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AIDS-associated central nervous system cryptococcosis: a Brazilian case study

Pappalardo, Mara CSMa; Paschoal, Regina Céliab; Melhem, Marcia SCb

doi: 10.1097/01.aids.0000287549.79368.33
Research Letters

In recent years the effect of HAART in patients with AIDS has been great at decreasing the incidence of opportunistic infections [1]. Nonetheless, patients with AIDS living in developing countries still present with severe central nervous system cryptococcosis, with high mortality rates [2]. The study of the clinical–epidemiological–laboratory aspects of the patients treated before the HAART era might be useful in an assessment of the impact of these drugs in the prognosis of cases.

aInstituto de Infectologia Emilio Ribas, Brazil

bInstituto Adolfo Lutz, Secretary of Health, São Paulo, Brazil.

Received 2 February, 2006

Accepted 18 May, 2006

Correspondence to Marcia Melhem, Instituto Adolfo Lutz, Secretary of Health, São Paulo, Brazil. E-mail:

Data from 35 patients who had been hospitalized from 1995 to 1997, at a reference hospital for infectious diseases located in São Paulo city, Brazil, were collected at the start of central nervous system cryptococcosis (CNSC) infection, and during further follow-ups. The characteristics of the patients are given in Table 1. The concomitant existence of neoplasia or opportunistic infection in the central nervous system, a CD4 cell count below 100 cells/μl, and treatment of the initial phase with just one drug were all co-factors in therapeutic failure. Furthermore, intracranial hypertension and cryptococcosis external to the neural site are among the most important factors leading to poor prognosis in cryptococcosis, and have been underdiagnosed, possibly contributing to the high lethality rate (62.8%) seen in this series. The data were grouped according to acute phase (first phase of treatment) and prophylactic phase (second phase of treatment). Therapeutic failure was considered to have occurred when there were no remissions of signs or symptoms or when cephalorachidian spinal fluid (CSF) culture remained positive until the 10th week of treatment, or else when there were CNSC-associated deaths. Clinical cure was defined as total or partial remission of the signs and symptoms, and laboratory cure was defined when negative culture of CSF to Cryptococcus neoformans was obtained. Relapse or recurrence was characterized by clinical worsening or rehospitalization, by having to increase the fluconazole dose (from 200 to 400 or 800 mg/day) or by having to use amphotericin B again.

In order to assess the lethality attributable to cryptococcosis the following criteria were accepted: CSF-positive culture and clinical presentation at death. A computerized tomography scan of the brain was performed in five patients. Intracranial pressure was assessed in two cases at the first attendance. The laboratory findings of the initial CSF for the 35 cases are: leukocytes 1–453; protein (27–387 mg/ml); glucose (10–60 mg/ml); positive test of China ink (in 20 patients) 90%; positive polysaccharide antigen (in 23 patients) 100%; title of polysacchride antigen 128–131 072. The aetiological agent was isolated from multiple samples (N = 3–11) of CSF for a total of 168 samples, collected at one to 240-day intervals. All 168 isolates were C. neoformans negative.

The importance of CNSC as an indication of opportunistic disease in AIDS was confirmed. C. neoformans was found to be the agent of CNSC in 100% of cases, reasserting how scarce the association with var. gatti infection and HIV is in Brazil, even though this variety has been repeatedly isolated from environmental sources [3–5].

Only three out of 35 cases (9%) were treated according to the recommendation of Saag et al. [6], using a regimen of drug combination (amphotericin B plus flucitosine). In Brazil, flucitosine has not been commercially available for a long time. For prophylaxis, fluconazole (21/24; 87.5%) or amphotericin B (12.5%) was used. Of the 21 patients who received fluconazole, nine died (42.9%); of those receiving amphotericin B, two out of three died (66.6%), totalling 11 obits. The period of follow-up among the survivors observed a total of 22 (62.8%) obits, including 16 (72.7%) culture-confirmed cases.

The analyses of cause of death reports and laboratory results showing positive cultures for C. neoformans in the CSF of 22 patients have made it possible to confirm the high mortality rate associated with cryptococcosis in this group. The death rate (31.4%) occurring during the acute phase was high according to international literature, which reported 10–25% mortality in the initial 2 weeks. These data could reflect the impact of cryptococcosis in the early 1990s, before the era of HAART, and the lack of facilities for monitoring intracranial pressure.

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The authors would like to acknowledge the help of Professor Marcelo Alvarez Correa from the Enteroparasitology Unit, Parasitoloy Department, Instituto Adolfo Lutz, São Paulo.

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