Comparison of cryptococcal meningitis in HIV-negative patients with and without lung infections.

OBJECTIVE: To investigate the clinical features and outcomes of cryptococcal meningitis (CM) in HIV-negative patients with and without lung infections. METHODS: We retrospectively reviewed the medical records of HIV-negative patients with CM admitted to two university hospitals in Southwest China over the past 5 years. RESULTS: Seventy-one patients were included, of whom 35 (49.3%) had lung disease. Compared with patients without lung infection, CM patients with lung infection tended to be male and younger (≤30 years), experienced more fever, less vomiting and fewer central nervous system symptoms; more often had low white blood cell (WBC) counts (<20 × 106/L), and fewer often had ethmoid sinusitis, maxillary sinusitis, paranasal sinusitis, and otitis media. Cryptococcus neoformans isolates from these patients were sensitive to itraconazole, voriconazole, fluconazole, and amphotericin B but resistant to flucytosine. CM patients with lung infection had higher mortality at discharge compared with patients without lung infection (8.6% vs. 0%). Multivariable analyses showed that a WBC count <20 × 106/L was significantly associated with poor treatment outcome (odds ratio 0.01, 95% confidence interval 0-0.83). CONCLUSION: HIV-negative CM patients with lung infections tended to be male and younger. Fever, fewer central nervous system symptoms, and WBC counts <20 × 106/L were characteristic of this patient group.

Favorable Evolution of Cryptococcal Meningitis in the Context of Flucytosine Resistance.

Cryptococcal meningitis is a critical illness affecting 0.2% to 5% solid-organ transplant recipients with a 40% to 50% mortality. We report the case of a 48-year-old lung transplant recipient, who, 15 months after a right lung graft, kept parakeets and developed meningitis due to Cryptococcus neoformans. Immunosuppressive treatment was based on a quadruple sequential immunosuppressive therapy that included induction therapy with thymoglobulin, followed by corticosteroids, calcineurin inhibitors, and mycophenolate mofetil. Antifungal susceptibility testing of Cryptococcus neoformans showed resistance to flucytosine and intermediate sensitivity to fluconazole. Initial treatment adhered to international guidelines; however, the patient could not tolerate an effective double-antifungal therapy during the first 2 months of treatment. Despite this delayed treatment for an aggressive infection in an immunocompromised patient, the patient survived without relapse and received maintenance treatment with fluconazole during the course of 3 years. Administration of calcineurin inhibitors as immunosuppressive treatment may partly explain this outcome, as this therapeutic class is known to protect from severe forms of cryptococcal meningitis.

Increased Antifungal Drug Resistance in Clinical Isolates of Cryptococcus neoformans in Uganda.

Cryptococcal antigen screening is recommended among people living with AIDS when entering HIV care with a CD4 count of <100 cells/µl, and preemptive fluconazole monotherapy treatment is recommended for those with subclinical cryptococcal antigenemia. Yet, knowledge is limited of current antimicrobial resistance in Africa. We examined antifungal drug susceptibility in 198 clinical isolates collected from Kampala, Uganda, between 2010 and 2014 using the CLSI broth microdilution assay. In comparison with two previous studies from 1998 to 1999 that reported an MIC50 of 4 µg/ml and an MIC90 of 8 µg/ml prior to widespread human fluconazole and agricultural azole fungicide usage, we report an upward shift in the fluconazole MIC50 to 8 µg/ml and an MIC90 value of 32 µg/ml, with 31% of isolates with a fluconazole MIC of ≥ 16 µg/ml. We observed an amphotericin B MIC50 of 0.5 µg/ml and an MIC90 of 1 µg/ml, of which 99.5% of isolates (197 of 198 isolates) were still susceptible. No correlation between MIC and clinical outcome was observed in the context of amphotericin B and fluconazole combination induction therapy. We also analyzed Cryptococcus susceptibility to sertraline, with an MIC50 of 4 µg/ml, suggesting that sertraline is a promising oral, low-cost, available, novel medication and a possible alternative to fluconazole. Although the CLSI broth microdilution assay is ideal to standardize results, limit human bias, and increase assay capacity, such assays are often inaccessible in low-income countries. Thus, we also developed and validated an assay that could easily be implemented in a resource-limited setting, with similar susceptibility results (P = 0.52).

Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-γ responses before antiretroviral therapy but not higher T-cell responses during therapy.

BACKGROUND: Cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS) may be driven by aberrant T-cell responses against cryptococci. We investigated this in human immunodeficiency virus (HIV)-infected patients with treated cryptococcal meningitis (CM) commencing combination antiretroviral therapy (cART). METHODS: Mitogen- and cryptococcal mannoprotein (CMP)-activated (CD25+CD134+) CD4+ T cells and -induced production of interferon-gamma (IFN-γ), IL-10, and CXCL10 were assessed in whole blood cultures in a prospective study of 106 HIV-CM coinfected patients. RESULTS: Patients with paradoxical C-IRIS (n = 27), compared with patients with no neurological deterioration (no ND; n = 63), had lower CMP-induced IFN-γ production in 24-hour cultures pre-cART and 4 weeks post-cART (P = .0437 and .0257, respectively) and lower CMP-activated CD4+ T-cell counts pre-cART (P = .0178). Patients surviving to 24 weeks had higher proportions of mitogen-activated CD4+ T cells and higher CMP-induced CXCL10 and IL-10 production in 24-hour cultures pre-cART than patients not surviving (P = .0053, .0436 and .0319, respectively). C-IRIS was not associated with higher CMP-specific T-cell responses before or during cART. CONCLUSION: Greater preservation of T-cell function and higher CMP-induced IL-10 and CXCL10 production before cART are associated with improved survival while on cART. Lower CMP-induced IFN-γ production pre-cART, but not higher CMP-specific T-cell responses after cART, were risk factors for C-IRIS.