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BACKGROUND: Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes. METHODS: We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers. RESULTS: Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9-42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002). CONCLUSIONS: The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop.

Background: Reflexed cryptococcal antigenaemia (CrAg) testing has been offered since 2016 in South Africa, on remnant CD4 specimens, for people with a count 100 cells/μL. Local guidelines recommended extending testing to 200 cells/μL. Objectives: This study assessed the cost per result and annual equivalent costs (AEC) for CD4 counts 100 cells/μL and 100 to 200 cells/μL, as well as determining the cost to find one CrAg-positive case. Method: An ingredients-based costing was used to determine the cost per result. The CrAg detection rate for 100 cells/μL was obtained from operational reports of 2019. For 100 cells/μL to 200 cells/μL, a CrAg detection rate of 2% was assumed. One-way sensitivity analysis determined the impact of varying CrAg detection rates on the cost to find one case. Local data from the Western Cape province, which offers testing for counts of 100 cells/μL to 200 cells/μL, from September 2022 to January 2023, were interrogated to establish detection rates. Results: There were 283 240 (AEC: $1 670 370) specimens with counts of 100 cells/μL and 300 624 (AEC: $1 772 890) with counts of 100 cells/μL to 200 cells/μL. A cost per result of $5.897 was reported. The cost to find one CrAg case ranged from $589.74 to $73.72 for a detection rate of 1% to 8%. Local data for a count of 100 cells/μL to 200 cells/μL revealed a CrAg detection rate of 1.6%. Conclusion: The study findings reveal that extending reflexed CrAg testing to 200 cells/μL would double test volumes with fewer positive cases reported for those with a count of 100 cells/μL to 200 cells/μL.

Clinical and epidemiological features of 7 human immunodeficiency virus–negative Peruvian patients coinfected with human T-lymphotropic virus type 1 (HTLV-1) and cryptococcosis (2006–2017) were studied. Most cases had meningeal involvement, were male, and originated from Peru's jungle. Patients with cryptococcosis should be tested for HTLV-1 in endemic areas of this retrovirus. [ABSTRACT FROM AUTHOR]

Abstract Background Cryptococcal meningitis (CM) and tuberculosis (TB) remain leading causes of hospitalization and death amongst people living with HIV, particularly those with advanced HIV disease. In hospitalized patients, prompt diagnosis of these diseases may improve patient outcomes. The advanced HIV rapid diagnostic tests such as determine TB urine lipoarabinomannan lateral flow assay (urine LAM), urine X-pert MTB/RIF assay (urine X-pert), and serum/blood cryptococcal antigen test (serum CrAg) are recommended but frequently not available in many resource-limited settings. We describe our experience providing these tests in a routine hospital setting. Method From 1 August 2016 to 31 January 2017, a prospective cohort study to diagnose TB and Cryptococcal meningitis using point of care tests was conducted in the medical wards at Kamuzu Central Hospital, in Lilongwe, Malawi. The tests offered were PIMA CD4 cell count, serum CrAg, urine LAM, and urine X-pert. The testing was integrated into an existing HIV/TB treatment room on the wards and performed close to admission time. Patients were followed until discharge or death in the ward. Results We included 438 HIV-positive patients; 76% had a previously known HIV diagnosis (87% already on ART). We measured CD4 count in 365/438 (83%), serum CrAg in 301/438 (69%), urine LAM in 363/438 (83%), and urine X-pert in 292/438 (67%). The median CD4 count was 144 cells/ml (IQR 46–307). Serum CrAg positivity rate was 23 /301 (8%) and CM was confirmed by CSF Crag in 13/23 (56%). The majority of CM patients 9/13 (69%) started antifungal therapy within two days of diagnosis. Urine LAM and urine X-pert positivity rates were 81/363(22%) and (14/292 (5%) respectively. The positivity rate of urine LAM was higher in patients with low CD4 cell counts (

ABSTRACT Cryptococcal disease (CD) is a leading cause of mortality among individuals with advanced HIV disease (AHD). Screening with serum cryptococcal antigen (sCrAg) lateral flow assay (LFA) enables early detection of subclinical disease but requires venipuncture and laboratory processing. Clinic-based point of care (POC) CrAg screening tests using urine or fingerprick whole blood could facilitate early diagnosis of CD. We evaluated the diagnostic performance of POC clinic-based fingerprick whole blood and urine CrAg compared to the gold standard laboratory sCrAg LFA in screening for CD among asymptomatic individuals with CD4 counts of

Background: Cryptococcal meningitis (CM) and tuberculosis (TB) remain leading causes of hospitalization and death amongst people living with HIV, particularly those with advanced HIV disease. In hospitalized patients, prompt diagnosis of these diseases may improve patient outcomes. The advanced HIV rapid diagnostic tests such as determine TB urine lipoarabinomannan lateral flow assay (urine LAM), urine X-pert MTB/RIF assay (urine X-pert), and serum/blood cryptococcal antigen test (serum CrAg) are recommended but frequently not available in many resource-limited settings. We describe our experience providing these tests in a routine hospital setting.Method: From 1 August 2016 to 31 January 2017, a prospective cohort study to diagnose TB and Cryptococcal meningitis using point of care tests was conducted in the medical wards at Kamuzu Central Hospital, in Lilongwe, Malawi. The tests offered were PIMA CD4 cell count, serum CrAg, urine LAM, and urine X-pert. The testing was integrated into an existing HIV/TB treatment room on the wards and performed close to admission time. Patients were followed until discharge or death in the ward.Results: We included 438 HIV-positive patients; 76% had a previously known HIV diagnosis (87% already on ART). We measured CD4 count in 365/438 (83%), serum CrAg in 301/438 (69%), urine LAM in 363/438 (83%), and urine X-pert in 292/438 (67%). The median CD4 count was 144 cells/ml (IQR 46-307). Serum CrAg positivity rate was 23 /301 (8%) and CM was confirmed by CSF Crag in 13/23 (56%). The majority of CM patients 9/13 (69%) started antifungal therapy within two days of diagnosis. Urine LAM and urine X-pert positivity rates were 81/363(22%) and (14/292 (5%) respectively. The positivity rate of urine LAM was higher in patients with low CD4 cell counts (< 100 cells/ml) and low BMI (< 18.5). Most patients with positive urine LAM started TB treatment on the same day. Despite the early diagnosis and treatment of TB and CM, the inpatient mortality was high; 30% and 25% respectively.Conclusion: Although advanced HIV rapid diagnostic tests are recommended, one key challenge in implementation is the limited trained personnel administering the tests. Despite the effective use of the point of care tests in the clinical care of hospitalized TB and CM patients, mortality among these patients remained unacceptably high. Henceforth we need to train other cadres apart from nurses, clinicians, and laboratory technicians to conduct the tests. There is an urgent need to identify and modify other risks of death from TB and CM.Trial Registration: Malawi National Health Science Research committee: Protocol # 1144. Registered 2 July 2014 and University Of North Carolina IRB #: UNCPM 21412, approved 13th October 2014. [ABSTRACT FROM AUTHOR]

Abstract INTRODUCTION: The clinical manifestations of cryptococcosis are usually associated with the infecting agents Cryptococcus neoformans (CN) and C. gattii (CG) species complexes and the host. In this study, non-HIV-infected patients, at a university hospital in southeastern Brazil, had epidemiological and clinical data associated with cryptococcal disease and isolated Cryptococcus species: CN - 24 patients and CG - 12 patients. METHODS: The comparison was comprised of demographic data, predisposing factors, clinical and laboratory manifestations, and outcomes of cryptococcosis patients treated between 2000 and 2016. Immunocompetent and immunosuppressed patients were also compared, irrespective of the infecting species. Cryptococcus spp. were genotyped by PCR-RFLP analysis of the URA5 gene. RESULTS: Infections by the CN species complex (100% VNI genotype) were associated with drug immunosuppression and fungemia, and patients infected with the CG species complex (83% VG II and 17% VGI genotypes) had more evident environmental exposure and higher humoral response. CN and CG affected patients with or without comorbidities. CONCLUSIONS: Diabetes mellitus, other chronic non-infectious diseases, and alcoholism were likely predisposing factors for infection by both CN and CG species. Immunocompetent patients, independent of the infecting Cryptococcus species complexes, showed a higher occurrence of meningitis and a trend toward less fungal dissemination and longer survival than immunosuppressed hosts.

Cryptococcosis is a severe fungal disease causing 220,000 cases of cryptococcal meningitis yearly. The etiological agents of cryptococcosis are taxonomically grouped into at least two species complexes belonging to the genus Cryptococcus. All of these yeasts are environmentally ubiquitous fungi (often found in soil, leaves and decaying wood, tree hollows, and associated with bird feces especially pigeon guano). Infection in a range of animals including humans begins following inhalation of spores or aerosolized yeasts. Recent advances provide fundamental insights into the factors from both the pathogen and its hosts which influence pathogenesis and disease. The complex interactions leading to disease in mammalian hosts have also updated from the availability of better genomic tools and datasets. In this review, we discuss recent genetic research on Cryptococcus , covering the epidemiology, ecology, and evolution of Cryptococcus pathogenic species. We also discuss the insights into the host immune response obtained from the latest genetic modified host models as well as insights from monogenic disorders in humans. Finally we highlight outstanding questions that can be answered in the near future using bioinformatics and genomic tools. [ABSTRACT FROM AUTHOR]

Background: Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-positive South Africans. Reflex cryptococcal antigen (CrAg) testing of remnant plasma was offered as a pilot prior to implementation in October 2016 in KwaZulu-Natal province. The national reflex CrAg positivity was 5.4% compared to 7.3% for KwaZulu-Natal. Objectives: The aim of this study was to interrogate CrAg positivity by health levels to identify hotspots. Method: Data for the period October 2016 to June 2017 were analysed. Health district CrAg positivity and prevalence were calculated, with the latter using de-duplicated patient data. The district CrAg positivity and the number of CrAg-positive specimens per health facility were mapped using ArcGIS. For districts with the highest CrAg positivity, a sub-district CrAg positivity analysis was conducted. Results: The provincial CrAg positivity was 7.6%. District CrAg positivity ranged from 5.7% (Ugu) to 9.6% (Umkhanyakude) with prevalence ranging from 5.5% (Ugu) to 9.7% (Umkhanyakude). The highest CrAg positivity was reported for the Umkhanyakude (9.6%) and King Cetswayo (9.5%) districts. In these two districts, CrAg positivity of 10% was noted in the Umhlabuyalingana (10.0%), Jozini (10.2%), uMhlathuze (10.5%) and Nkandla (10.8%) subdistricts. In these subdistricts, 135 CrAg-positive samples were reported for the Ngwelezane hospital followed by 41 and 43 at the Hlabisa and Manguzi hospitals respectively. Conclusion: Cryptococcal antigen positivity was not uniformly distributed at either the district or sub-district levels, with identified facility hotspots in the Umkhanyakude and King Cetswayo districts. This study demonstrates the value of laboratory data to identify hotspots for planning programmatic interventions.

Over the last decade, an upsurge in both the frequency and severity of fungal infections due to the HIV/AIDS epidemic and the use of immunosuppressive therapy has occurred. Even diagnostic methods like culture and microscopy, which have low sensitivity and longer turnaround times, are not widely available, leading to delays in timely antifungal therapy and detrimental patient outcomes. The evolution of cryptococcal antigen (CrAg) testing to develop inexpensive and more sensitive methods to detect cryptococcal antigen is significant. These newer tests employ immunoassays as part of point-of-care platforms, which do not require complex laboratory infrastructure, and they have the potential to detect early disease and reduce time to diagnosis of cryptococcal infection. Advocacy for widely available and efficacious life-saving antifungal treatment should be the only remaining challenge. [ABSTRACT FROM AUTHOR]

Cryptococcal disease remains a significant source of global morbidity and mortality for people living with HIV, especially in resource-limited settings. The recently updated estimate of cryptococcal disease revealed a global incidence of 223,100 cases annually with 73% of these cases being diagnosed in sub-Saharan Africa. Furthermore, 75% of the estimated 181,100 deaths associated with cryptococcal disease occur in sub-Saharan Africa. Point-of-care diagnostic assays have revolutionised the diagnosis of this deadly opportunistic infection. The theory of asymptomatic cryptococcal antigenaemia as a forerunner to symptomatic meningitis and death has been conclusively proven. Thus, cryptococcal antigenaemia screening coupled with pre-emptive antifungal therapy has been demonstrated as a cost-effective strategy with survival benefits and has been incorporated into HIV national guidelines in several countries. However, this is yet to be implemented in a number of other high HIV burden countries. Flucytosine-based combination therapy during the induction phase is associated with improved survival, faster cerebrospinal fluid sterilisation and fewer relapses. Flucytosine, however, is unavailable in many parts of the world. Studies are ongoing on the efficacy of shorter regimens of amphotericin B. Early diagnosis, proactive antifungal therapy with concurrent management of raised intracranial pressure creates the potential to markedly reduce mortality associated with this disease.

Cryptococcal meningitis (CM) is the leading cause of death among people with AIDS. The World Health Organization issued a conditional recommendation in 2011 for countries to consider serum cryptococcal antigen (CrAg) screening in patients with CD4 count <100 cells/μL in order to identify those at risk for CM and to treat them preemptively with fluconazole to prevent progression to CM. This paper outlines the evidence behind CrAg screening, the prevalence of CrAg in various settings, and our current understanding of the state of CrAg screening programs. A growing number of countries are incorporating CrAg screening into their national HIV treatment guidelines and are beginning to implement national screening programs, while others are piloting in select regions to assess the feasibility of such programs. Strategies used to conduct CrAg screening, including reflexive laboratory-based screening, provider-initiated screening, and point-of-care screening, are also discussed. Countries considering large-scale rollout of CrAg screening should assess what combination of screening methods works best in their specific contexts. [ABSTRACT FROM AUTHOR]

Background: Cryptococcus gattii emerged on Vancouver Island, British Columbia (BC), Canada, in 1999, causing human and animal illness. Environmental sampling for C. gattii in southwestern BC has isolated the fungal organism from native vegetation, soil, air, and water. Objectives: Our aim was to help public health officials in BC delineate where C. gattii is currently established and forecast areas that could support C. gattii in the future. We also examined the utility of ecological niche modeling (ENM) based on human and animal C. gattii disease surveillance data. Methods: We performed ENM using the Genetic Algorithm for Rule-set Prediction (GARP) to predict the optimal and potential ecological niche areas of C. gattii in BC. Human and animal surveillance and environmental sampling data were used to build and test the models based on 15 predictor environmental data layers. Results: ENM provided very accurate predictions (> 98% accuracy, p-value < 0.001) for C. gattii in BC. The models identified optimal C. gattii ecological niche areas along the central and south eastern coast of Vancouver Island and within the Vancouver Lower Mainland. Elevation, biogeoclimatic zone, and January temperature were good predictors for identifying the ecological niche of C. gattii in BC. Conclusions: The use of human and animal case data for ENM proved useful and effective in identifying the ecological niche of C. gattii in BC. These results are shared with public health to increase public and physician awareness of cryptococcal disease in regions at risk of environmental colonization of C. gattii. [ABSTRACT FROM AUTHOR]

Cryptococcosis is a severe fungal disease causing 220,000 cases of cryptococcal meningitis yearly. The etiological agents of cryptococcosis are taxonomically grouped into at least two species complexes belonging to the genus Cryptococcus. All of these yeasts are environmentally ubiquitous fungi (often found in soil, leaves and decaying wood, tree hollows, and associated with bird feces especially pigeon guano). Infection in a range of animals including humans begins following inhalation of spores or aerosolized yeasts. Recent advances provide fundamental insights into the factors from both the pathogen and its hosts which influence pathogenesis and disease. The complex interactions leading to disease in mammalian hosts have also updated from the availability of better genomic tools and datasets. In this review, we discuss recent genetic research on Cryptococcus, covering the epidemiology, ecology, and evolution of Cryptococcus pathogenic species. We also discuss the insights into the host immune response obtained from the latest genetic modified host models as well as insights from monogenic disorders in humans. Finally we highlight outstanding questions that can be answered in the near future using bioinformatics and genomic tools., (© 2020 Elsevier Inc. All rights reserved.)