Association between neuroimaging and clinical outcomes in individuals with central nervous system cryptococcosis.

BACKGROUND: The radiological manifestations of central nervous system (CNS) cryptococcosis are diverse and often subtle. There is heterogeneity on how different neuroimaging patterns impact prognosis. This study aims to assess the association between the neuroimaging and clinical outcomes of CNS cryptococcosis. METHODS: All patients with CNS cryptococcosis between July 2017 and April 2023 who underwent brain magnetic resonance imaging (MRI) were included. The primary outcome was mortality during hospitalisation. Secondary outcomes were readmission, ventricular shunting, duration of hospitalisation and time to the first negative cerebrospinal fluid culture. We compared the outcomes for each of the five main radiological findings on the brain MRI scan. RESULTS: We included 46 proven CNS cryptococcosis cases. The two main comorbidity groups were HIV infection (20, 43%) and solid organ transplantation (10, 22%), respectively. Thirty-nine patients exhibited at least one radiological abnormality (85%), with the most common being meningeal enhancement (34, 74%). The mortality rates occurred at 11% (5/46) during hospitalisation. We found no significant disparities in mortality related to distinct radiological patterns. The presence of pseudocysts was significantly associated with the need for readmission (p = .027). The ventricular shunting was significantly associated with the presence of pseudocysts (p = .005) and hydrocephalus (p = .044). CONCLUSION: In this study, there is no association between brain MRI findings and mortality. Larger studies are needed to evaluate this important issue.

Cryptococcosis-a systematic review to inform the World Health Organization Fungal Priority Pathogens List.

Cryptococcosis causes a high burden of disease worldwide. This systematic review summarizes the literature on Cryptococcus neoformans and C. gattii infections to inform the World Health Organization's first Fungal Priority Pathogen List. PubMed and Web of Science were used to identify studies reporting on annual incidence, mortality, morbidity, antifungal resistance, preventability, and distribution/emergence in the past 10 years. Mortality rates due to C. neoformans were 41%-61%. Complications included acute renal impairment, raised intracranial pressure needing shunts, and blindness. There was moderate evidence of reduced susceptibility (MIC range 16-32 mg/l) of C. neoformans to fluconazole, itraconazole, ketoconazole, voriconazole, and amphotericin B. Cryptococcus gattii infections comprised 11%-33% of all cases of invasive cryptococcosis globally. The mortality rates were 10%-23% for central nervous system (CNS) and pulmonary infections, and ∼43% for bloodstream infections. Complications described included neurological sequelae (17%-27% in C. gattii infections) and immune reconstitution inflammatory syndrome. MICs were generally low for amphotericin B (MICs: 0.25-0.5 mg/l), 5-flucytosine (MIC range: 0.5-2 mg/l), itraconazole, posaconazole, and voriconazole (MIC range: 0.06-0.5 mg/l). There is a need for increased surveillance of disease phenotype and outcome, long-term disability, and drug susceptibility to inform robust estimates of disease burden.

Features of cryptococcosis among 652 HIV-seronegative individuals in France: a cross-sectional observational study (2005-2020).

OBJECTIVES: We aimed to describe features and outcomes of cryptococcosis among HIV-seronegative individuals in a large surveillance network for cryptococcosis in France. METHODS: We included incident cases of cryptococcosis in HIV-seronegative individuals from 2005 to 2020. We compared patient characteristics, disease presentations, cryptococcal antigen results, and induction antifungal treatments according to underlying disease. We examined factors associated with 90-day mortality. Among patients with disseminated infections, we investigated whether receipt of flucytosine and polyene combination was associated with lower mortality. RESULTS: Among 652 individuals, 209 (32.1%) had malignancy, 130 (19.9%) were solid-organ transplant recipients, 204 (31.3%) had other immunocompromising conditions, and 109 (16.7%) had no reported underlying factor. The commonest presentations were disseminated infections (63.3%, 413/652) and isolated pulmonary infections (25.3%, 165/652). Solid-organ transplant patients were most likely to have disseminated infections and a positive serum cryptococcal antigen result. Patients with malignancy were older and less likely to receive a flucytosine-containing regimen for disseminated infections than others (58.7%, 78/133 vs. 73.2%, 194/265; p 0.029). The crude 90-day case-fatality ratio was 27.2% (95% CI, 23.5%-31.1%). Age ≥60 years (aOR: 2.75 [1.78-4.26]; p < 0.001), meningitis/fungaemia (aOR: 4.79 [1.80-12.7]; p 0.002), and malignancy (aOR: 2.4 [1.14-5.07]; p 0.02) were associated with higher 90-day mortality. Receipt of flucytosine and polyene combination was associated with lower 90-day mortality (aOR: 0.40 [0.23-0.71]; p 0.002) in multivariable analysis and inverse probability of treatment weighted analysis (aOR: 0.45 [0.25-0.80]; p 0.006). DISCUSSION: HIV-seronegative individuals with cryptococcosis comprise a wide range of underlying conditions with different presentations and outcomes, requiring a tailored approach to diagnosis and management.

Antifungal susceptibility testing with YeastONE™ is not predictive of clinical outcomes of Cryptococcus neoformans var. grubii fungemia.

Mortality rates due to Cryptococcus neoformans var. grubii fungemia remain significant despite treatment with antifungal drugs. The predictive function of antifungal susceptibility and its correlation with treatment outcome remains controversial. A retrospective study was conducted from January 1, 2009, to December 31, 2016, on 85 patients with C. neoformans var. grubii fungemia confirmed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Antifungal drug susceptibility was determined using the YeastONE™ colorimetric broth microdilution method coupled with Vizion™ System following the Clinical and Laboratory Standards Institute guidelines. Six antifungal agents-amphotericin B, fluconazole, flucytosine, itraconazole, posaconazole, and voriconazole-were tested. The patients' demographic data and clinical information were abstracted for further analyses. Antifungal regimens consisting of amphotericin B with or without fluconazole or flucytosine were administered for induction treatment of these patients, followed with intravenous or oral fluconazole for maintenance therapy. Clinical outcomes were defined by 14- and 30-day mortality rates. Risk factors associated with outcomes were fitted in a logistic regression model by univariate or multivariate method. Eighty-five patients with C. neoformans var. grubii fungemia were enrolled in the study. The Sequential Organ Failure Assessment Score, Glasgow Coma Scale, Charlson comorbidity score, and adequate duration of therapy for amphotericin B were predictors for mortality in univariate analysis. Antifungal susceptibility testing with YeastONE™ does not predict clinical outcomes of C. neoformans var. grubii fungemia. Greater disease severity, high comorbidities, poor consciousness level, and inappropriate treatment were associated with increased mortality in cryptococcemia cases.

Cryptococcus neoformans is an encapsulated yeast living in both plants and animals that is composed of three main serotypes: C. neoformans var. grubii, C. neoformans var. gattii, and C. neoformans var. neoformans. C. neoformans var. grubii is the most common disease-causing Cryptococcus species worldwide. C. neoformans var. gattii is more prevalent than C. neoformans var. neoformans in both tropical and subtropical regions of Asia. C. neoformans causes severe, even fatal, diseases such as pulmonary infection, bloodstream infection, skin and soft tissue infection, bone and joint infection, central nervous system infection, and disseminated infection, regardless of host immunocompetence. We conducted a retrospective study on 85 patients who contracted cryptococcemia from January 1, 2009, to December 31, 2016. This work conducted both microbiological and clinical studies involving in vitro susceptibility testing, demographic data, comorbidities, treatment modalities, and treatment outcomes. We utilized a modern medical technique-based instrument, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS; Biotyper, Bruker Daltonics, Inc.), which determines the unique proteomic fingerprint of an organism, to identify the C. neoformans serotype. We utilized Thermo Fisher Scientific™ Sensititre™ YeastONE™ colorimetric broth microdilution plates coupled with a Vizion™ Digital MIC Viewing System (a computer-assisted optical reading machine) to determine the in vitro susceptibility of amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, and voriconazole against 85 C. neoformans var. grubii blood isolates. In conclusion, the susceptibility patterns of these antifungal agents did not correlate significantly with treatment outcomes. However, a lower disease severity score, a lower Glasgow Coma Scale score, fewer comorbidities, and adequate amphotericin B treatment duration were predictors for treatment success in univariate analysis.

Changing demographics and risk factors for cryptococcosis: A 12-year review at a tertiary care centre.

BACKGROUND: Cryptococcosis is classically associated with the immunocompromised patients but there is a rising appreciation for its impact on the immunocompetent hosts. We sought to analyse the trends, diagnosis, treatment of different hosts and the effect of immunodeficiency and chronic liver disease on relapse and in-house mortality. METHODS: This is a retrospective study of 12 years of patients with cryptococcosis, divided into three different groups: HIV-infected, transplant and non-HIV non-transplant (NHNT). Data were analysed with Chi-square, unpaired parametric t test, simple and multivariate logistic regression analysis. RESULTS: Of 114 identified patients, 23 (20.2%) had HIV infection, 11 (9.6%) had transplant, 80 (70.2%) were NHNT patients. Overall, mortality was 28.1% (32/114) and relapse occurred in 10.5% (12/114) of patients. The mortality trend was higher (OR = 2.346, p = .287) in the transplant group (45.5%, 5/11) than in HIV (26.1%, 6/23) and NHNT groups (26.3%, 21/80). HIV was associated with relapse; 30.4% (7/23) for HIV-positive patients and 5.5% (5/91) for HIV-negative patients (OR = 7.525, p = .002). Chronic liver disease had a large and statistically significant association with mortality on multivariate analysis (OR = 3.583, p = .013) which was more pronounced than the HIV or transplant groups. It was independently associated with mortality by chi-square analysis (OR 3.137, p = .012). CONCLUSION: Chronic liver disease represented 30.7% (35/114) of all studied patients. It was a risk factor for in-hospital mortality. HIV infection and transplant were not statistically significant for mortality. Relapse was highest in the HIV-infected patients at 30.4% (7/23). These data highlight the effect of type and degree of immunocompromise on cryptococcosis.

Enlarged periventricular space and periventricular lesion extension on baseline brain MRI predicts poor neurological outcomes in cryptococcus meningoencephalitis.

In Cryptococcus neoformans meningoencephalitis, brain MRI findings might reflect the phathomechanism of disease progression that is fungal accumulation in the peri-venular space and consequent invasion into the parenchyma. This study analyzed serial brain MRI findings of 76 patients with cryptococcus meningoencephalitis in association with the disease progression and outcomes. MRI parameters included the enlarged periventricular space (ePVS) score (range 0-8), periventricular lesion extension, cryptococcoma, and hydrocephalus. Clinical outcomes at 2-week, 10-week, and 6-month were evaluated using modified Rankin scale (mRS). At 6 months, 15 (19.7%) patients died and 34 (44.1%) had poor neurological outcomes (mRS scores > 2). At baseline, an ePVS score of ≥ 5 (Odds-ratio [OR]: 94.173, 95% confidence-interval [95%CI]: 7.507-1181.295, P < .001), periventricular lesion extension (OR: 51.965, 95%CI: 2.592-1041.673, P = .010), and presence of encephalitis feature (OR: 44.487, 95%CI: 1.689-1172.082, P = .023) were associated with 6-month poor outcomes. Presence of two or more risk factors among encephalitis feature, ePVS score ≥ 5, and periventricular lesion extension at baseline, was associated with 6-month poor outcomes (area under the curve [AUC]: 0.978, P < .001) and mortality (AUC: 0.836, P < .001). Disease progression was associated with interval development of cryptococcoma and hydrocephalus. Brain MRI findings might be useful in predicting outcomes and monitoring the progression of cryptococcus meningoencephalitis.

Treatment and mortality outcomes in patients with other extrapulmonary cryptococcal disease compared with central nervous system disease.

BACKGROUND: Determining the extent of cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localised pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. METHODS: This is a retrospective, single-centre study of all hospitalised patients with nonpulmonary cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox regression analysis. RESULTS: Of 193 patients analysed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, p = .9). In the comorbidity-adjusted multivariable Cox regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, p < .001). CONCLUSION: Patients with OE CD had similar 90-day mortality compared to those with CNS disease. Despite current guideline recommendations, patients with OE disease were less likely to receive appropriate induction therapy with AmB and flucytosine compared to patients with CNS disease.

Correlation between clinical outcome and tissue inflammatory response in kidney transplant recipients with cryptococcosis.

Cryptococcosis is the second most common invasive fungal infection reported in renal transplant recipients. Tissue granulomatous inflammation is necessary to contain Cryptococcus infection. This study aims to analyze the granuloma patterns and in situ expression of regulatory T (Treg) immune response in tissue samples from 12 renal transplant recipients with cryptococcosis. Fungal isolates were molecularly identified as Cryptococcus neoformans species complex. A detailed characterization of granulomas in tissue samples from 12 kidney transplant recipients with cryptococcosis was described by checking six lung and six skin biopsies by conventional histology and for immunohistochemical detection of CD4 and Treg markers: forkhead box P3 (FoxP3), interleukin (IL)-10 and transforming-growth factor (TGF)-ß. Granulomas were classified as compact, loose or mixed. Patients with mixed (n = 4) and compact (n = 3) granulomatous inflammation patterns were associated with a better prognosis and presented a higher number of CD4+FoxP3+T cells compared to the group of patients with loose granulomas. In counterpart, three out of five patients with loose granulomas died with cryptococcosis. We suggest that Treg may have a protective role in the tissue response to Cryptococcus infection given its association with compact and mixed granulomas in patients with better clinical outcomes.

Early Cardiopulmonary Cryptococcus neoformans Infection After Liver Transplant: A Case Report.

Cryptococcal infection (CI) is an uncommon fungal disease that poses a particular fatal risk to liver transplant (LT) recipients because of the potential rapid development and dissemination of the disease. Depending on the pathophysiology, CI may manifest with a wide range of clinical presentations that may delay early diagnosis and timely treatment. Additionally, most anticryptococcal therapies may threaten LT recipients owing to the associated hepatotoxicity of these medications. We report a case of a 25-year-old woman who received an LT for cryptogenic cirrhosis and developed rapidly progressive CI with pulmonary, myocardial, and cerebral involvement within a month of transplantation. She presented with severe pulmonary hypertension refractory to medical management and subsequently died despite our efforts. Herein, we review the etiology of cryptococcosis, the natural history of cryptococcal disease, and standard treatments for CI, and we highlight peculiarities of Cryptococcus neoformans infection in solid organ transplant recipients.

Cryptococcus neoformans Evades Pulmonary Immunity by Modulating Xylose Precursor Transport.

Cryptococcus neoformans is a fungal pathogen that kills almost 200,000 people each year and is distinguished by abundant and unique surface glycan structures that are rich in xylose. A mutant strain of C. neoformans that cannot transport xylose precursors into the secretory compartment is severely attenuated in virulence in mice yet surprisingly is not cleared. We found that this strain failed to induce the nonprotective T helper cell type 2 (Th2) responses characteristic of wild-type infection, instead promoting sustained interleukin 12p40 (IL-12p40) induction and increased IL-17A (IL-17) production. It also stimulated dendritic cells to release high levels of proinflammatory cytokines, a behavior we linked to xylose expression. We further discovered that inducible bronchus-associated lymphoid tissue (iBALT) forms in response to infection with either wild-type cryptococci or the mutant strain with reduced surface xylose; although iBALT formation is slowed in the latter case, the tissue is better organized. Finally, our temporal studies suggest that lymphoid structures in the lung restrict the spread of mutant fungi for at least 18 weeks after infection, which is in contrast to ineffective control of the pathogen after infection with wild-type cells. These studies demonstrate the role of xylose in modulation of host response to a fungal pathogen and show that cryptococcal infection triggers iBALT formation.

Cryptococcus neoformans Chitin Synthase 3 Plays a Critical Role in Dampening Host Inflammatory Responses.

Cryptococcus neoformans infections are significant causes of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. One of the main interfaces between the fungus and the host is the fungal cell wall. The cryptococcal cell wall is unusual among human-pathogenic fungi in that the chitin is predominantly deacetylated to chitosan. Chitosan-deficient strains of C. neoformans were found to be avirulent and rapidly cleared from the murine lung. Moreover, infection with a chitosan-deficient C. neoformans strain lacking three chitin deacetylases (cda1Δcda2Δcda3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild-type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase-mediated formation of chitosan. Mice inoculated with the chs3Δ strain at a dose previously shown to induce protection with the cda1Δcda2Δcda3Δ strain die within 36 h after installation of the organism. Mortality was not dependent on viable fungi, as mice inoculated with a heat-killed preparation of the chs3Δ strain died at the same rate as mice inoculated with a live chs3Δ strain, suggesting that the rapid onset of death was host mediated, likely caused by an overexuberant immune response. Histology, cytokine profiling, and flow cytometry indicate a massive neutrophil influx in the mice inoculated with the chs3Δ strain. Mice depleted of neutrophils survived chs3Δ inoculation, indicating that death was neutrophil mediated. Altogether, these studies lead us to conclude that Chs3, along with chitosan, plays critical roles in dampening cryptococcus-induced host inflammatory responses.IMPORTANCECryptococcus neoformans is the most common disseminated fungal pathogen in AIDS patients, resulting in ∼200,000 deaths each year. There is a pressing need for new treatments for this infection, as current antifungal therapy is hampered by toxicity and/or the inability of the host's immune system to aid in resolution of the disease. An ideal target for new therapies is the fungal cell wall. The cryptococcal cell wall is different from the cell walls of many other pathogenic fungi in that it contains chitosan. Strains that have decreased chitosan are less pathogenic and strains that are deficient in chitosan are avirulent and can induce protective responses. In this study, we investigated the host responses to a chs3Δ strain, a chitosan-deficient strain, and found that mice inoculated with the chs3Δ strain all died within 36 h and that death was associated with an aberrant hyperinflammatory immune response driven by neutrophils, indicating that chitosan is critical in modulating the immune response to Cryptococcus.

Prevalence and mortality of cryptococcal disease in adults with advanced HIV in an urban tertiary hospital in Sierra Leone: a prospective study.

BACKGROUND: The global annual estimate for cryptococcal disease-related deaths exceeds 180,000, with three fourth occurring in sub-Saharan Africa. The World Health Organization (WHO) recommends cryptococcal antigen (CrAg) screening in all HIV patients with CD4 count < 100/µl. As there is no previous published study on the burden and impact of cryptococcal disease in Sierra Leone, research is needed to inform public health policies. We aimed to establish the seroprevalence and mortality of cryptococcal disease in adults with advanced HIV attending an urban tertiary hospital in Sierra Leone. METHODS: A prospective cohort study design was used to screen consecutive adult (18 years or older) HIV patients at Connaught Hospital in Freetown, Sierra Leone with CD4 count below 100 cells/mm3 from January to April 2018. Participants received a blood CrAg lateral flow assay (IMMY, Oklahoma, USA). All participants with a positive serum CrAg had lumbar puncture and cerebrospinal fluid (CSF) CrAg assay, and those with cryptococcal diseases had fluconazole monotherapy with 8 weeks followed up. Data were entered into Excel and analysed in Stata version 13.0. Proportions, median and interquartile ranges were used to summarise the data. Fisher's exact test was used to compare categorical variables. RESULTS: A total of 170 patients, with median age of 36 (IQR 30-43) and median CD4 count of 45 cells/mm3 (IQR 23-63) were screened. At the time of enrolment, 54% were inpatients, 51% were newly diagnosed with HIV, and 56% were either ART-naïve or newly initiated (≤ 30 days). Eight participants had a positive blood CrAg, giving a prevalence of 4.7% (95% CI: 2.4-9.2%). Of those with a positive CrAg, CSF CrAg was positive in five (62.5%). Five (62.5%) CrAg-positive participants died within the first month, while the remaining three were alive and established on ART at 8 weeks. CONCLUSION: A substantial prevalence of cryptococcal antigenaemia and poor outcome of cryptococcal disease were demonstrated in our study. The high mortality suggests a need for the HIV programme to formulate and implement policies on screening and pre-emptive fluconazole therapy for all adults with advanced HIV in Sierra Leone, and advocate for affordable access to effective antifungal therapies.

Cryptococcus neoformans infection in Human Immunodeficiency Virus (HIV)-infected and HIV-uninfected patients at an inner-city tertiary care hospital in the Bronx.

Cryptococcus neoformans causes life-threatening meningoencephalitis. Human immunodeficiency virus (HIV) infection is the most significant predisposing condition, but persons with other immunodeficiency states as well as phenotypically normal persons develop cryptococcosis. We retrospectively reviewed medical records of all patients with a diagnosis of cryptococcosis between 2005 and 2017 at our inner-city medical center in the Bronx, an epicenter of AIDS in New York City, and analyzed demographic data, clinical manifestations, laboratory findings, treatment, and mortality for these patients. In sum, 63% of the cases over this 12-year period occurred in HIV-infected patients. And 61% of the HIV-infected patients were non-adherent with antiretroviral therapy, 10% were newly diagnosed with AIDS, and 4% had unmasking cryptococcus-associated immune reconstitution inflammatory syndrome. The majority were Hispanic or black in ethnicity/race. HIV-uninfected patients (47/126) were older (P < .0001), and the majority had an immunocompromising condition. They were less likely to have a headache (P = .0004) or fever (P = .03), had prolonged time to diagnosis (P = .04), higher cerebrospinal fluid (CSF) glucose levels (P = .001), less CSF culture positivity (P = .03), and a higher 30-day mortality (P = .03). Cases in HIV-uninfected patients were often unsuspected during their initial evaluation, leading to a delay in infectious diseases consultation, which was associated with mortality (P = .03). Our study indicates that HIV infection remains the most important predisposing factor for cryptococcosis despite availability of antiretroviral therapy and highlights potential missed opportunities for earlier diagnosis and differences in clinical and prognostic factors between HIV-infected and HIV-uninfected patients.

Lower Mortality Rates from Cryptococcosis in Women and Whites with Human Immunodeficiency Virus in the United States.

Cryptococcosis is an opportunistic mycotic infection often found in pigeon droppings and other bird excrement. This serious disease is often fatal and, not unexpectedly, far more common in patients with immune deficiency, including those with human immunodeficiency virus (HIV). It has been hypothesized that women with cryptococcosis and HIV have a more favorable mortality experience than men. In addition, the availability of highly active anti-retroviral therapy (ART) for HIV in the United States (US) has been associated with greater racial disparities in mortality. The US Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (WONDER) database afforded a unique opportunity to explore mortality rates due to cryptococcosis by gender and race in the US among patients with HIV from 1999 to 2016. Mortality rate ratios from cryptococcosis were significantly lower in women and whites with HIV. These descriptive data lead to the formulation of hypotheses requiring testing in analytic studies designed a priori to do so and pose clinical and public health challenges in reducing mortality from cryptococcosis in patients with HIV.

CRyptOcoccosis in Newcastle and the hUnTer (CRONUT) - An epidemiological study.

BACKGROUND: Cryptococcus neoformans and Cryptococcus gattii are yeasts responsible for invasive infection, primarily pulmonary and neurological. Their clinical epidemiology has been previously described in an Australian national study, but this included no data from the Hunter region, where we anecdotally noted a high incidence of infection. We aimed to describe the epidemiology, management and outcomes of cryptococcal disease in the Hunter region and to compare this with previous Australian data. METHODS: We searched our laboratory database for positive cryptococcal antigen and culture results from January 2003-December 2016. We extracted demographic factors, risk factors, clinical presentation, treatment and outcomes from medical records. We used the 2010 census-derived estimated resident population to calculate population-based incidences. RESULTS: Over a 13-year period, 107 patients had either a positive culture or a positive cryptococcal antigen with a compatible clinical syndrome. Of these, 46 (42.2%) were C. neoformans, 28 (25.7%) C. gattii, and 33 (30.3%) antigen only. The crude incidence (per million with 95% CI) for all disease was 9.5, and for culture proven disease was 2.5 for C. gattii and 4.1 for C. neoformans. Geospatial mapping by species revealed no evident cluster. Of the 63 patients where detailed information was available, around half were immunocompromised (3 [15%] for C. gattii and 25 [81%] for C. neoformans, p < 0.001). Complications were common, including visual loss (11 cases, 17.7%) and hearing loss (5 cases, 8%). Adverse outcomes at one year (death or neurological sequelae) occurred in 42%, and was significantly more likely (OR = 5.2, 95% CI 1.4-18.8) in those with raised intracranial pressure at baseline. Adverse outcomes were no more common in those treated with lower doses of liposomal amphotericin (≤150 mg/day, 5/10) than those treated with the recommended dose of 3-5 mg/kg (≥150 mg; 13/27). CONCLUSION: Although a rare disease, cryptococcosis is more common in the Hunter region than in other parts of Australia, and long-term sequelae are serious and common.

Targeted Theranostic of Cryptococcal Encephalitis by a Novel Polypyridyl Ruthenium Complex.

Cryptococcus neoformans (C. neoformans) is one of the most well-known zoonotic fungal pathogens. Cryptococcal encephalitis remains a major cause of morbidity and mortality in immunocompromised hosts. Effective and targeting killing of C. neoformans in the brain is an essential approach to prevent and treat cryptococcal encephalitis. In this study, a fluorescent polypyridyl ruthenium complex RC-7, {[phen2Ru(bpy-dinonyl)](PF6)2 (phen = 1,10-phenanthroline, bpy-dinonyl = 4,4'-dinonyl-2,2'-bipyridine)}, was screened out, which showed a highly fungicidal effect on C. neoformans. The values of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) in antifungal activities were significantly lower than fluconazole as the control. Moreover, RC-7 was prepared as a brain-targeting nanoliposome (RDP-liposome; RDP is a peptide derived from rabies virus glycoprotein) for in vivo application. The results revealed that the liposomes could accumulate in the encephalitis brain and play an antifungal role. Compared with the cryptococcal encephalitis model mice, the RDP-liposomes remarkably prolonged the survival days of the encephalitis-bearing mice from 10 days to 24 days. Here, we introduce a polypyridyl ruthenium complex that could be used as a novel antifungal agent, and this study may have a broad impact on the development of targeted delivery based on ruthenium complex-loaded liposomes for theranostics of cryptococcal encephalitis.

Cryptococcal antigenemia prevalence and clinical data in HIV-infected patients from the reference centre at INI-FIOCRUZ, Rio de Janeiro, Southeast of Brazil.

Cryptococcal meningitis is a several disease common in late stage of HIV infection. Detection of cryptococcal antigen (CrAg) is an important for early diagnosis of this invasive mycosis. The pre-emptive treatment for isolated antigenemia prevents the onset of meningoencephalitis. Screening CrAg in patients with low CD4 count is cost-effective in countries with prevalence of antigenemia above 3%. However, in Brazil, the number of prevalence studies on cryptococcosis and HIV is insufficient. The objective of this study is to estimate the prevalence of CrAg and describe clinical characteristics from a cohort of patients followed at a reference center in Brazil. CrAg screening was performed in 89 inpatients with CD4 count ≤200 cells/mm3 or WHO stage III/IV from the National Institute of Infecttious Disease, Rio de Janeiro. Patients with isolated antigenemia received pre-emptive therapy with fluconazole and patients with meningoencephalitis were treated with Amphotericin B. Individuals were followed up for 12 months. Prevalence of serum CrAg was 11.23%, cryptococcal meningoencephalitis 6.74% and isolated antigenemia 4.81%. None of the patients with isolated antigenemia developed meningoencephalitis during the follow up. Signs and symptoms of meningoencephalitis were unspecific or absent. Our study suggests the need of CrAg screening in Brazil and highlights that lumbar puncture is mandatory in all individuals CrAg positive to exclude asymptomatic meningoencephalitis.

Mortality After Cryptococcal Infection in the Modern Antiretroviral Therapy Era.

BACKGROUND: The prevalence of cryptococcosis in people living with HIV (PLWH) in the developed world has decreased considerably in the modern antiretroviral therapy (ART) era. Although early mortality of PLWH with opportunistic infections is well understood, overall mortality has not been previously evaluated. METHODS: We conducted a retrospective cohort study of cryptococcosis in PLWH from January 1, 2002, to July 1, 2017. Data were also evaluated before and after 2008 to evaluate the possible effect of modern ART on outcomes. Death date was obtained from the hospital's medical informatics database and the Social Security Death Index. Participants were grouped as survivors, early-mortality (death <90 days), and late-mortality (death ≥90 days) individuals. RESULTS: We reviewed 105 PLWH with cryptococcosis, with 55 survivors (52.4%), 17 early-mortality (16.2%), and 33 late-mortality individuals (31.4%). Overall, mortality was 47.6% (n = 50) with a median follow-up of 3.7 years (interquartile range 1.1, 8.1 years). Late-mortality individuals were less likely to be virally suppressed at the last observation compared with survivors (24% vs 62%, P < 0.001). Individuals diagnosed in the modern ART era had significantly lower mortality (hazard ratio 0.5, confidence interval: 0.2 to 0.8) and were more likely to be virally suppressed at the last observation (57% vs 29%, P = 0.003). Individuals with government-provided insurance had a higher mortality compared to those with private insurance (hazard ratio 2.8, confidence interval: 1.1 to 7.2, P = 0.013). CONCLUSIONS: Despite improvements in ART, PLWH have high mortality after cryptococcal infection that persists beyond their initial hospitalization. Lower mortality was associated with increased HIV viral suppression and private insurance in the modern ART era.

Mortality by cryptococcosis in Brazil from 2000 to 2012: A descriptive epidemiological study.

BACKGROUND: Cryptococcosis is a neglected and predominantly opportunistic mycosis that, in Brazil, poses an important public health problem, due to its late diagnosis and high lethality. METHODS: The present study analysed cryptococcosis mortality in Brazil from January 2000 to December 2012, based on secondary data (Mortality Information System/SIM-DATASUS and IBGE). RESULTS: Out of 5,755 recorded deaths in which cryptococcosis was mentioned as one of the morbid states that contributed to death, two distinct groups emerged: 1,121 (19.5%) registered cryptococcosis as the basic cause of death, and 4,634 (80.5%) registered cryptococcosis associated with risk factors, mainly AIDS (75%), followed by other host risks (5.5%). The mortality rate by cryptococcosis as the basic cause was 6.19/million inhabitants, whereas the mortality rate by cryptococcosis as an associated cause was 25.19/million inhabitants. Meningitis was the predominant clinical form (80%), males were the more affected (69%), and 39.5 years old was the mean age. The highest mortality rate due to cryptococcosis as basic cause occurred in the state of Mato Grosso (10.96/million inhabitants). Mortality rates due to cryptococcosis as associated cause were highest in the states of Santa Catarina (70.41/million inhabitants) and Rio Grande do Sul (64.40/million inhabitants), both in the South Region. Southeast, Northeast and South showed significant time trends in mortality rates. CONCLUSIONS: This study is relevant because it shows the magnitude of cryptococcosis mortality linked to AIDS and removes the invisibility of a particular non-AIDS-related disease, accounting for almost 20% of all cryptococcosis deaths. It can also contribute to control and surveillance programs, beyond highlighting the urgent prioritization of early diagnosis and proper treatment to reduce the unacceptable mortality rate of this neglected mycosis in Brazil.