis is endemic in the western and southwestern United States and northern Mexico. Coccidioides immitis exists in the soil, and the primary route of infection is inhalation of the spores. The organism is a large, 5 - 60 ,uM, thick-walled, round cell which contains endospores. Symptomatic infections occur in approximately 40% of exposed normal host individuals. The disease is manifest in the lower respiratory tract. Erythema nodosum or erythema multiforme may develop during infection. Immunosuppression predisposes the patient to reactivation of quiescent disease or to a progressive infection that may disseminate. Patients with AIDS have been reported with disseminated coccidioidomycosis both within and without endemic areas.26,27 In Arizona, a highly endemic area, infection occurred in AIDS patients in one report.26 The skin manifestations of coccidioidal disease in AIDS do not appear to be common, but if present, they may be helpful in making the diagnosis. The clinical presentation in the AIDS patient is fever, malaise, and cough with a chest x-ray demonstrating diffuse, bilateral reticulo nodular infiltrates. No typical lesions of disseminated disease, such as cutaneous abscesses, joint effusions, or bone destruction, were noted in any of these patients.26
Clinics in Dermatology 1991:9:65-69 There is a report of one AIDS patient with disseminated coccidioidomycosis. This patient had tender abscesses of the buttock at sites of pentamidine injections. Cultures subsequently grew C. immitis.27 The diagnosis of disseminated coccidioidomycosis is made by isolating the organism from involved tissues. The treatment of C. immitis infections in the AIDS patient is problematic since amphotericin B is not fungicida1 for the organism2* and host immunity is an important factor in recovery. Four out of seven patients in one study were treated solely with amphotericin B; three patients initially improved, but subsequently relapsed and died. Three additional patients were treated with a combination of amphotericin B and ketoconazole. Again, the patients initially responded, but eventually relapsed and died.26 Initial therapy with males also include amphoteritin B for a cumulative dose of 1 - 2.5 g, followed by suppressive therapy with ketoconazole (400 mg/day). Paracoccidioides brasiliensis is a dimorphic fungus and the etiologic agent of paracoccidioidomycosis, or South American blastomycosis. It is endemic in South America. The fungus is an oval cell (4 - 40 PM) and reproduces by multiple budding “pilot wheels” with refractile capsules. The lungs are the primary site of infection and dissemination is common even in the normal host. The disease may have a long latency of up to 30 years.29 The primary infection may be subclinical and may become reactivated when the host is immunosuppressed. Mucosal and cutaneous manifestation are common. The mucosal lesions are peri- and intraoral ulcerations and infiltrations. The skin lesions are warty, ulcerated nodules around the nose and mouth.31 There is one report of a patient with disseminated paracoccidioidomycosis with skin lesions.30 He was a homosexual man from Brazil who presented with small ulcers with raised borders surrounded by an erythematous halo around the nose and mouth and on the right thigh. Biopsy of an ulcer showed a granuloma with round spores surrounded by a doubly refractile capsule which morphologically resembled P. brazilieusis. The chest x-ray demonstrated diffuse bilateral micronodules. The authors do not state if the organism was cultured from the ulcers. The patient was treated with amphotericin B, with complete resolution of lesions. The diagnosis of disseminated paracoccidioidomycosis is made by demonstrating the organism in affected tissues. Successful treatment in the normal host is with sulfadiazine 4 - 6 g/day until lesions clear, then 2 - 3 g/day for 3 -5 year, amphotericin B, 0.4 -0.6 mg/kg/day or ketoconazole 200 -400 mg/day for 6- 18 months.31 Sporothrix schenckii is a dimorphic fungus that is found in the soil and in living plants. The cells are 4-6 PM,
ANGELES FUNGAL AND MYCOBACTERIAL SKIN INFECTIONS
67
cigar-shaped or oval structures. The clinical presentation of infection is primarily cutaneous. The typical lesion begins as an erythematous papule and then develops suppurative nodules along the lymphatic channels.32 In the immunocompromised host an extracutaneous disseminated form and a multifocal cutaneous form of the disease are described.32 The primary route of infection may be cutaneous or pulmonary with hematogenous spread. Disseminated sporotrichosis is reported in two patients with AIDS.33*34 One had many cutaneous ulcerations and end-ophthalmitis secondary to disseminated disease,34 and the other had subcutaneous nodules and erythematous pustules on the trunk and extremities with tender joints. Sporotrichosis was diagnosed by biopsies, skin scraping and culture. Diagnosis of sporotrichosis is made by KOH preparation of skin scrapings and culture of biopsied lesions. Potassium iodide is effective in localized sporotrichosis, but disseminated disease requires amphotericin B IV 0.4 0.6 mg/kg/day. There are scattered case reports of the successful use of 5-fluorocytosine in sporotrichosis.35 No disseminated infections with Blastomyces dermatitidis have been described in AIDS patients to date. This may be due to differences in immunopathogenesis of these infections.
Mycobacterial
Infections
in AIDS
Skin Manifesfafions Mycobacteria are frequently the cause of opportunistic infections in AIDS patients. It is reported that 50% of all AIDS patients will develop mycobacterial infection at some stage of the disease. 36 Cutaneous disease rarely occurs in the absence of disseminated disease. The most commonly isolated organism is Mycobacterium avium-intrucellulare (MAI). Several reports indicate that 25-67% of mycobacterial isolates are MA1 in the AIDS population. 36,37The typical presentation is fever, malaise, weight loss, diarrhea and abdominal pain. Cutaneous involvement does occur and in one study MA1 was cultured from the skin postmortum in 37% of patients with disseminated disease.37 Several cutaneous lesions have been reported: cutaneous abscesses, ill-defined mascular discolored lesions simulating Kaposi’s sarcoma,38,39 and perineal ulcerations.38 Barbara et a1.39 reported three AIDS patients who developed skin abscesses while under treatment with zidovudine. Disease was skin-limited and was apparently cured by surgical drainage in each case. The diagnosis of MA1 infection is made by Ziehl-Neilsen staining of purulent drainage or histologic staining of
68
ANGELES
Clinics in Dermatology 1991;9:65-69
skin biopsies and AFB culture. Effective and reliable treatment of MA1 infections is not currently available. The organism is resistant to all standard antituberculous agents. Experimental regimens involving a variety of antibacterial agents are being investigated.40,41 Other mycobacterial species have been implicated in case reports of cutaneous disease in AIDS patients. M. hemophilum was isolated from tender nodules on the upper arm in two patients. 43 The smears demonstrated numerous acid-fast bacilli. M. marinum was isolated from numerous ecthymatous lesions of the upper arm, and a biopsy revealed numerous acid-fast rods. The infection responded to INH, rifampin and amkicin.44 M. leprue was isolated from an annular anaesthetic lesion with raised borders and healing center from a Brazilian homosexual man. The lesion responded to INH, rifampin and ethambutol.45 Drug Names amphotericin B: Fungizone ketonconazole: Nizoral rifampin
References 1. Klein RS, Harris CA, Small CP, et al. Oral candidiasis in high risk patients. N Engl J Med 1984;6:354-58. 2. Welch K, Finkbeiner W, Alpers C, et al. Autopsy findings in the acquired immunodeficiency syndrome. Am J Path01 1983;112:357-82. 3. Kaplan MH, Sadick N, McNutt S, et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol 1987;3:485-506. 4. Goodman DS, Tepliz ED, Wishner A, et al. Prevalance of cutaneous disease in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. J Am Acad Dermatol 1987;2:210-20. 5. Whimby E, Gold JW, Polsky B, et al. Bacteria and fungemia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986;104:511-14. 6. Glott AE, Chergwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;22:1439-48. 7. Muhlemann MF, Anderson MG, Paradinas FJ, et al. Early warning skin signs in AIDS and persistent gemeralized lymphadenopathy. Br J Dermatol 1986;114:419-24. 8. Torssander J, Wasserman J, Morfeldt-Manson L, et al. Persistent generalized lymphadenopathy immunological and mycological investigations. Acta Dermatol Venereol 1985;65:515-20. 9. Penneys NS, Hichs B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;5:845-52.
10. Kovacs JA, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985;103:533-38. 11. Chu AC, Hay RJ, MacDonald DM. Cutaneous cryptococcosis. Br J Dermatol 1980;103:95-99. 12. Rico MJ, Penneys NS. Cutaneous cryptococcosis resembling molluscum contagiosum in a patient with AIDS. Arch Dermatol 1985;121:901-02. 13. Jones X, Orengo I, Rosen T, Ellmer K. Cutaneous cryptococcosis simulating Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Cutis 1990;45:163-67. 14. Borton LK, Wintronb BU. Disseminated cryptococcosis presenting as herpetiform lesions in a homosexual man with acquired immunodeficiency syndrome. J Am Acad Dermatol 1984;2:387-90. 15. Goodwin RA, Loyd JE, DesPrez RM. Histoplasmosis in normal hosts. Medicine 1981;60:231-66. 16. Bonner JR, Alexander WJ, Sismukes WE, et al. Disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Arch Intern Med 1984;144:217881. 17
Graybill JR. Histoplasmosis 1988;3:623-26.
and AIDS. Int Infect
Dis
18. Martin RA, Williams T, Montalto N. AIDS with disseminated histoplasmosis. J Fam Pratt 1989;6:628-32. 19. Mayoral F, Penneys NS. Disseminated histoplasmosis presenting as a transepidermal elimination disorder in an AIDS victim. J Am Acad Dermatol 1985;5:842-44. 20. Ibanez HE, Ibanez MA. Case report: a new presentation of disseminated histoplasmosis in a homosexual man with AIDS. Am J Med Sci 1989;6:407-09. 21. Samovitz M, Dillon TK. Disseminated histoplasmosis presenting as exfoliative erythroderma. Arch Dermatol 1970;101:216-19. 22. Kalter DC, Tschen JA, Klima M. Maculopapular rash in a patient with acquired immunodeficiency syndrome. Arch Derm 1985;121:1454-59. 23. Chanda JJ, Callen JP. Isolated nodular cutaneous histoplasmons. Arch Dermatol 1978;114:1197-98. 24. Studdard J, Sneed WF, Taylor MR. Cutaneous histoplasmosis. Am Rev Resp Dis 1976;113:689-93. 25. McKinsey DS, Gupta MR, Riddler SH, et al. Longterm amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome [AIDS). Ann Intern Med 1989;111:655-59. 26. Bronnimann DA, Adam RD, Galgiani JN et al. Coccidiodomycosis in the acquired immunodeficiency syndrome. Ann Intern Med 1987;103:372-79. 27. Wolfe JE, Pappagianis D, Kobayashi GS. Disseminated coc:idioidomycosis in a patient with acquired immunodefiziency syndrome. Diag Micro Infect Dis 1986;5:331-36. 28. Drutz DJ, Cutanzaro A. Coccidioidomycosis Rev Resp Dis 1978;117:727.
(Part II). Am
ANGELES
Clinics in Dermatology 1991;9:65-69
29. Ristrepo A. Paracoccidioides brasiliensis. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Disease. 3rd Ed. New York, Churchill Livingstone 1989:202-31. 30. Bahos L, Kronfeld M, Hompe S, et al. Disseminated paracoccidioidomycosis with skin lesions in a patient with acquired immunodeficiency syndrome. J Am Acad Dermatol 1989;5:854-55. 31. Sugar AM, Restrepo A, Steven DA. Paracoccidioidomycosis in the immunosuppressed host. Report of a case and review of the literature. Am Rev Resp Dis 1984;129:34952. 32. Bennett JE. Sporothrix Schenchii. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Disease. 3rd Ed. New York, Churchill Livingstone, 1989: 1972-75. 33. Lipstein-Kresch E, Isenber HD, Singer C, et al. Disseminated Sporothrix Schenchii infection with arthritis in a patient with acquired immunodeficiency syndrome. J Rheumotol 1985;4:805-81.
FUNGAL AND MYCOBACTERIAL
69
SKIN INFECTIONS
avirum complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 105:184-88. 38. Penneys NS, Hicks B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;5:845-52. 39. Freed JA, Pervez NK, Chen V, et al. Cutaneous mycobacteriosis: occurrence and significance in two patients with the acquired immunodeficiency syndrome. Arch Dermatol 1987;123:1601-03. 40. Barbaro DJ, Orcutt VL, Coldiron BM. Mycobacterium avium-intracellulave infection limited to the skin and lymphnodes in patients with AIDS. Rev Infect Dis 1989;11:625-28. 41. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;22:1439-48. 42. Prince DS, Pterson DD, Steiner RM, et al. Infection with Mycobacterium avium-complex in patients without predisposing conditions. N Engl J Med 1989;321:863-68.
34. Kurosawa A, Polloch SC, Collins MI’, et al. Sporothrix Schenchii endophtholmitis in a patient wi:h human immunodeficiency virus infection. Arch Ophthamol 1988; 106:376-80.
43. Rogers PL, Walker RE, Lane HC. Disseminated mycobacterium haemophilum infection in two patients with the acquired immunodeficiency syndrome. Am J Med 1988; 84:640-42.
35. Shelly WB, Sicca PA. Disseminated sporotrichosis of skin and bone cured with 5-flurocytosine: photosensitivity as a complication. J Am Acad Dermatol 1983;8:229-35.
44. Kaplan MH, Sadick N, McNutt NS, et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol1987;16:485-506.
36. Collins FM. Mycobacterial disease, immunosuppression and acquired immunodeficiency syndrome. Clin Microbial Rev 1989;4:360-77.
45. Lamfers EJ, Bastiaans Ah, Mravunac M, et al. Leprosy in the acquired immunodeficiency syndrome. Am Intern Med 1987;1:111-12.
37. Hawkins CC, Gold JW, Whimby E, et al. Mycobacterium
M. ANGELES,
MD
he manifestations of opportunistic infections in AIDS patients are dependent upon the nature and severity of the patients’ immunologic defects. AIDS patients have, primarily, a cell-mediated immunodeficiency and are subsequently at increased risk for developing fungal infections. Fungal infections can be divided into two categories: superficial and systemic.
T
Superficial Superficial infections are generally less aggressive and do not usually produce disseminated disease, even in the most severely compromised cases. Candida species are a common cause of superficial infection in the AIDS patient, and Candida ulbicuns is one of the most commonly isolated pathogens. C. ulbicans is a 4-6 ,uM oval budding cell which forms hyphae and pseudo-hyphae and is isolated in over 80% of AIDS cases.’ The most common candidal lesion is the buccal or lingual plaque (thrush) (Plate 24), which may extend to involve the oropharynx. This is frequently an incidental finding that may prompt an HIV work-up. The presence of unexplained oral candidiasis in a prospective study of IV drug abusers and homosexual men predated the diagnosis of AIDS in 59% of the patients.* In AIDS patients, the pattern of infection caused by Candida is similar to that seen in other immunocompromised hosts, except that the lesions may be more extensive and may require prolonged therapy. Paronychia and onycholysis secondary to Cundidu have also been reported in HIV patients, and Kaplan and colleagues3 suggest that there is a correlation between decreased numbers of T-helper cells and severity of disease. Candida may also cause chronic infection of vulva, From the Department of Dermatology, Jefferson Medical College, Thomas jefferson University, Philadelphia, Pennsylvania. Address correspondence to: Anne M. Angeles, MD, 509 Prescott Road, Merion, PA 19066.
0
1991
by Elsevier
Science Publishing Co., Inc. 0738-081x/91/$3.50 l
groin or glabrous skin. 4 Candidemia is a rare occurrence in AIDS patients, which may be due to relatively intact phagocytes and B-cell immunity. Candidemia is most often found in patients with an indwelling catheter.5 The diagnosis of candidal infection may be made by biopsy or scraping of a lesion and demonstrating budding yeast with pseudohyphae on potassium hydroxide (KOH) preparation Culture of the lesions is often useful on the skin, but may yield misleading data when mucosae are cultured, because the yeast may be present in normal individuals. The treatment of mucocutaneous candidosis usually requires topical or systemic ketoconazole (200 - 400 mg/ day) or clotrimazole (30 -50 mg/day). Amphotericin B IV may be used for severe pharyngitis. Recurrences are common and maintenance therapy is often required.6 Dermatophyte infections are very common in AIDS patients and are reported to affect 30 - 56% of this population.3*4*7,8These infections have atypical morphologies and may be widespread and in unusual locations. The most common dermatophytoses are tinea pedis and onychomycosis causing deformity and discoloration.4 Tinea corporis and cruris have the typical clinical appearance, but are usually more extensive and somewhat less exuberant than when seen in the normal host (Plates 25 and 26). Tinea faciale resembling erythema multiforme and discrete flat-topped papules has been reported.9 As in the noncompromised form, Trichophyfon rubrum is a frequent isolate. The diagnosis of dermatophytosis is made by KOH preparation and cultures of scrapings or biopsies. Often, biopsy is required to demonstrate a fungal element. Dermatophyte infections may be treated successfully with newer antifungal creams such as griseofulvin or ketoconazole in usual doses.
Systemic Cutaneous manifestations of systemic fungal infections are also noted in AIDS patients. The clinical cutaneous
65
66
ANGELES
involvement may be subtle and a high index of suspicion together with appropriate biopsies for pathologic and microbiologic evaluation will permit early and accurate diagnosis of these diseases. Cyptococcus neofOrmans is a pathogen in patients with immune suppression other than AIDS, including transplant recipients, and patients with lymphoreticular malignancies, diabetes mellitus and systemic lupus erythematosus. Infections are also seen in normal hosts. In AIDS patients, C. neoformans is reported to be the fourth most commonly recognized cause of life-threatening infection.‘O The organism, a soil saprophyte, is also found in pigeon excreta and is a round budding yeast with a prominant capsule. C. neoformuns infections are acquired by inhalation of the spores into the lungs with subsequent dissemination. The central nervous system and skin are the most commonly involved extrapulmonary sites.” Cutaneous involvement is seen in 10 - 20% of disseminated disease in AIDS patients.” There is no typical lesion morphology. A fungal etiology is often unsuspected since the lesions may appear very nonspecific. Reported presentations include subcutaneous nodules, nonhealing ulcers, cellulitus and acneiform lesions. In addition, symptoms may include atypical, polymorphic umbillicated papules (resembling molluscum contagiosum),12 violacious papules and plaques simulating Kaposi’s sarcornal and herpetiform lesions.14 Since cutaneous signs may be the first manifestations of systemic disease, early diagnosis may be lifesaving and a high index of suspicion is required. The diagnosis of infection is made by visualization of the organism in smears from involved tissue on india ink or Tzank preparations. On skin biopsy, the organism stains red with PAS and mucicarmine. The treatment of disseminated cryptococcosis is IV amphotericin B (0.4-0.6 mg/kg/day), with a total dose of 1.5 - 2 g. Therapy with amphotericin B is not curative and relapses occur in over 50% of patients6 One study demonstrated that maintenance therapy of amphotericin B (100 mg/week) prevented relapse.6 Efficacy of treatment with ketoconazole (800 - 1000 mg/day), fluconozole and itraconozole remains to be studied. Histoplasma capsulutum is a dimorphic fungus endemic to the river valleys of the eastern and central United States, the Caribbean and South America. The organism is virulent and will infect exposed normal individuals, but the illness is usually asymptomatic or causes only very mild upper respiratory tract symptoms. With moderate exposure, symptomatic respiratory illness may be noted. Reinfection with dissemination may be seen in the heavily-exposed normal host or in the immunocompromised host.15 The organism is 3 - 4 PM, oval, budding, uninucleated, intracellular, and surrounded by a halo resem-
Clinics in Dermatology 1991;9:65-69 bling a capsule, but which is actually an artifact of the staining technique. AIDS patients develop a disseminated, more aggressive infection than the normal host. The typical clinical presentation is that of a prolonged, febrile course with hypotension, hypoxia, renal, and hepatic insufficiency.16*17 Fungemia is reported in 2 - 37% of infected AIDS patients.5J7 Cutaneous lesions are reported in approximately 10% of patients with disseminated disease and are rarely the presenting symptom.16 Like cryptococcosis, disseminated histoplasmosis has protein cutaneous manifestations. Oral ulcerations or nodules,23 papules and plaques with or without keratinous plugs,19,22 deep ulcers,24 exfoliative erythroderma,*l and pustules20 all have been reported. The diagnosis may be confirmed by the presence of the budding yeast in biopsied tissues on stained smears. The organism is small, intracellular and budding, and found within macrophages. It may be detected using PAS stain, but it does not stain with mucicarmine. The treatment of disseminated histoplasmosis with amphotericin B (0.6 mg/kg/day) in the non-AIDS patient shows a cure rate of approximately 90%. In the AIDS patients, amphotericin B is much less effective and a high relapse rate is reported. Maintenance therapy with ketoconozole (400 mg/day) is recommended.25 Coccidioidomycosis is endemic in the western and southwestern United States and northern Mexico. Coccidioides immitis exists in the soil, and the primary route of infection is inhalation of the spores. The organism is a large, 5 - 60 ,uM, thick-walled, round cell which contains endospores. Symptomatic infections occur in approximately 40% of exposed normal host individuals. The disease is manifest in the lower respiratory tract. Erythema nodosum or erythema multiforme may develop during infection. Immunosuppression predisposes the patient to reactivation of quiescent disease or to a progressive infection that may disseminate. Patients with AIDS have been reported with disseminated coccidioidomycosis both within and without endemic areas.26,27 In Arizona, a highly endemic area, infection occurred in AIDS patients in one report.26 The skin manifestations of coccidioidal disease in AIDS do not appear to be common, but if present, they may be helpful in making the diagnosis. The clinical presentation in the AIDS patient is fever, malaise, and cough with a chest x-ray demonstrating diffuse, bilateral reticulo nodular infiltrates. No typical lesions of disseminated disease, such as cutaneous abscesses, joint effusions, or bone destruction, were noted in any of these patients.26
Clinics in Dermatology 1991:9:65-69 There is a report of one AIDS patient with disseminated coccidioidomycosis. This patient had tender abscesses of the buttock at sites of pentamidine injections. Cultures subsequently grew C. immitis.27 The diagnosis of disseminated coccidioidomycosis is made by isolating the organism from involved tissues. The treatment of C. immitis infections in the AIDS patient is problematic since amphotericin B is not fungicida1 for the organism2* and host immunity is an important factor in recovery. Four out of seven patients in one study were treated solely with amphotericin B; three patients initially improved, but subsequently relapsed and died. Three additional patients were treated with a combination of amphotericin B and ketoconazole. Again, the patients initially responded, but eventually relapsed and died.26 Initial therapy with males also include amphoteritin B for a cumulative dose of 1 - 2.5 g, followed by suppressive therapy with ketoconazole (400 mg/day). Paracoccidioides brasiliensis is a dimorphic fungus and the etiologic agent of paracoccidioidomycosis, or South American blastomycosis. It is endemic in South America. The fungus is an oval cell (4 - 40 PM) and reproduces by multiple budding “pilot wheels” with refractile capsules. The lungs are the primary site of infection and dissemination is common even in the normal host. The disease may have a long latency of up to 30 years.29 The primary infection may be subclinical and may become reactivated when the host is immunosuppressed. Mucosal and cutaneous manifestation are common. The mucosal lesions are peri- and intraoral ulcerations and infiltrations. The skin lesions are warty, ulcerated nodules around the nose and mouth.31 There is one report of a patient with disseminated paracoccidioidomycosis with skin lesions.30 He was a homosexual man from Brazil who presented with small ulcers with raised borders surrounded by an erythematous halo around the nose and mouth and on the right thigh. Biopsy of an ulcer showed a granuloma with round spores surrounded by a doubly refractile capsule which morphologically resembled P. brazilieusis. The chest x-ray demonstrated diffuse bilateral micronodules. The authors do not state if the organism was cultured from the ulcers. The patient was treated with amphotericin B, with complete resolution of lesions. The diagnosis of disseminated paracoccidioidomycosis is made by demonstrating the organism in affected tissues. Successful treatment in the normal host is with sulfadiazine 4 - 6 g/day until lesions clear, then 2 - 3 g/day for 3 -5 year, amphotericin B, 0.4 -0.6 mg/kg/day or ketoconazole 200 -400 mg/day for 6- 18 months.31 Sporothrix schenckii is a dimorphic fungus that is found in the soil and in living plants. The cells are 4-6 PM,
ANGELES FUNGAL AND MYCOBACTERIAL SKIN INFECTIONS
67
cigar-shaped or oval structures. The clinical presentation of infection is primarily cutaneous. The typical lesion begins as an erythematous papule and then develops suppurative nodules along the lymphatic channels.32 In the immunocompromised host an extracutaneous disseminated form and a multifocal cutaneous form of the disease are described.32 The primary route of infection may be cutaneous or pulmonary with hematogenous spread. Disseminated sporotrichosis is reported in two patients with AIDS.33*34 One had many cutaneous ulcerations and end-ophthalmitis secondary to disseminated disease,34 and the other had subcutaneous nodules and erythematous pustules on the trunk and extremities with tender joints. Sporotrichosis was diagnosed by biopsies, skin scraping and culture. Diagnosis of sporotrichosis is made by KOH preparation of skin scrapings and culture of biopsied lesions. Potassium iodide is effective in localized sporotrichosis, but disseminated disease requires amphotericin B IV 0.4 0.6 mg/kg/day. There are scattered case reports of the successful use of 5-fluorocytosine in sporotrichosis.35 No disseminated infections with Blastomyces dermatitidis have been described in AIDS patients to date. This may be due to differences in immunopathogenesis of these infections.
Mycobacterial
Infections
in AIDS
Skin Manifesfafions Mycobacteria are frequently the cause of opportunistic infections in AIDS patients. It is reported that 50% of all AIDS patients will develop mycobacterial infection at some stage of the disease. 36 Cutaneous disease rarely occurs in the absence of disseminated disease. The most commonly isolated organism is Mycobacterium avium-intrucellulare (MAI). Several reports indicate that 25-67% of mycobacterial isolates are MA1 in the AIDS population. 36,37The typical presentation is fever, malaise, weight loss, diarrhea and abdominal pain. Cutaneous involvement does occur and in one study MA1 was cultured from the skin postmortum in 37% of patients with disseminated disease.37 Several cutaneous lesions have been reported: cutaneous abscesses, ill-defined mascular discolored lesions simulating Kaposi’s sarcoma,38,39 and perineal ulcerations.38 Barbara et a1.39 reported three AIDS patients who developed skin abscesses while under treatment with zidovudine. Disease was skin-limited and was apparently cured by surgical drainage in each case. The diagnosis of MA1 infection is made by Ziehl-Neilsen staining of purulent drainage or histologic staining of
68
ANGELES
Clinics in Dermatology 1991;9:65-69
skin biopsies and AFB culture. Effective and reliable treatment of MA1 infections is not currently available. The organism is resistant to all standard antituberculous agents. Experimental regimens involving a variety of antibacterial agents are being investigated.40,41 Other mycobacterial species have been implicated in case reports of cutaneous disease in AIDS patients. M. hemophilum was isolated from tender nodules on the upper arm in two patients. 43 The smears demonstrated numerous acid-fast bacilli. M. marinum was isolated from numerous ecthymatous lesions of the upper arm, and a biopsy revealed numerous acid-fast rods. The infection responded to INH, rifampin and amkicin.44 M. leprue was isolated from an annular anaesthetic lesion with raised borders and healing center from a Brazilian homosexual man. The lesion responded to INH, rifampin and ethambutol.45 Drug Names amphotericin B: Fungizone ketonconazole: Nizoral rifampin
References 1. Klein RS, Harris CA, Small CP, et al. Oral candidiasis in high risk patients. N Engl J Med 1984;6:354-58. 2. Welch K, Finkbeiner W, Alpers C, et al. Autopsy findings in the acquired immunodeficiency syndrome. Am J Path01 1983;112:357-82. 3. Kaplan MH, Sadick N, McNutt S, et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol 1987;3:485-506. 4. Goodman DS, Tepliz ED, Wishner A, et al. Prevalance of cutaneous disease in patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex. J Am Acad Dermatol 1987;2:210-20. 5. Whimby E, Gold JW, Polsky B, et al. Bacteria and fungemia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986;104:511-14. 6. Glott AE, Chergwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;22:1439-48. 7. Muhlemann MF, Anderson MG, Paradinas FJ, et al. Early warning skin signs in AIDS and persistent gemeralized lymphadenopathy. Br J Dermatol 1986;114:419-24. 8. Torssander J, Wasserman J, Morfeldt-Manson L, et al. Persistent generalized lymphadenopathy immunological and mycological investigations. Acta Dermatol Venereol 1985;65:515-20. 9. Penneys NS, Hichs B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;5:845-52.
10. Kovacs JA, Kovacs AA, Polis M, et al. Cryptococcosis in the acquired immunodeficiency syndrome. Ann Intern Med 1985;103:533-38. 11. Chu AC, Hay RJ, MacDonald DM. Cutaneous cryptococcosis. Br J Dermatol 1980;103:95-99. 12. Rico MJ, Penneys NS. Cutaneous cryptococcosis resembling molluscum contagiosum in a patient with AIDS. Arch Dermatol 1985;121:901-02. 13. Jones X, Orengo I, Rosen T, Ellmer K. Cutaneous cryptococcosis simulating Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Cutis 1990;45:163-67. 14. Borton LK, Wintronb BU. Disseminated cryptococcosis presenting as herpetiform lesions in a homosexual man with acquired immunodeficiency syndrome. J Am Acad Dermatol 1984;2:387-90. 15. Goodwin RA, Loyd JE, DesPrez RM. Histoplasmosis in normal hosts. Medicine 1981;60:231-66. 16. Bonner JR, Alexander WJ, Sismukes WE, et al. Disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome. Arch Intern Med 1984;144:217881. 17
Graybill JR. Histoplasmosis 1988;3:623-26.
and AIDS. Int Infect
Dis
18. Martin RA, Williams T, Montalto N. AIDS with disseminated histoplasmosis. J Fam Pratt 1989;6:628-32. 19. Mayoral F, Penneys NS. Disseminated histoplasmosis presenting as a transepidermal elimination disorder in an AIDS victim. J Am Acad Dermatol 1985;5:842-44. 20. Ibanez HE, Ibanez MA. Case report: a new presentation of disseminated histoplasmosis in a homosexual man with AIDS. Am J Med Sci 1989;6:407-09. 21. Samovitz M, Dillon TK. Disseminated histoplasmosis presenting as exfoliative erythroderma. Arch Dermatol 1970;101:216-19. 22. Kalter DC, Tschen JA, Klima M. Maculopapular rash in a patient with acquired immunodeficiency syndrome. Arch Derm 1985;121:1454-59. 23. Chanda JJ, Callen JP. Isolated nodular cutaneous histoplasmons. Arch Dermatol 1978;114:1197-98. 24. Studdard J, Sneed WF, Taylor MR. Cutaneous histoplasmosis. Am Rev Resp Dis 1976;113:689-93. 25. McKinsey DS, Gupta MR, Riddler SH, et al. Longterm amphotericin B therapy for disseminated histoplasmosis in patients with the acquired immunodeficiency syndrome [AIDS). Ann Intern Med 1989;111:655-59. 26. Bronnimann DA, Adam RD, Galgiani JN et al. Coccidiodomycosis in the acquired immunodeficiency syndrome. Ann Intern Med 1987;103:372-79. 27. Wolfe JE, Pappagianis D, Kobayashi GS. Disseminated coc:idioidomycosis in a patient with acquired immunodefiziency syndrome. Diag Micro Infect Dis 1986;5:331-36. 28. Drutz DJ, Cutanzaro A. Coccidioidomycosis Rev Resp Dis 1978;117:727.
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29. Ristrepo A. Paracoccidioides brasiliensis. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Disease. 3rd Ed. New York, Churchill Livingstone 1989:202-31. 30. Bahos L, Kronfeld M, Hompe S, et al. Disseminated paracoccidioidomycosis with skin lesions in a patient with acquired immunodeficiency syndrome. J Am Acad Dermatol 1989;5:854-55. 31. Sugar AM, Restrepo A, Steven DA. Paracoccidioidomycosis in the immunosuppressed host. Report of a case and review of the literature. Am Rev Resp Dis 1984;129:34952. 32. Bennett JE. Sporothrix Schenchii. In: Mandell GL, Douglas RG, Bennett JE, eds. Principles and Practice of Infectious Disease. 3rd Ed. New York, Churchill Livingstone, 1989: 1972-75. 33. Lipstein-Kresch E, Isenber HD, Singer C, et al. Disseminated Sporothrix Schenchii infection with arthritis in a patient with acquired immunodeficiency syndrome. J Rheumotol 1985;4:805-81.
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SKIN INFECTIONS
avirum complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 105:184-88. 38. Penneys NS, Hicks B. Unusual cutaneous lesions associated with acquired immunodeficiency syndrome. J Am Acad Dermatol 1985;5:845-52. 39. Freed JA, Pervez NK, Chen V, et al. Cutaneous mycobacteriosis: occurrence and significance in two patients with the acquired immunodeficiency syndrome. Arch Dermatol 1987;123:1601-03. 40. Barbaro DJ, Orcutt VL, Coldiron BM. Mycobacterium avium-intracellulave infection limited to the skin and lymphnodes in patients with AIDS. Rev Infect Dis 1989;11:625-28. 41. Glatt AE, Chirgwin K, Landesman SH. Treatment of infections associated with human immunodeficiency virus. N Engl J Med 1988;22:1439-48. 42. Prince DS, Pterson DD, Steiner RM, et al. Infection with Mycobacterium avium-complex in patients without predisposing conditions. N Engl J Med 1989;321:863-68.
34. Kurosawa A, Polloch SC, Collins MI’, et al. Sporothrix Schenchii endophtholmitis in a patient wi:h human immunodeficiency virus infection. Arch Ophthamol 1988; 106:376-80.
43. Rogers PL, Walker RE, Lane HC. Disseminated mycobacterium haemophilum infection in two patients with the acquired immunodeficiency syndrome. Am J Med 1988; 84:640-42.
35. Shelly WB, Sicca PA. Disseminated sporotrichosis of skin and bone cured with 5-flurocytosine: photosensitivity as a complication. J Am Acad Dermatol 1983;8:229-35.
44. Kaplan MH, Sadick N, McNutt NS, et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol1987;16:485-506.
36. Collins FM. Mycobacterial disease, immunosuppression and acquired immunodeficiency syndrome. Clin Microbial Rev 1989;4:360-77.
45. Lamfers EJ, Bastiaans Ah, Mravunac M, et al. Leprosy in the acquired immunodeficiency syndrome. Am Intern Med 1987;1:111-12.
37. Hawkins CC, Gold JW, Whimby E, et al. Mycobacterium
