A prospective descriptive study of cryptococcal meningitis in HIV uninfected patients in Vietnam - high prevalence of Cryptococcus neoformans var grubii in the absence of underlying disease

Abstract

BackgroundMost cases of cryptococcal meningitis occur in patients with HIV infection: the course and outcome of disease in the apparently immunocompetent is much more poorly understood. We describe a cohort of HIV uninfected Vietnamese patients with cryptococcal meningitis in whom underlying disease is uncommon, and relate presenting features of patients and the characteristics of the infecting species to outcome.MethodsA prospective descriptive study of HIV negative patients with cryptococcal meningitis based at the Hospital for Tropical Diseases, Ho Chi Minh City. All patients had comprehensive clinical assessment at baseline, were cared for by a dedicated study team, and were followed up for 2 years. Clinical presentation was compared by infecting isolate and outcome.Results57 patients were studied. Cryptococcus neoformans var grubii molecular type VN1 caused 70% of infections; C. gattii accounted for the rest. Most patients did not have underlying disease (81%), and the rate of underlying disease did not differ by infecting species. 11 patients died while in-patients (19.3%). Independent predictors of death were age ≥ 60 years and a history of convulsions (odds ratios and 95% confidence intervals 8.7 (1 - 76), and 16.1 (1.6 - 161) respectively). Residual visual impairment was common, affecting 25 of 46 survivors (54.3%). Infecting species did not influence clinical phenotype or outcome. The minimum inhibitory concentrations of flucytosine and amphotericin B were significantly higher for C. neoformans var grubii compared with C. gattii (p < 0.001 and p = 0.01 respectively).ConclusionIn HIV uninfected individuals in Vietnam, cryptococcal meningitis occurs predominantly in people with no clear predisposing factor and is most commonly due to C. neoformans var grubii. The rates of mortality and visual loss are high and independent of infecting species. There are detectable differences in susceptibility to commonly used antifungal drugs between species, but the clinical significance of this is not clear.

Cryptococcus gattii Infections

“…IRIS has been described infrequently in association with C. gattii infection: occasional cases were reported in apparently healthy hosts in association with pregnancy and in immunocompromised individuals (216,217,241,299). No cases were reported for 10 HIV-negative Vietnamese patients with C. gattii meningitis (239). However, in an Australian study, IRIS occurred in 9.4% of patients, two-thirds of whom had no underlying immunocompromise, although one patient was postpartum (299).…”

“…Lower death rates of 0 to 15% were reported in three other Australian studies conducted between the late 1980s and 2007 (27,28,299). In a recent Vietnamese study, 1 of 10 C. gattii-infected patients died (239). Mortality is likely to be influenced not only by patient factors but also by medical awareness and access to health resources, which vary between countries.…”

“…Cranial nerve palsies developed in 5 of 13 (38%) cases from the United States that were not associated with the outbreaks (251), but long-term sequelae (if any) from the C. gattii case clusters have not yet been reported. In a Vietnamese study, a large proportion of patients with cryptococcal meningitis had neurological sequelae (14 of 20; 70%); however, the frequency of sequelae was not specified for those with C. gattii infection (239). Whether there are species-dependent effects on neurological outcomes or whether these differences reflect differences between patients in seeking medical attention is uncertain.…”

“…As the antibody used in these tests was developed from a strain of C. neoformans, in theory, occasional false-negative results may result from a lower affinity of the antibody for C. gattii. In clinical practice, the sensitivity of the test for C. gattii infection remains high, including for HIV-positive patients-90% for lung disease, with 87 to 100% sensitivity for CSF CRAG tests (29,98,130,239). The level of detection of most LAT kits is at least 10 ng of polysaccharide/ml.…”

Extensive Genetic Diversity within the Dutch Clinical Cryptococcus neoformans Population

“…Furthermore, genotyping studies revealed that 33.9% of the isolates from Madrid, Spain, fell into the hybrid genotype cluster AFLP3 (serotype AD) and 19.6% in genotype AFLP2 (serotype D) (20). Other epidemiological surveys from Brazil, China, South Korea, Taiwan, and Vietnam revealed that serotype D isolates are rarely found or are absent (2,(9)(10)(11)29).…”