- Email: [email protected]
Molluscum or a Mimic?
The American Journal of Medicine (2006) 119, 927-929
IMAGES IN DERMATOLOGY Parwathi “Uma” Paniker, MD, Section Editor
AJM Theme Issue: Infectious Disease
Molluscum or a Mimic? Jonas A. de Souza, MD Department of Internal Medicine, The University of Texas Health Science Center, Houston, Tex.
PRESENTATION A 42-year-old Hispanic man, diagnosed with HIV/AIDS in 1990, presented with a 3-week history of diffuse headache and a 2-week history of asymptomatic papules on his head, neck, and extremities. Some of the skin lesions had been treated with curettage the week before by his primary care physician, who suspected Molluscum contagiosum. The patient decided to seek medical attention again when the symptoms remained unresolved. His past medical history was also significant for Pneumocystis jiroveci pneumonia, anal Herpes simplex infection, and oral candidiasis. He was not taking any medication and had a history of noncompliance with his antiretroviral treatment.
ASSESSMENT Upon examination, the patient had normal vital signs and was in no distress. The lesions on his head, neck, and extremities were firm, dome-shaped, well-defined, skin-colored papules, measuring 2-4 mm in diameter. A few had central umbilication and a hemorrhagic crust (Figures 1-2). He had no nuchal rigidity or focal neurologic deficits. A thorough ophthalmologic examination showed no papilledema, hemorrhage, or retinitis. An initial laboratory examination indicated pancytopenia, a CD4 count of 23 cells/ mm3, a nondetectable viral load, and an estimated creatinine clearance of 44 mL/min. The chest x-ray was normal. Lumbar puncture, performed to investigate the patient’s headache, disclosed an opening pressure of 280 mm of water. Protein levels in the cerebrospinal fluid were 55 mg/dL; glucose levels were 38 mg/dL. No white cells were present. The India ink examination showed encapsulated yeast, and cryptococcal capsular antigen was detectable in both the cerebrospinal fluid and serum specimens with titers greater than 1:256 and 1:512, respectively. Cultures of blood, cerebrospinal fluid, and bone marrow yielded CrypRequests for reprints should be addressed to Jonas de Souza, MD, Department of Internal Medicine, The University of Texas Health Science Center, 6431 Fannin Street, MSB 1.150, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.08.018
tococcus neoformans. Examination of biopsy specimens from the lesions on the neck and left hand also identified the organism.
DIAGNOSIS Centrally-umbilicated papules are highly suggestive of Molluscum contagiosum, but cutaneous papules or nodules in HIV-seropositive patients can also be seen with fungal infections caused by Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, or atypical and typical mycobacteria; leishmaniasis; bacterial infections caused by Bartonella quintana and B. henselae; human papillomavirus infections; and Kaposi’s sarcoma.1,2 Based on our findings, a diagnosis of disseminated cryptococcal infection with meningeal, skin, and bone marrow involvement was rendered. Although the number of cryptococcosis cases has declined since the availability of highly active antiretroviral therapy, it is still one of the most common systemic fungal diseases in HIV-infected patients.3 The skin can be involved in 10% of those with systemic disease, and while the lesions can occur anywhere, the most common sites are the head and neck.4 Reported cutaneous findings include subcutaneous nodules, papules, ulcers (including ulcers suggestive of pyoderma gangrenosum), cellulitis, palpable purpura, herpetiform lesions, and lesions resembling Kaposi’s sarcoma.4,5,6 As in our patient, cryptococcal lesions presenting as umbilicated papules can be mistaken for M. contagiosum. Similarly, vesicles are often wrongly diagnosed as H. simplex or H. zoster, or on occasion, bacterial cellulitis, which is then erroneously treated with antibiotics.7 Papules, a more acute onset, and the presence of a tiny central hemorrhagic crust are characteristic of cryptococcosis and help distinguish it from M. contagiosum.8 Cutaneous lesions of cryptococcosis almost always represent hematogenous dissemination and require a thorough work-up to determine what other organs are involved. The diagnosis of invasive cryptococcosis can be made by detection of cryptococcal polysaccharide antigen in
928
The American Journal of Medicine, Vol 119, No 11, November 2006
Figure 1
Lesions were mainly localized on the head and neck.
the serum, cerebrospinal fluid, or urine. Latex agglutination and enzyme immunoassay tests are greater than 90% sensitive and specific for the antigen.9 While most clinical experience has been obtained with cerebrospinal and serum specimens, the tests have also been used on urine or bronchoalveolar lavage fluid.10 India ink stain can be used to show the large cryptococcus capsule— over 80% of patients with AIDS and cryptococcal meningitis have
Figure 2
a positive stain when cerebrospinal fluid is tested. The mucocutaneous biopsy can be confirmed with the periodic acid-Schiff, mucicarmine, methenamine silver, and/or the Fontana-Masson stain.4 The Gram’s stain usually reveals poorly-stained, gram-positive yeast. Lesions must be biopsied when suspecting cutaneous cryptococcosis, not only because they usually represent disseminated disease, but because C. neoformans may occur
Papules were centrally-umbilicated papules, and a few had a hemorrhagic crust.
de Souza
Images in Dermatology
simultaneously with other infectious diseases or Kaposi’s sarcoma.1,11
MANAGEMENT The treatment of choice for acute cryptococcal disease is intravenous amphotericin B and oral flucytosine for a 2-week induction period, followed by consolidation therapy with oral fluconazole for at least 8 weeks.12,13 While combining flucytosine and amphotericin B during acute treatment does not improve immediate outcome, it decreases the risk for relapse.13 Even with use of highly active antiretroviral therapy, it is recommended that HIV-infected individuals who have had cryptococcosis continue maintenance antifungal therapy for life, usually with oral fluconazole.14 Recent data suggest that with adherence to highly active antiretroviral therapy, the immune system might recover sufficiently to allow discontinuation of antifungal agents after 1-2 years of therapy if patients have a CD4 count above 200 cells/mm3 for a period of at least 6 months, a nondetectable viral load, and a negative serum cryptococcal antigen. However, formal recommendations have yet to be devised.15,16 Our patient received the liposomal amphotericin B, Ambisome, 4 mg/kg/d, due to his impaired renal function.17 He also took oral flucytosine, 100 mg/kg/d. After 2 weeks he was switched to oral fluconazole, 200 mg/d, for 8 weeks, and then finally, the dosage was decreased to 100 mg/d as maintenance therapy. He was also restarted on highly active antiretroviral therapy. The patient did well, suffering no headaches after induction therapy, and the lesions gradually resolved. Three months later, his skin was free of lesions. This case clearly illustrates that in the HIV-seropositive population, infectious diseases can easily mimic each other. In these patients, biopsy of new lesions with culture and histopathology is essential, since these might be sentinel symptoms of disseminated disease.
References 1. Garman ME, Tyring SK. The cutaneous manifestations of HIV infection. Dermatol Clin. 2002;20:193-208. 2. Aftergut K, Cockerell CJ. Update on the cutaneous manifestations of HIV infection. Clinical and pathologic features. Dermatol Clin. 1999; 17:445-71.
929 3. Mirza SA, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis. 2003;36:789794. 4. Hernandez AD. Cutaneous cryptococcosis. Dermatol Clin. 1989;7: 269-274. 5. Jones C, Orengo I, Rosen T, Ellner K. Cutaneous cryptococcosis simulating Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Cutis. 1990; 45:163-167. 6. Manrique P, Mayo J, Alvarez JA., Ganchequi X, Zabalza I, Flores M. Polymorphous cutaneous cryptococcosis: nodular, herpes-like, and molluscum-like lesions in a patient with the acquired immunodeficiency syndrome. J Am Acad Dermatol. 1992;26:122-124. 7. Gauder JP. Cryptococcal cellulitis. JAMA. 1977;237:672-673. 8. Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol. 1996;132:545-548. 9. Tanner DC, Weinstein MP, Fedorciw B., Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol. 1994;32:1680-1684. 10. Baughman RP, Rhodes JC, Dohn MN, Henderson H, Frame PT. Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. Am Rev Respir Dis. 1992;145: 1126-1129. 11. Glassman SJ, Hale MJ. Cutaneous cryptococcosis and Kaposi’s sarcoma occurring in the same lesions in a patient with the acquired immunodeficiency syndrome. Clin Exp Dermatol. 1995;20:480-486. 12. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents. MMWR Morb Mortal Wkly Rep 2004;53(RR-15):1-112. 13. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for the treatment of cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med. 1990;113:183-187. 14. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med. 1992;326:793-798. 15. Martinez E, Garcia-Viejo MA, Marcos MA. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy. AIDS. 2000; 14:2615-2617. 16. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus–infected patients treated with highly active antiretroviral therapy: A prospective, multicenter randomized study. Clin Infect Dis. 2003;36:1329-1331. 17. Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (Ambisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 1997;11:1463-1471.
IMAGES IN DERMATOLOGY Parwathi “Uma” Paniker, MD, Section Editor
AJM Theme Issue: Infectious Disease
Molluscum or a Mimic? Jonas A. de Souza, MD Department of Internal Medicine, The University of Texas Health Science Center, Houston, Tex.
PRESENTATION A 42-year-old Hispanic man, diagnosed with HIV/AIDS in 1990, presented with a 3-week history of diffuse headache and a 2-week history of asymptomatic papules on his head, neck, and extremities. Some of the skin lesions had been treated with curettage the week before by his primary care physician, who suspected Molluscum contagiosum. The patient decided to seek medical attention again when the symptoms remained unresolved. His past medical history was also significant for Pneumocystis jiroveci pneumonia, anal Herpes simplex infection, and oral candidiasis. He was not taking any medication and had a history of noncompliance with his antiretroviral treatment.
ASSESSMENT Upon examination, the patient had normal vital signs and was in no distress. The lesions on his head, neck, and extremities were firm, dome-shaped, well-defined, skin-colored papules, measuring 2-4 mm in diameter. A few had central umbilication and a hemorrhagic crust (Figures 1-2). He had no nuchal rigidity or focal neurologic deficits. A thorough ophthalmologic examination showed no papilledema, hemorrhage, or retinitis. An initial laboratory examination indicated pancytopenia, a CD4 count of 23 cells/ mm3, a nondetectable viral load, and an estimated creatinine clearance of 44 mL/min. The chest x-ray was normal. Lumbar puncture, performed to investigate the patient’s headache, disclosed an opening pressure of 280 mm of water. Protein levels in the cerebrospinal fluid were 55 mg/dL; glucose levels were 38 mg/dL. No white cells were present. The India ink examination showed encapsulated yeast, and cryptococcal capsular antigen was detectable in both the cerebrospinal fluid and serum specimens with titers greater than 1:256 and 1:512, respectively. Cultures of blood, cerebrospinal fluid, and bone marrow yielded CrypRequests for reprints should be addressed to Jonas de Souza, MD, Department of Internal Medicine, The University of Texas Health Science Center, 6431 Fannin Street, MSB 1.150, Houston, TX 77030. E-mail address: [email protected]
0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2006.08.018
tococcus neoformans. Examination of biopsy specimens from the lesions on the neck and left hand also identified the organism.
DIAGNOSIS Centrally-umbilicated papules are highly suggestive of Molluscum contagiosum, but cutaneous papules or nodules in HIV-seropositive patients can also be seen with fungal infections caused by Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus neoformans, Histoplasma capsulatum, Paracoccidioides brasiliensis, Sporothrix schenckii, or atypical and typical mycobacteria; leishmaniasis; bacterial infections caused by Bartonella quintana and B. henselae; human papillomavirus infections; and Kaposi’s sarcoma.1,2 Based on our findings, a diagnosis of disseminated cryptococcal infection with meningeal, skin, and bone marrow involvement was rendered. Although the number of cryptococcosis cases has declined since the availability of highly active antiretroviral therapy, it is still one of the most common systemic fungal diseases in HIV-infected patients.3 The skin can be involved in 10% of those with systemic disease, and while the lesions can occur anywhere, the most common sites are the head and neck.4 Reported cutaneous findings include subcutaneous nodules, papules, ulcers (including ulcers suggestive of pyoderma gangrenosum), cellulitis, palpable purpura, herpetiform lesions, and lesions resembling Kaposi’s sarcoma.4,5,6 As in our patient, cryptococcal lesions presenting as umbilicated papules can be mistaken for M. contagiosum. Similarly, vesicles are often wrongly diagnosed as H. simplex or H. zoster, or on occasion, bacterial cellulitis, which is then erroneously treated with antibiotics.7 Papules, a more acute onset, and the presence of a tiny central hemorrhagic crust are characteristic of cryptococcosis and help distinguish it from M. contagiosum.8 Cutaneous lesions of cryptococcosis almost always represent hematogenous dissemination and require a thorough work-up to determine what other organs are involved. The diagnosis of invasive cryptococcosis can be made by detection of cryptococcal polysaccharide antigen in
928
The American Journal of Medicine, Vol 119, No 11, November 2006
Figure 1
Lesions were mainly localized on the head and neck.
the serum, cerebrospinal fluid, or urine. Latex agglutination and enzyme immunoassay tests are greater than 90% sensitive and specific for the antigen.9 While most clinical experience has been obtained with cerebrospinal and serum specimens, the tests have also been used on urine or bronchoalveolar lavage fluid.10 India ink stain can be used to show the large cryptococcus capsule— over 80% of patients with AIDS and cryptococcal meningitis have
Figure 2
a positive stain when cerebrospinal fluid is tested. The mucocutaneous biopsy can be confirmed with the periodic acid-Schiff, mucicarmine, methenamine silver, and/or the Fontana-Masson stain.4 The Gram’s stain usually reveals poorly-stained, gram-positive yeast. Lesions must be biopsied when suspecting cutaneous cryptococcosis, not only because they usually represent disseminated disease, but because C. neoformans may occur
Papules were centrally-umbilicated papules, and a few had a hemorrhagic crust.
de Souza
Images in Dermatology
simultaneously with other infectious diseases or Kaposi’s sarcoma.1,11
MANAGEMENT The treatment of choice for acute cryptococcal disease is intravenous amphotericin B and oral flucytosine for a 2-week induction period, followed by consolidation therapy with oral fluconazole for at least 8 weeks.12,13 While combining flucytosine and amphotericin B during acute treatment does not improve immediate outcome, it decreases the risk for relapse.13 Even with use of highly active antiretroviral therapy, it is recommended that HIV-infected individuals who have had cryptococcosis continue maintenance antifungal therapy for life, usually with oral fluconazole.14 Recent data suggest that with adherence to highly active antiretroviral therapy, the immune system might recover sufficiently to allow discontinuation of antifungal agents after 1-2 years of therapy if patients have a CD4 count above 200 cells/mm3 for a period of at least 6 months, a nondetectable viral load, and a negative serum cryptococcal antigen. However, formal recommendations have yet to be devised.15,16 Our patient received the liposomal amphotericin B, Ambisome, 4 mg/kg/d, due to his impaired renal function.17 He also took oral flucytosine, 100 mg/kg/d. After 2 weeks he was switched to oral fluconazole, 200 mg/d, for 8 weeks, and then finally, the dosage was decreased to 100 mg/d as maintenance therapy. He was also restarted on highly active antiretroviral therapy. The patient did well, suffering no headaches after induction therapy, and the lesions gradually resolved. Three months later, his skin was free of lesions. This case clearly illustrates that in the HIV-seropositive population, infectious diseases can easily mimic each other. In these patients, biopsy of new lesions with culture and histopathology is essential, since these might be sentinel symptoms of disseminated disease.
References 1. Garman ME, Tyring SK. The cutaneous manifestations of HIV infection. Dermatol Clin. 2002;20:193-208. 2. Aftergut K, Cockerell CJ. Update on the cutaneous manifestations of HIV infection. Clinical and pathologic features. Dermatol Clin. 1999; 17:445-71.
929 3. Mirza SA, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis. 2003;36:789794. 4. Hernandez AD. Cutaneous cryptococcosis. Dermatol Clin. 1989;7: 269-274. 5. Jones C, Orengo I, Rosen T, Ellner K. Cutaneous cryptococcosis simulating Kaposi’s sarcoma in the acquired immunodeficiency syndrome. Cutis. 1990; 45:163-167. 6. Manrique P, Mayo J, Alvarez JA., Ganchequi X, Zabalza I, Flores M. Polymorphous cutaneous cryptococcosis: nodular, herpes-like, and molluscum-like lesions in a patient with the acquired immunodeficiency syndrome. J Am Acad Dermatol. 1992;26:122-124. 7. Gauder JP. Cryptococcal cellulitis. JAMA. 1977;237:672-673. 8. Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol. 1996;132:545-548. 9. Tanner DC, Weinstein MP, Fedorciw B., Joho KL, Thorpe JJ, Reller L. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol. 1994;32:1680-1684. 10. Baughman RP, Rhodes JC, Dohn MN, Henderson H, Frame PT. Detection of cryptococcal antigen in bronchoalveolar lavage fluid: a prospective study of diagnostic utility. Am Rev Respir Dis. 1992;145: 1126-1129. 11. Glassman SJ, Hale MJ. Cutaneous cryptococcosis and Kaposi’s sarcoma occurring in the same lesions in a patient with the acquired immunodeficiency syndrome. Clin Exp Dermatol. 1995;20:480-486. 12. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents. MMWR Morb Mortal Wkly Rep 2004;53(RR-15):1-112. 13. Larsen RA, Leal MA, Chan LS. Fluconazole compared with amphotericin B plus flucytosine for the treatment of cryptococcal meningitis in AIDS: a randomized trial. Ann Intern Med. 1990;113:183-187. 14. Powderly WG, Saag MS, Cloud GA, et al. A controlled trial of fluconazole or amphotericin B to prevent relapse of cryptococcal meningitis in patients with the acquired immunodeficiency syndrome. The NIAID AIDS Clinical Trials Group and Mycoses Study Group. N Engl J Med. 1992;326:793-798. 15. Martinez E, Garcia-Viejo MA, Marcos MA. Discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients responding to highly active antiretroviral therapy. AIDS. 2000; 14:2615-2617. 16. Vibhagool A, Sungkanuparph S, Mootsikapun P, et al. Discontinuation of secondary prophylaxis for cryptococcal meningitis in human immunodeficiency virus–infected patients treated with highly active antiretroviral therapy: A prospective, multicenter randomized study. Clin Infect Dis. 2003;36:1329-1331. 17. Leenders AC, Reiss P, Portegies P, et al. Liposomal amphotericin B (Ambisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS. 1997;11:1463-1471.