Cryptococcosis

SUMMARY

The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized on the left forearm, caused by Cryptococcus neoformans var. gattii serotype B. Oral treatment with fluconazole was successful.

A review of the literature showed the rarity of this localization in HIV-negative patients. In contrast, skin lesions frequently occurs in HIV-positive patients, with Cryptococcus neoformans var. neoformans serotype A predominating as the etiological agent.

In this paper, the pathogenicity of C. neoformans to skin lesions in patients immunocompromised or not, is discussed, showing the efficacy of fluconazole for the treatment of these processes.

KEYWORDS: Cryptococcus neoformans var. gattii; Serotype B; Immunocompetent patient; Cutaneous cryptococcosis.

INTRODUCTION

Cryptococcosis is a fungal infection caused by two varieties of Cryptococcus neoformans, with five serotypes. We traditionally consider the varieties C. neoformans var. neoformans (serotypes A, D and AD) and C neoformans var. gattii (serotypes B and C) (LACAZ et al. 1991)12. According to some researchers, C. neoformans var. grubii represents strains of serotype A, var. neoformans (serotypes D e AD) and var. gattii (serotypes B and C) (FRANZOT et al., 1999)7. Based on sequential analysis of intergenic rDNA spaces, DIAZ et al., (2001)6 consider two pathogenic varieties: C. neoformans (serotypes A, D and AD) and C. bacillisporus (serotypes B and C), the latter corresponding to C. neoformans var. gattii.

The sexual states of C. neoformans are assigned to Filobasidiella, with the species neoformans and bacillispora. A heterothallic yeast, C. neoformans presents two types of conjugating hyphae: alpha and a (KWON-- CHUNG & BENNETT, 1992; TAKEO et al. 1993)10,25.

A capsulated yeast, C. neofonnans (SANFELICE, 1894) Vuillemin, 1901 can be isolated in a relatively easy manner, making possible the study of its sexuality and of its antigenic and genetic structure.

Current research has been mainly directed at the study of the genome of C. neoformans, its life cycle and ecological niche (LAZERA et al., 2000; MONTENEGRO & PAULA, 2000)13,17.

C. neoformans var. gattii has been isolated in Brazil by several investigators, mainly from hollow trees (LAZERA et al., 2000)13 but also from soil and plant detritus (LAZERA et al., 1998)14.

BARRETO DE OLIVEIRA (2001)2 observed that 40 of 58 serotyped strains (70%) were serotype A, 10 (17%) serotype B, 5 (8%) serotype D, 2 (3%) serotype C, and 1 (2%) serotype AD. C. neoformans var. neoformans serotype A predominates in Brazil, followed by the variety gattii, serotype B at lower frequency.

Cryptococcosis has been reported to be associated with AIDS in most cases, or with other immunodeficiencies, being rarely observed in immunocompetent patients (KWON-CHUNG & BENNETT, 1992; SPEED & DUNT, 1995)11,24. According to SEVERO et al. (1999) 23, cryptococcosis induced by C. neoformans var. neoformans usually occurs in immunocompromised patients and C. neoformans var. gattii occurs in immunocompetent subjects.

In a study on immunosuppressed Wistar rats, ALMEIDA FILHO (2001)1 observed that C. neoformans var. neoformans, serotype A, is more virulent to these animals than var. gattii, serotype B.

MITCHELL & PERFECT (1995)16, in a review of cryptococcosis during the AIDS era, reported that this fungal infection is causing great suffering to mankind.

CASE REPORT

T.U, patient attended in the Faculty of Medicine of ABC, Santo Andre, Sao Paulo, 65 years old, a male seller horned in Japan and living in Sao Bernardo do Campo, presented an extensive ulceration with erythematous borders and irregular infiltrates on the left forearm starting 50 days before his consultation (Fig. 1). According to the patient, the lesion had started with a macula that progressed to ulceration.

The culture of the lesion was positive for Cryptococcus neoformans var. gattii, serotype B (Fig. 2). Histopathological examination was positive for C. neoformans (mucicarmin method) (Fig. 3). A chest X-ray was normal. A search for anti-HIV antibodies was negative. Blood count and cerebrospinal fluid were normal. A latex test applied to serum for the detection of circulating Cryptococcus neoformans antigen was positive. Skull tomography showed no alterations and digestive tomography revealed mild erosive gastritis. Glucose: 70 mg/dL; Creatinine: 0.8 mg/dL. Treatment with fluconazole, 150 mg/3 capsules a day, led to a complete cure within 45 days (Fig. 4).

DISCUSSION

Cutaneous cryptococcosis in its generalized forms, especially in patients with AIDS, presents multiple lesions, most of them simulating molluscum contagiosum. Acneiform, nodular, or herpetiform lesions, or cellulitis are frequently recorded (LACAZ et al., 1991; RICCHI et al., 1991; MANRIQUE et al., 1992)12,15,20. HECKER & WEINBERG (2001)9 recorded one case of cutaneous cryptococcosis simulating a cheloid in a man with AIDS.

In the case described here, a hypothesis that might be raised is that the site of entry of the fungus was by inhalation of small yeast propagula, probably its basidiospores, that were first installed in the lungs and were radiologically undetectable, followed by skin lesion (KWON-CHUNG & BENNETT, 1992)10. Direct examination of biopsy with a drop of India ink, showed yeast cells with capsules. The fungus isolated from the lesion was identified as C. neoformans var. gattii, serotype B.

The literature reports marked dermotropism of the so-called grubii variety of C. neoformans, serotype A (FRANZOT et al., 1999)7. We should point out the absence of trauma preceding the lesion and of any detected immunosuppression.

According to RODRIGUES et al. (1999)21, when the host is immunocompromised, C. neoformans cells try to escape the defenses of the organism by producing sialic acid, capsulated polysaccharides, melanin, mannitol and phospholipase. In contrast, in immunocompetent hosts the mechanisms of pathogenicity have not been carefully clarified. In cryptococcosis, melanin seems to interfere with the virulence of the yeast, with great tropism for the central nervous system, rich in catecholamines.

PAPPAS et al. (2001)18 conducted a review study in the United States involving 15 American Medical Centers from 1990 to 1996 and a total of 306 patients with cryptococcosis, all of them HIV negative. Of these, 109 presented pulmonary lesions, 157 central nervous system lesions, and 40 lesions located at other sites. Fluconazole was administered to approximately 2/3 of the patients, with therapeutic success in 74% of them.

BOHNE et al. (1996)3 reported an erysipela-like lesion induced by C. neoformans in a female patient with sarcoidosis after a traumatic injury, which was treated with corticoids. This patient was treated successfully with itraconazole.

HAMANN et al. (1997)8, in Australia, reported an immunocompetent patient with cellulitis induced by C. neoformans var. gattii.

PATEL et al. (2000)19 reported a case of cutaneous cryptococcosis involving an immunocompetent elderly woman (85 years of age) induced by C. neoformans which was cured with fluconazole.

VELEGRAKI et al. (2001)26, in Greece, reported two cases of cryptococcosis induced by C. neoformans var. gattii serotype B, one involving an HIV-positive patient and the other a patient with systemic lupus erythematosus.

SEVERO et al. (1999)13 in Rio Grande do Sul (Brazil), reported three cases of cryptococcosis induced by C. neoformans var. gattii, affecting HIV-positive patients. SEVERO et al. (2001)22 also reported a case of cutaneous cryptococcosis induced by C. neoformans var. gattii in an immunocompetent host.

In Teresina (Piaui), C. neoformans var. gattii is the causal agent of cryptococcosis in 91.2% of HIV-negative patients (CAVALCANTI, 1997)4. This variety has been found in Belem (Para) as an agent of pediatric neurocryptococcosis (CORRIA, 2001)5.

In Brazil, the serotypes of C neoformans strains predominantly belongs to A, followed by B (LACAZ & RODRIGUES, 1983)11. For the patient reported here, we emphasize the excellent therapeutic result obtained after 45 days of fluconazole treatment.

RESUMO

Criptococose cutanea primaria causada por Cryptococcus neoformans var. gattii sorotipo B em paciente imunocomprometido

Os autores registram em paciente do sexo masculino, vendedor ambulante sem qualquer doenca de base, lesao cutanea extensa, localizada no antebraco esquerdo, sob forma ulcerada, provocada pelo Cryptococcus neoformans var. gattii sorotipo B. Sucesso terapeutico com fluconazol, por via oral.

Revisao da literatura foi realizada, mostrando raridade de tal localizacao em pacientes HIV-negativos. JS em pacientes HIV-positivos, les6es cutaneas ocorrem com frequencia, predominando como agente etiologico o Cryptococcus neoformans var. neoformans, sorotipo A.

A patogenicidade do C. neoformans nas lesoes cutaneas e discutida em pacientes imunocomprometidos ou nao, mostrando a eficacia do fluconazol no tratamento de tais processos.

REFERENCIAS

1. ALMEIDA FILHO, O.M. de - Avaliacao da virulencia de Cryptococcus neoformans (Vuillemin, 1901) variedade neoformans (Vuillemin, 1901) e var. gattii (Vanbreuseghem & Takashiro, 1970) em ratos imunossuprimidos. Rio Claro, 2001. (Tese de Doutorado - Universidade Estadual Paulista).

2. BARRETO DE OLIVEIRA, M.T. - Sorotipos, diversidade genetica, determinacao de "mating - types" em amostras ambientais e clinicas de Cryptococcus neoformans isoladas no Brasil. Sao Paulo, 2001. (Tese de Doutorado - Instituto de Ciencias Biomedicas da Universidade de Sao Paulo).

3. BOHNE, T.; SANDER, A.; PFISTER-WARTHA, A. & SCHOPF, E. - Primary cutaneous cryptococcosis following trauma of the right forearm. Mycoses, 39: 457-459, 1996.

4. CAVALCANTI, M. dos A.S. - Criptococose sistemica endemica pela variedade gattii no meio Norte do Brasil. Teresina, 1997. (Tese de Doutorado - Universidade Federal do Piaui.

5. CORREA, M. do P.S.C. - Neurocriptococose pediatrics no Estado do ParA: espectro de achados tomograficos na infeccao por Cryptococcus neoformans var. gattii. Belem, 2001. (Dissertacao de Mestrado - Universidade Federal do Part).

6. DIAZ, MR.; BOEKHOUT, T.; THEELEN, B. & FELL, LW. - Molecular sequence analysis of the intergenic spacer (IGS) associated with rDNA of the two varieties of the pathogenic yeast C. neoformans. System. appl. Microbiol., 23: 535-545, 2000.

7. FRANZOT, S.P.; SALKIN, LF. & CASADEVALL, A.F. - Cryptococcus neoformans var. grubii: separate varietal status for Cryptococcus neoformans serotype A isolates. J. clin. Microbiol., 37: 838-840, 1999.

8. HAMANN, LD.; GILLESPIE, R.J. & FERGUSON, J.K. - Primary cryptococcal cellulitis caused by Cryptococcus neoformans var. gattii in immunocompetent host. Aust. J. Dean, 38: 29-32, 1997.

9. HECKER, M.S. & WEINBERG, J.M. - Cutaneous cryptococcosis mimicking keloid. Dermatology, 202: 78-79, 2001.

10. KWON-CHUNG, K.J. & BENNETT, J.E., - Medical Mycology. Philadepphia, Lea & Febiger, 1992. p. 430.

11. LACAZ, C. da. S. & RODRIGUES, M.C. - Sorotipagem de Cryptococcus neoformans. Rev. bras. Med., 40: 297-300, 1983.

12. LACAZ, C. da S.; PORTO, E. & MARTINS, J.C. - Micologia medica: fungos, actinomicetos e algae de interese medico. 8. ed. Sao Paulo, SARVIER, 1991.

13. LAZERA, M.S.; SALMITO CAVALCANTI, M.A.; LONDERO, A.T. et al. - Possible primary ecological niche of Cryptococcus neoformans. Med. Mycol., 38: 379-383, 2000.

14. LAZERA, M.S.; SALMITO CAVALCANTI. M.A.; TRILLES, L.; NISHIKAWA, M.M. & WANKE, B. - Cryptococcus neoformans var. gattii: evidence for a natural habitat related to decaying wood in pottery tree hollow. Med. Mycol., 36: 119-122, 1998.

15. MANRIQUE, P.; MAYO, J.; ALVAREZ, J.A. et al. - Polymorphous cutaneous cryptococcosis: nodular, herpes-like, and molluscum-like lesions in a patient with the acquired immunodeficiency syndrome. J. Amer. Acad. Derm., 26: 122-124, 1992.

16. MITCHELL, T.G. & PERFECT, J.R. - Cryptococcosis in the era of AIDS - 100 years after the discovery of Cryptococcus neoformans. Clin. Microbiol. Rev., 8: 515-548, 1995.

17. MONTENEGRO, H. & PAULA, C.R. - Environmental isolation of Cryptococcus neoformans var. gattii and C. neoformans var. neoformans in the city of Sao Paulo, Brazil. Med. Mycol., 38: 385-390, 2000.

18. PAPPAS, P.G.; PERFECT, J.R.; CLOUD, G.A. et at. - Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin. infect Dis., 33: 690-699, 2001.

19. PATEL, P.; RAMANATHAN, J.; KAYSER, M. & BARAN Jr., J. - Primary cutaneous cryptococcosis of the nose in an immunocompetent woman. J. Amer. Acad. Derm., 43: 344-345, 2000.

20. RICCHI, E.; MANFREDI, R.; SCARANI, P.; COSTIGLIOLA, P. & CHIODO, F. Cutaneous cryptococcosis and AIDS. J. Amer. Acad. Derm., 25: 335-336, 1991.

21. RODRIGUES, M.L.; ALVIANO, C.S. & TRAVASSOS, L.R. - Pathogenicity of Cryptococcus neoformans virulence factors and immunological mechanisms. Microbes Infect, 1: 293-301, 1999.

22. SEVERO, L.C.; BERTA E ZARDO, 1. & LONDERO, A.T. - Cutaneous cryptococcosis due to Cryptococcus neoformans var. gattii. Rev. iberoamer. Micol., 18: 200-201, 2001.

23. SEVERO, L.C.; MATTOS OLIVEIRA, F. & LONDERO, A.T. - Cryptococcosis due to Cryptococcus neoformans var. gattii in Brazilian patients with AIDS. Report of three cases. Rev. iberoamer. Micol., 16: 152-154, 1999.

24. SPEED, B. & DUNT, D. - Clinical and host differences between infections with the two varieties of Cryptococcus neoformans. Clin. infect. Dis., 21: 28-34, 1995.

25. TAKEO, K.; TANAKA, R.; TANIGUCHI, H. & NISHIMURA, K. - Analysis of ploidy and sexual characteristics of natural isolates of Cryptococcus neoformans. Can. J. Microbiol., 39: 958-963, 1993.

26. VELEGRAKI, A.; KLOSSES, V.G.; PITSOUNI, H. et al. - First report of Cryptococcus neoformans var. galdi serotype B from Greece. Med. Mycol., 39: 419-422, 2001.

Received: 26 April 2002

Accepted: 18 June 2002

Carlos da Silva LACAZ(1), Elisabeth Maria HEINS-VACCARI(1), Giovanna L. HERNANDEZ-ARRIAGADA(l), Eduardo Lacaz MARTINS(2), Cilia A.L. PREARO(2), Simone Miwa CORIM(1) & Marilena dos Anjos MARTINS(3)

Financial support: FAPESP

(1) Laboratorio de Micologia Medica do Instituto de Medicina Tropical de So Paulo e LIM-53 do Departamento de Dermatologia do Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, SP, Brasil

(2) Clinica Dermatologica da Faculdade de Medicina do ABC, Santo Andre, SP, Brasil

(3) Laboratorio de Micologia Medica do Instituto Adolfo Lutz, Sao Paulo, SP, Brasil.

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