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Background. Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis. Methods. Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis. Results. High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003). Conclusion. These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM. Funding. This work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201). The funding sources had no role in the design or conduct of this study, nor in preparation of the manuscript., Introduction Cryptococcal meningoencephalitis (CM), caused by the fungus C. neoformans, is a leading cause of mortality in HIV-infected individuals globally (1). Sub-Saharan Africa, with the highest HIV burden, is the [...]

After an imported case of Marburg hemorrhagic fever was reported in 2008 in the Netherlands, control measures to prevent transmission were implemented. To evaluate consequences of these measures, we administered [...]

Background The development of efficacious combination antiretroviral therapy (cART) has led to a dramatic decrease in mortality in HIV-positive patients. Specific data on the impact in HIV/hepatitis B virus (HBV)–coinfected patients are lacking. In this study, all-cause and cause-specific mortality risks stratified per era of diagnosis are investigated. Methods Data were analyzed from HIV/HBV-coinfected patients enrolled in the ATHENA cohort between January 1, 1998, and December 31, 2017. Risk for (cause-specific) mortality was calculated using Cox proportional hazard regression analysis, comparing patients diagnosed before 2003 with those diagnosed ≥2003. Risk factors for all-cause and liver-related mortality were also assessed using Cox proportional hazard regression analysis. Results A total of 1301 HIV/HBV-coinfected patients were included (14 882 person-years of follow-up). One-hundred ninety-eight patients (15%) died during follow-up. The adjusted hazard ratio (aHR) for all-cause mortality in patients diagnosed in or after 2003 was 0.50 (95% CI, 0.35–0.72) relative to patients diagnosed before 2003. Similar risk reduction was observed for liver-related (aHR, 0.29; 95% CI, 0.11–0.75) and AIDS-related mortality (aHR, 0.44; 95% CI, 0.22–0.87). Use of a tenofovir-containing regimen was independently associated with a reduced risk of all-cause and liver-related mortality. Prior exposure to didanosine/stavudine was strongly associated with liver-related mortality. Ten percent of the population used only lamivudine as treatment for HBV. Conclusions All-cause, liver-related, and AIDS-related mortality risk in HIV/HBV-coinfected patients has markedly decreased over the years, coinciding with the introduction of tenofovir. Tenofovir-containing regimens, in absence of major contraindications, should be strongly encouraged in this population. [ABSTRACT FROM AUTHOR]

Background. Although Cryptococcus neoformans is a fungal pathogen that causes human disease predominantly in the immunocompromised host, severe cryptococcal infections are occasionally encountered in apparently immunocompetent individuals. Activation of cellular immunity by proinflammatory cytokines plays a central role in anticryptococcal defense. Methods. We describe 2 patients with severe cryptococcal meningitis who appeared to have idiopathic CD4 lymphopenia. For these patients and for 4 healthy volunteers, ex vivo stimulation of whole blood with microbial stimuli was used to investigate putative defects in cytokine production capacity. Results. Assessment of the cytokine released from the 2 patients with CD4 lymphopenia revealed a defective production of the proinflammatory cytokines interferon (IFN)- γ and tumor necrosis factor (TNF) but not of the anti-inflammatory cytokine interleukin-10 (IL-10). One patient with disease progression despite receipt of antifungal treatment was administered immunotherapy with recombinant IFN- γ. Administration of recombinant IFN-γ resulted in both restoration of immunological parameters and a sustained clinical recovery. Conclusions. Refractory meningitis may be due to defective TNF and IFN-γ production, and IFN-γ treatment may be useful in patients with an impaired cellular immune response and refractory cryptococcal meningitis. [ABSTRACT FROM AUTHOR]

Pneumonia is a common manifestation of melioidosis, the disease caused by Burkholderia pseudomallei. In this study, we defined the prognostic significance of a positive sputum culture. A total of 712 patients presenting to Sappasithiprasong Hospital, Ubon Ratchathani, Thailand, with melioidosis between January 1992 and December 2002 had a sputum culture performed during admission, which was positive for B. pseudomallei in 444 patients (62%). The median duration of sputum positivity was 9 days (range, 1 to 49 days). Sputum cultures were negative in 32% of patients with radiologic changes suggestive of pulmonary involvement. Overall in-hospital mortality was 48%. A positive sputum culture was associated with mortality (adjusted OR 2.8, 95% CI: 1.9, 4.0; P < 0.001). This was independent of renal disease, a prior history of melioidosis, positive blood cultures, and other potential confounders. The presence of B. pseudomallei in the sputum of patients with melioidosis is associated with a poorer prognosis.

In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-gamma, TNF-alpha, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-alpha, IFN-gamma, and IL-6 levels and baseline cryptococcal CFU. Log IFN-gamma, G-CSF, TNF-alpha, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-gamma remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-gamma secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-gamma in the treatment of refractory HIV-associated cryptococcosis.