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Unlabelled: Cryptococcus neoformans is a human opportunistic fungal pathogen causing severe disseminated meningoencephalitis, mostly in patients with cellular immune defects. This species is divided into three serotypes: A, D, and the AD hybrid. Our objectives were to compare population structures of serotype A and D clinical isolates and to assess whether infections with AD hybrids differ from infections with the other serotypes. For this purpose, we analyzed 483 isolates and the corresponding clinical data from 234 patients enrolled during the CryptoA/D study or the nationwide survey on cryptococcosis in France. Isolates were characterized in terms of ploidy, serotype, mating type, and genotype, utilizing flow cytometry, serotype- and mating type-specific PCR amplifications, and multilocus sequence typing (MLST) methods. Our results suggest that C. neoformans serotypes A and D have different routes of multiplication (primarily clonal expansion versus recombination events for serotype A and serotype D, respectively) and important genomic differences. Cryptococcosis includes a high proportion of proven or probable infections (21.5%) due to a mixture of genotypes, serotypes, and/or ploidies. Multivariate analysis showed that parameters independently associated with failure to achieve cerebrospinal fluid (CSF) sterilization by week 2 were a high serum antigen titer, the lack of flucytosine during induction therapy, and the occurrence of mixed infection, while infections caused by AD hybrids were more likely to be associated with CSF sterilization. Our study provides additional evidence for the possible speciation of C. neoformans var. neoformans and grubii and highlights the importance of careful characterization of causative isolates., Importance: Cryptococcus neoformans is an environmental fungus causing severe disease, estimated to be responsible for 600,000 deaths per year worldwide. This species is divided into serotypes A and D and an AD hybrid, and these could be considered two different species and an interspecies hybrid. The objectives of our study were to compare population structures of serotype A and serotype D and to assess whether infections with AD hybrids differ from infections with serotype A or D isolates in terms of clinical presentation and outcome. For this purpose, we used clinical data and strains from patients diagnosed with cryptococcosis in France. Our results suggest that, according to the serotype, isolates have different routes of multiplication and high genomic differences, confirming the possible speciation of serotypes A and D. Furthermore, we observed a better prognosis for infections caused by AD hybrid than those caused by serotype A or D, at least for those diagnosed in France., (Copyright © 2015 Desnos-Ollivier et al.)

Background: Cryptococcosis is a life-threatening opportunistic fungal infection in both HIV-positive and -negative patients. Information on clinical presentation and therapeutic guidelines, derived mostly from clinical trials performed before introduction of highly active antiretroviral therapy in patients with cryptococcal meningoencephalitis, is missing data on extrameningeal involvement and infections by serotype D as opposed to serotype A of Cryptococcus neoformans., Methods and Findings: The prospective multicenter study CryptoA/D was designed in France (1997-2001) to analyse the factors influencing clinical presentation and outcome without the bias of inclusion into therapeutic trials. Of the 230 patients enrolled, 177 (77%) were HIV-positive, 50 (22%) were female, and 161 (72.5%) were infected with serotype A. Based on culture results at baseline, cryptococcosis was more severe in men, in HIV-positive patients, and in patients infected with serotype A. Factors independently associated with mycological failure at week 2 independent of HIV status were initial dissemination (OR, 2.4 [95% confidence interval (CI), 1.2-4.9]), high (>1:512) serum antigen titre (OR, 2.6 [1.3-5.4]), and lack of flucytosine during induction therapy (OR, 3.8 [1.9-7.8]). The three-month survival was shorter in patients with abnormal neurology or brain imaging at baseline, and in those with haematological malignancy., Conclusions: Thus sex, HIV status, and infecting serotype are major determinants of presentation and outcome during cryptococcosis. We propose a modification of current guidelines for the initial management of cryptococcosis based on systematic fungal burden evaluation.

Objective: To study the pharmacoepidemiology of the prescription of systemic antifungal agents in 48 French haematology, intensive care and infectious diseases units., Patients and Methods: Cases of invasive fungal infections (IFI) were identified retrospectively over a 1 year period. Data on underlying condition, IFI diagnosis, antifungal treatment and outcome were collected on the last five cases in each centre. Factors associated with first line therapy and with death were identified by multivariate analysis., Results: Two hundred and nine cases were included (102 aspergillosis, 86 candidiasis, 15 cryptococcosis). Amphotericin B, in different formulations, was the first line therapy in 60%, azoles in 32%, combinations in 8%. Haematological malignancies and neutropenia were associated with less frequent initial prescription of azoles [OR = 0.3 (0.1-0.8) and OR = 0.3 (0.1-0.9), respectively]. In aspergillosis, younger age and neutropenia were associated with less frequent initial prescription of azoles [OR = 0.03 (0.002-0.6) and OR = 0.09 (0.03-0.3), respectively] and previous history of IFI was associated with a higher probability of azole prescription [OR = 17.2 (2.4-124.3)]. In candidiasis, haematological malignancy and co-prescription of nephrotoxic agents were associated with a less frequent initial prescription of azoles [OR = 0.1 (0.04-0.4) and OR = 0.2 (0.06-0.9), respectively]. Three factors were associated with a lower risk of death: cryptococcosis [OR = 0.16 (0.03-0.98)], hospitalization in infectious diseases units [OR = 0.40 (0.16-0.97)] and recent surgery [OR = 0.26 (0.08-0.80)]. Severe renal insufficiency was associated with a higher probability of death [OR = 8.77 (1.97-38.97)]., Conclusions: Our results emphasize factors associated with the antifungal therapeutic decision and with the outcome of IFI.

Purpose: Cryptococcus is an opportunistic infection that affects immunodepressed patients and is a classical complication of AIDS-stage HIV infection. The aim of this study was to investigate Cryptococcus neoformans infections in patients with hematological malignancies., Methods: Six cases have been described of cryptococcosis detected in Nantes, France over the past 10 years in patients with hematological malignancies., Results: This infection has been found particularly in the context of lymphoproliferative disorders (chronic lymphocytic leukemia, Waldenström macroglobulinemia, Hodgkin's disease, and non-Hodgkin's lymphoma), and also following cytotoxic therapy. In four cases, the patients were treated with fludarabine, which rapidly caused long-duration marked lymphocytopenia, notably in CD4 cells. Cell-mediated immunity plays a major role in systemic defense against C. neoformans. It therefore seems that fludarabine favors the spread of cryptococcal infections., Conclusion: In the context of lymphoproliferative syndromes treated with cytotoxic drugs, in particular fludarabine, it appears important to take into account the possible presence of cryptococcal infection in the presence of respiratory, neurological or cutaneous disorders, so that a correct diagnosis can be made and the appropriate treatment administered.

We retrospectively analyzed clinical outcome of meningeal and extrameningeal cryptococcosis in HIV-negative patients treated with amphotericin B (43 patients) or fluconazole (40 patients). Amphotericin B and fluconazole were prescribed equally to patients with neoplastic diseases and no risk factor, but organ transplant recipients and patients with other diseases were mostly given fluconazole and amphotericin B, respectively. Patients with more severe infections (i.e., meningitis, neurological disorders, or higher levels of antigen in cerebrospinal fluid) were more frequently treated with amphotericin B. A cure rate of > 70% was achieved regardless of the initial treatment and the severity of the infection. A Cox regression analysis showed that age of > 60 years, neoplastic disease, abnormal mental status, disseminated infection at the time of diagnosis, and therapeutic failure were independent predictors of death. Although fluconazole appears to be as effective as amphotericin B, only a prospective multicenter study will determine the best treatment regimen for patients with cryptococcal meningitis who do not have AIDS.