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Neurology India, Vol. 51, No. 3, July, 2003, pp. 364-366 Cryptococcal infection in patients with clinically diagnosed meningitis in a tertiary care center Prasad KN, Agarwal J, Nag VL, Verma AK, Dixit AK, Ayyagari A Correspondence Address: Code Number: ni03118 ABSTRACT A retrospective analysis of 326 clinically diagnosed cases with meningitis over a period of five-and-a-half years was carried out to determine the prevalence of cryptococcal infection, its associated risk factors and therapeutic outcome. Fifty-four (16.6%) patients with cryptococcal meningitis were identified by smear examination, culture and/or cryptococcal antigen latex agglutination test. Records of 45 cryptococcal meningitis patients were available; 18 (40%) of them were apparently healthy immunocompetent individuals, 13 (28.9%) had human immunodeficiency virus (HIV) infection, 9 (20%) were renal transplant recipients, 4 (8.9%) were diabetic and 1 (2.2%) had systemic lupus erythematosus. Ten (22.2%) patients died and 11 (24.4%) patients (all HIV-positive) left against medical advice. The present study indicates that cryptococcal infection is associated with high mortality. Presenting symptoms being indistinguishable from other causes of central nervous system infection, all patients with a clinical diagnosis of meningitis, irrespective of their immune status should be investigated for cryptococcal infection. INTRODUCTION Cryptococcal meningitis is an important and fatal infection. Its signs and symptoms are indistinguishable from other subacute and chronic central nervous system (CNS) infections. The treatment being entirely different, early diagnosis of cryptococcal infection is necessary for appropriate management. Cryptococcosis is generally thought to be associated with an immunocompromised status. Major risk factors for this disease are human immunodeficiency virus (HIV) infection, leukemia, lymphoma, and organ transplantation and connective tissue disorders.[1],[2],[3],[4] An increased frequency of cryptococcal CNS infection has been reported worldwide since the onset of the AIDS epidemic.[5] Literature is available on cryptococcal meningitis in immunocompetent individuals and apparently normal hosts.[67],[8],[9],[10],[11],[12],[13] Data on its overall incidence or prevalence is sparse, especially from the developing world. In the present study we have tried to estimate the prevalence of cryptococcosis among clinically diagnosed meningitis cases presenting in a tertiary care center and to evaluate the clinical features, associated risk factors and outcome in these patients. The sensitivity pattern of these cryptococcal isolates to amphotericin B and fluconazole was also determined. MATERIAL AND METHODS The study population constituted all patients admitted to our hospital with the clinical diagnosis of meningitis from January 1996 to June 2001. Various specimens obtained from these patients included cerebrospinal fluid (CSF), urine, blood, and endotracheal aspirate (only in 4 patients on ventilatory support). For the diagnosis of cryptococcal meningitis, direct microscopy on centrifuged deposits of all the specimens except blood was performed with wet and India ink preparations. Centrifuged deposit of the specimen was cultured on Sabouraud dextrose agar, and blood was cultured on biphasic brain heart infusion medium (Difco, USA). Cryptococcus was identified based on colony morphology, wet and India ink examination, urease production, nitrate assimilation, sugar assimilation and fermentation tests.14 Cryptococcal antigen was tested in the CSF of all the patients and in the blood of only 14 patients using cryptococcal antigen latex agglutination test (CALAS, Meridian Diagnostics Inc., Italy). A titer of 8 or more was considered positive for cryptococcal infection. However, final antigen titer was determined neither in the serum nor in the CSF in all cases. Specimens showing discordant results between smear/ culture and CALAS were treated with pronase B and retested to rule out the false positivity by CALAS. Biotyping of all cryptococcal isolates was done using canavanine glycine blue medium.15 All isolates were subjected to sensitivity testing to fluconazole and amphotericin B using the National Committee for Clinical Laboratory Standards (NCCLS, USA) broth macro-dilution method.16 Patients' demography, clinical signs and symptoms at the time of presentation, underlying disease, HIV status, antifungal therapy and outcome were analyzed retrospectively. RESULTS A total of 326 patients with a clinical diagnosis of meningitis were screened during a period of five-and-a-half years; 54 (16.6%) of them were found positive for Cryptococcus by one or more of the tests. Records of 45 patients were available for analysis. Two patients had acute presentation and the remaining 43 patients presented with chronic meningitis. The age of the patients ranged from 18 to 65 years; the male: female ratio was 33:12. Of the 45 cases whose records were analyzed, CSF smear/ culture along with CALAS was positive in 35 patients. Only CALAS was positive in 10 patients. The sensitivity of smear/ culture in our study was 77.8% when compared with CALAS. Blood plus endotracheal aspirate and urine, both blood and urine, and only blood culture was positive in 2, 3 and 1 patients respectively. No identifiable risk factors could be detected in 18 (40%) patients; known underlying risk factors in the remaining 27 (60%) patients were as follows: HIV infection 13 (28.9%), renal transplant 9 (20%), non-insulin-dependent diabetes mellitus (NIDDM) 4 (8.9%), and systemic lupus erythematosus (SLE) 1 (2.2%) [Table-1]. The presenting symptoms were headache in 39 (89.5%), fever in 34 (78.9%), altered sensorium in 11 (23.7%), neck rigidity in 6 (13.2%), seizure in 4 (10.5%), hydrocephalus in 5 (11.1%) and raised intracranial tension in 3 (7.9%) patients. A total of 43 patients received antifungal therapy, 39 received amphotericin B with fluconazole, 2 received amphotericin B with 5-fluorocytosine and 2 patients received amphotericin alone as per the standard recommended dose. Two patients expired before the diagnosis could be established, hence antifungal treatment could not be initiated. Among the patients who received antifungal therapy, 55.8% (24/43) showed improvement/ recovery, 18.6% (8/43) died, while 25.6% (11/43, all HIV positive) left against medical advice. The mean (S.D) duration of the antifungal therapy in patients who died was 7 + 2 days. Of the total 22.2% (10/45) patients who expired, 2 had HIV infection, one was a renal allograft recipient, one was diabetic with septicemia and 6 were apparently healthy adults [Table-1]; 4 of the 6 apparently healthy patients who died of cryptococcal meningitis had received anti-tubercular treatment for more than 6 weeks before being referred to our center and 2 of them had disseminated cryptococcosis as evidenced by blood, urine and endotracheal aspirate yielding the organism by culture. The result of biotyping revealed all isolates to be Cryptococcous neoformans var neoformans. All strains were sensitive to amphotericin B (MIC < 0.5 µg/ml) and fluconazole (MIC < 2.0 µg/ml) by the broth macro-dilution technique. DISCUSSION Before the AIDS era, cryptococcosis was a well recognized but rare disease worldwide and was mostly reported to occur in patients not having underlying risk factors.[17] Now it is one of the most frequent forms of meningitis/ meningo-encephalitis in patients with AIDS. Published literature shows that cryptococcal meningitis was the first AIDS-defining illness in 45% and 88% AIDS patients with cryptococcosis in USA and Zimbabwe respectively.[18],[19] There were 1,264 cases reported in USA during the 12-year period from 1965 to 1977; and in 1991 (~ 10 years after the onset of the AIDS epidemic) an estimated 1,277 cases were reported in New York City alone in a single year, signifying the magnitude of this infection. Of these 96.3% cases were related to the HIV infection, 2.3% were associated with lymphoma, 0.7% were patients with organ transplant and 0.7% were patients with no identifiable risk factors.[5] Another study from Rwanda reported an increase in the number of cryptococcal meningitis from 1 case in 1983 to 130 new cases in 1992.[20] Cryptococcosis has been reported from different parts of India in apparently healthy individuals as well as in those with underlying risk factors.[10],[11],[12],[13],[21],[22],[23] Published literature and the present findings clearly show the high prevalence of this infection in India. In our center, renal transplant recipients and patients with non-insulin-dependent diabetes mellitus have emerged as important risk groups besides HIV infected patients. Males are more commonly involved than females, which may reflect a difference of exposure rather than a difference in host susceptibility. Since all the strains are sensitive to amphotericin B and fluconazole, the emergence of drug resistance does not appear to be a problem for this particular pathogen. Although Cryptococcous neoformans var gatti has been reported from India,[24] we did not find it in our patient population. Mortality was associated with immunosuppression, disseminated infection and delay in diagnosis. Two-thirds (4 out of 6) of the apparently normal individuals who expired due to cryptococcal infection had received anti-tubercular therapy for more than 6 weeks prior to being referred to our hospital. Early diagnosis and appropriate treatment could have saved these patients. This finding emphasizes the need for cryptococcal CNS infection to be differentiated from tuberculosis at an early stage of the disease, especially in countries endemic to mycobacterial infections; this will reduce the morbidity and mortality. Cryptococcal meningitis is generally considered rare in immunocompetent patients and diagnosis is often delayed because of non-specific symptoms. Since in our study and also in other series,[10],[12],[13] a large number of patients did not have an identifiable risk factor, cryptococcosis should be considered as a differential diagnosis in patients with cerebro-meningeal symptoms and fever. The disease being potentially curable, should be differentiated from tubercular meningitis. Early diagnosis and specific treatment appear to improve the outcome. REFERENCES
Copyright 2003 - Neurology India. Also available online at http://www.neurologyindia.com The following images related to this document are available:Photo images[ni03118t1.jpg] |
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