Prevalence, treatment, and factors associated with cryptococcal meningitis post introduction of integrase inhibitors antiretroviral based regimens among People Living with HIV in Tanzania.

OBJECTIVE: This study aimed to assess the prevalence of Cryptococcal Meningitis (CM), treatment practice, and the associated factors post-introduction of Tenofovir Lamivudine and Dolutegravir (TLD) regimen among People Living with HIV (PLHIV) in Tanzania. METHODS: This was an analytical cross-sectional study, and the data was collected retrospectively in three public regional referral hospitals (RRHs) in Dar es Salaam, Tanzania. A total of 405 files of the PLHIV admitted in the medical wards on the TLD regimen from January 2019 to December 2022 were reviewed. The collected information includes the patient's demographic characteristics, Cryptococcal status, CD4 level at the time of CM diagnosis, status of using ART, CM treatment approach, and outcome. Data was analyzed using SPSS software version 23. RESULTS: Out of 405 patients, the majority 267(65.9%) were female, 224(55.3%) were aged between 36-55 years, and 293(72.3%) were married. ART defaulters were found to be 37(9.1%). The prevalence of CM was found to be 48(11.9%), out of which 42(87.5%) received fluconazole alone. ART defaulter and marital status significantly (p-value < 0.05) were associated with those who tested CM positive. CONCLUSION: The study found the prevalence of CM among PLHIV to be significantly high and the majority were treated with fluconazole alone. ART defaulters and marital status were significantly associated with one being CM positive. Responsible authorities and stakeholders should enforce guideline adherence and PLHIV should be encouraged on medication adherence.

The prognostic factors for cryptococcal meningitis in non-human immunodeficiency virus patients: An observational study using nationwide database.

BACKGROUND: Cryptococcal meningitis (CM) is an invasive fungal infection with a poor prognosis that often occurs in both healthy individuals and compromised hosts, such as patients infected with human immunodeficiency virus (HIV). Unlike CM in HIV patients, evidence regarding CM in non-HIV patients is limited to small retrospective studies. OBJECTIVE: To identify the pretreatment prognostic factors for CM in non-HIV patients. METHODS: We conducted a large retrospective analysis of CM in non-HIV patients using data from a nationwide Japanese database. The study included hospitalized patients diagnosed with CM between 1 April 2010 and 31 March 2017. All-cause mortality was compared between patients with CM with and without HIV infection. Poor diagnostic factors were analysed in the non-HIV CM group. RESULTS: Overall, 533 (64 HIV and 469 non-HIV) patients met the criteria. The mortality rate at 90 days was significantly lower in the HIV group (6.3% vs. 25.4% p = .0002). In a logistic regression analysis of the non-HIV group, age ≥ 65 y (odds ratio [OR] 2.37, 95% CI 1.17-4.78), impaired consciousness (Japan Coma Scale ≥1) (OR 2.25, 95% CI 1.29-3.93), haemodialysis (OR 3.53, 95% CI 1.12-11.20) and previous corticosteroid usage (OR 2.40, 95% CI 1.37-4.19) were associated with poor prognosis at 30 days after diagnosis. CONCLUSION: More caution is suggested when treating non-HIV with CM in older patients with impaired consciousness, previous corticosteroid usage and haemodialysis.

The incidences and clinical outcomes of cryptococcosis in Taiwan: A nationwide, population-based study, 2002-2015.

Large-scale epidemiological data on cryptococcosis other than cryptococcal meningitis (CM), human immunodeficiency virus (HIV)- or solid organ transplantation (SOT)-associated cryptococcosis are limited. This study investigated the disease burden of cryptococcosis in Taiwan over 14 years. Incident episodes of cryptococcosis, comorbidities, treatment, and outcomes were captured from Taiwan's National Health Insurance Research Database and National Death Registry between 2002 and 2015. Of 6647 episodes analyzed, the crude incidence rate per 100 000 population increased from 1.48 in 2002 to 2.76 in 2015, which was driven by the growing trend in the non-CM group (0.86-2.12) but not in the CM group (0.62-0.64). The leading three comorbidities were diabetes mellitus (23.62%), malignancy (22.81%), and liver disease (17.42%). HIV accounted for 6.14% of all episodes and was associated with the highest disease-specific incidence rate (269/100 000 population), but the value dropped 16.20% biennially. Within 90 days prior to cohort entry, 30.22% of episodes had systemic corticosteroid use. The in-hospital mortality of all episodes was 10.80%, which varied from 32.64% for cirrhosis and 13.22% for HIV to 6.90% for SOT. CM was associated with a higher in-hospital mortality rate than non-CM (19.15% vs. 6.33%). At diagnosis, only 48.53% of CM episodes were prescribed an amphotericin-based regimen. The incidence rate of cryptococcosis was increasing, especially that other than meningitis and in the non-HIV population. A high index of clinical suspicion is paramount to promptly diagnose, treat, and improve cryptococcosis-related mortality in populations other than those with HIV infection or SOT.

This nationwide study showed that the incidence rate of cryptococcosis doubled from 2002 to 2015. Non-meningeal cryptococcosis and non-HIV/nontransplant (NHNT)-associated cryptococcosis contributed to this increase. Our study highlighted the underestimated burden of cryptococcosis in the NHNT hosts.

Genetic diversity and microevolution in clinical Cryptococcus isolates from Cameroon.

Cryptococcal meningitis is the second most common cause of death in people living with HIV/AIDS, yet we have a limited understanding of how cryptococcal isolates change over the course of infection. Cryptococcal infections are environmentally acquired, and the genetic diversity of these infecting isolates can also be geographically linked. Here, we employ whole genome sequences for 372 clinical Cryptococcus isolates from 341 patients with HIV-associated cryptococcal meningitis obtained via a large clinical trial, across both Malawi and Cameroon, to enable population genetic comparisons of isolates between countries. We see that isolates from Cameroon are highly clonal, when compared to those from Malawi, with differential rates of disruptive variants in genes with roles in DNA binding and energy use. For a subset of patients (22) from Cameroon, we leverage longitudinal sampling, with samples taken at days 7 and 14 post-enrollment, to interrogate the genetic changes that arise over the course of infection, and the genetic diversity of isolates within patients. We see disruptive variants arising over the course of infection in several genes, including the phagocytosis-regulating transcription factor GAT204. In addition, in 13% of patients sampled longitudinally, we see evidence for mixed infections. This approach identifies geographically linked genetic variation, signatures of microevolution, and evidence for mixed infections across a clinical cohort of patients affected by cryptococcal meningitis in Central Africa.

Cryptococcal meningitis, caused by Cryptococcus, results in approximately half a million deaths per year globally. We compare clinical Cryptococcus samples from Cameroon and Malawi to explore the genetic diversity of these isolates. We find instances of mixed-strain infections and identify genetic variants arising in Cryptococcus over disease.

Cryptococcal meningitis.

Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell-mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decreased over the past decade, cryptococcosis still accounts for one in five AIDS-related deaths globally due to the persistent burden of advanced HIV disease. Moreover, mortality remains high (~50%) in low-resource settings. The armamentarium to decrease cryptococcosis-associated mortality is expanding: cryptococcal antigen screening in the serum and pre-emptive azole therapy for cryptococcal antigenaemia are well established, whereas enhanced pre-emptive combination treatment regimens to improve survival of persons with cryptococcal antigenaemia are in clinical trials. Short courses (≤7 days) of amphotericin-based therapy combined with flucytosine are currently the preferred options for induction therapy of cryptococcal meningitis. Whether short-course induction regimens improve long-term morbidity such as depression, reduced neurocognitive performance and physical disability among survivors is the subject of further study. Here, we discuss underlying immunology, changing epidemiology, and updates on the management of cryptococcal meningitis with emphasis on HIV-associated disease.

Reduction in mortality from HIV-related CNS infections in routine care in Africa (DREAMM): a before-and-after, implementation study.

BACKGROUND: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection. METHODS: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379. FINDINGS: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01). INTERPRETATION: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals. FUNDING: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.

Cryptococcosis among HIV negative liver disease patients: Epidemiology, underlying conditions, antifungal susceptibility profile from tertiary care hepatobiliary center.

PURPOSE: Cryptococcus neoformans is an encapsulated yeast. It is a significant pathogen among immunocompromised people with HIV & Non-HIV vulnerable populations. These conditions include cancer, corticosteroid usage, immunosuppression following sarcoidosis, organ transplantation, immunosuppressive medication, and liver cirrhosis. In cirrhotic, it accounts for 6-21% of systemic infections. METHODS: The retrospective study was conducted in tertiary care hepatobiliary center in New Delhi, India. Samples of blood, cerebrospinal fluid (CSF), urine, body fluids, and serum were processed for gram stain, India ink, fungal culture and identification, and cryptococcal antigen. Antifungal susceptibility was assessed using the micro-broth dilution technique. RESULTS: 30 patients with cryptococcal infection were analysed, and 40 isolates from various samples were recovered. Out of 40 samples, C. neoformans was isolated from blood (62.5%), urine (15%), ascitic fluid (10%), MiniBAL (5%), bone marrow, CSF, and pleural fluid in one sample each. India ink positivity was 56% and all samples were positive for Cryptococcal antigen. Alcoholic liver disease & Hepatitis B & C associated chronic liver disease were seen in 43% & 20% of patients. Other underlying conditions were diabetes mellitus (20%), TB (10%), autoimmune hepatitis (6.6%), autoimmune disease (autoimmune hemolytic anemia, Sjogren syndrome) (6.6%), sarcoidosis (3.3%), hepatocellular carcinoma (3.3%). 7.5%, 5%, 2.5%, 7.5%, and 2.5% of C. neoformans strains were the non-wild type to fluconazole, 5-fluorocytosine, amphotericin B, posaconazole, and itraconazole respectively, but all strains were wildtype to voriconazole. CONCLUSION: According to the study liver conditions are a significant risk factor for cryptococcal infection. Therefore, cryptococcal isolation and antifungal susceptibility testing, as well as appropriate antifungal drug use, should be studied and paid attention too.

High prevalence of central nervous system cryptococcosis using a fingerprick whole-blood lateral flow assay in individuals with neurological symptoms and advanced HIV disease in a Brazilian emergency department.

Timely diagnosis is key in managing central nervous system (CNS) cryptococcosis in people living with HIV/AIDS (PLWHA). There are few data on implementing fingerprick whole-blood cryptococcal antigen (CrAg) lateral flow assay (LFA) as the first test for diagnosing CNS cryptococcosis. We evaluated the prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood in a referral emergency department (ED) in São Paulo, Brazil. This was a prospective cohort study of consecutive adult PLWHA with advanced HIV disease and neurological symptoms. Fingerprick whole-blood CrAg LFA was performed at bedside. Seventy-four individuals were enrolled (median age = 40 years; males = 62%). Prevalence of CNS cryptococcosis was 17.6% (13/74); 95% confidence interval (CI), 9.4-30.0%, and prevalence of positive fingerprick whole-blood CrAg LFA was 25.7% (19/74); 95% CI, 15.5-40.1%. Among the six (8.1%) patients with positive fingerprick whole-blood CrAg LFA and negative CSF CrAg LFA, four (5.4%) had isolated asymptomatic cryptococcal antigenemia, one (1.3%) had symptomatic cryptococcal antigenemia, and one (1.3%) had cryptococcemia. Prevalence of CNS cryptococcosis and cryptococcal antigenemia using fingerprick whole-blood CrAg LFA was high. Point-of-care testing was important for diagnosing CNS cryptococcosis in an ED from a middle-income country.

Screening for cryptococcal antigen in asymptomatic people with HIV: urgent need in Eastern India.

OBJECTIVE: Cryptococcal meningitis (CM) is a leading cause of mortality in people with HIV (PWH). Despite recommendation by the National programme, cryptococcal antigen (CrAg) screening in PWH with CD4 + <200/µl has not been implemented in practice. Therefore, we conducted a prospective study in government funded Antiretroviral treatment centre to determine the prevalence of asymptomatic cryptococcal antigenemia in PWH with CD4 + cell count <200 cells/µl, subclinical cryptococcal meningitis in serum CrAg positive subjects and their outcome. METHOD: Serum CrAg (BIOSYNEX CryptoPS) screening was conducted in newly diagnosed asymptomatic retro-positive adults with CD4 + <200/µl between January 2021 and March 2022. We also conducted cerebrospinal fluid (CSF) CrAg testing in all PWH who were serum CrAg positive and appropriate therapy was instituted. All the enrolled participants were followed up till February 2023. RESULT: Among enrolled 142 PWH patients, 22 (15.49%) were positive for serum CrAg. Among these 22, seven (31.8%) patients had CD4 + cell count between 100 and 199 cells/µl. CSF CrAg was positive in 11 (50%) serum CrAg positive cases. Serum CrAg positivity was significantly associated with low CD4 + cell count, poor clinical stage and concomitant Pneumocystis pneumonia. However, mortality was not significantly different in Serum CrAg positive and negative PWH. None of the deaths in CrAg positive PWH was due to cryptococcal disease. CONCLUSION: Higher prevalence of cryptococcal antigenemia and subclinical CM among PWH with CD4 + cell count <200 cells/µl with good treatment outcomes with therapy reiterates the need for CrAg screening among PWH in Eastern India.

Cryptococcal meningitis post-covid-19 infection: Immunomodulation, a double-edged sword.

Cryptococcal meningitis is an opportunistic infection associated with altered immunity. Immunomodulatory agent use in severe coronavirus disease 2019 (COVID-19) may predispose such infections. Here, we present a 75-year-old male patient who presented with fever and altered general status after severe COVID-19 infection and developed cryptococcal meningitis. Opportunistic infection may arise from the use of immunomodulation in severe COVID-19, especially in the elderly population. This article describes the case and extensively reviews cryptococcal disease post-COVID-19 literature, highlighting the risk from immunosuppressive treatment.

Cryptococcal meningoencephalitis: Risk factors associated to death in a hospital in Northeastern Brazil.

INTRODUCTION: Cryptococcosis is an opportunistic systemic mycosis caused by pathogenic encapsulated yeasts of the genus Cryptococcus. The objective of the present study was to evaluate the risk factors associated with death of patients diagnosed with meningitis due to Cryptococcus spp. METHODS: This retrospective cohort study included patients admitted to the São José Hospital (SJH) with Cryptococcal Meningoencephalitis (CM) who were diagnosed between 2010 and 2018. Data collection was carried out by reviewing the patients' medical records. Death during hospitalization was considered the primary outcome. RESULTS: From 2010 to 2018, 21,519 patients were admitted to the HSJ, 124 of whom were hospitalized due to CM. The CM incidence rate was 5.8 cases/103 hospitalizations. We included 112 patients in the study. Male patients were the most affected (82.1%), and the median age was 37 years [IQR: 29-45]. HIV coinfection occurred in 79.4% of the patients. Fever (65.2%) and headache (88.4%) were the most frequent symptoms. Greater cellularity in the CSF was the most related factor to CM in non-HIV individuals (p < 0.05). Death during hospitalization occurred in 28.6% (n = 32) of the patients. The independent risk factors associated with death during the hospitalization were women (p = 0.009), age > 35 years (p = 0.046), focal neurological deficits (p = 0.013), altered mental status (p = 0.018) and HIV infection (p = 0.040). The twelve-month survival was lower in HIV-positive patients (p < 0.05). CONCLUSION: Early diagnosis, optimal treatment, and clinical follow-up strategies, especially in HIV patients, should be prioritized.

Six months survival and risk factors for attrition for patients detected with cryptococcal antigenemia through screening in Malawi.

MAIN OBJECTIVE: A cohort of adult Malawian people living with HIV (PLHIV) testing positive for cryptococcal antigenemia was observed and followed to determine the outcomes and risk factors for attrition. METHODS CONCEPT: Eligible PLHIV were enrolled at 5 health facilities in Malawi, representing different levels of health care. ART naïve patients, ART defaulters returning to care, and patients with suspected or confirmed ART treatment failure with CD4 <200 cells/µL or clinical stage 3 or 4 were enrolled and received CrAg tests on whole blood specimens from August 2018 to August 2019. Hospitalized PLHIV were enrolled and tested for CrAg from January 2019 to August 2019, regardless of CD4 or clinical stage. Patients with cryptococcal antigenemia were managed per Malawian clinical guidelines and were followed up for six months. Survival and risk factors for attrition at six months were assessed. RESULTS: A total of 2146 patients were screened and 112 (5.2%) had cryptococcal antigenemia. Prevalence ranged from 3.8% (Mzuzu Central Hospital) to 25.8% (Jenda Rural Hospital). Of the 112 patients with antigenemia, 33 (29.5%) were diagnosed with concurrent CM at the time of enrollment. Six-month crude survival of all patients with antigenemia (regardless of CM status) ranged from 52.3% (assuming lost-to-follow-up (LTFU) patients died) to 64.9% (if LTFU survived). Patients who were diagnosed with concurrent CM by CSF test had poor survival (27.3-39.4%). Patients with antigenemia who were not diagnosed with concurrent CM had 71.4% (if LTFU died)- 89.8% (if LTFU survived) survival at six months. In adjusted analyses, patients with cryptococcal antigenemia detected after admission to inpatient care (aHR: 2.56, 1.07-6.15) and patients with concurrent CM at the time of positive antigenemia result (aHR: 2.48, 1.04-5.92) had significantly higher hazard of attrition at six months. CONCLUSIONS: Overall, our findings indicate a need for routine access to CrAg screening and pre-emptive fluconazole treatment as a way to detect cryptococcal antigenemia and prevent CM in outpatient and inpatient settings. Rapid access to diagnosis and treatment for cryptococcal meningitis (CM) with gold-standard antifungals is needed to improve survival of patients with advanced HIV in Malawi.

Cryptococcus neoformans, a global threat to human health.

BACKGROUND: Emerging fungal pathogens pose important threats to global public health. The World Health Organization has responded to the rising threat of traditionally neglected fungal infections by developing a Fungal Priority Pathogens List (FPPL). Taking the highest-ranked fungal pathogen in the FPPL, Cryptococcus neoformans, as a paradigm, we review progress made over the past two decades on its global burden, its clinical manifestation and management of cryptococcal infection, and its antifungal resistance. The purpose of this review is to drive research efforts to improve future diagnoses, therapies, and interventions associated with fungal infections. METHODS: We first reviewed trends in the global burden of HIV-associated cryptococcal infection, mainly based on a series of systematic studies. We next conducted scoping reviews in accordance with the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses extension for Scoping Reviews using PubMed and ScienceDirect with the keyword Cryptococcus neoformans to identify case reports of cryptococcal infections published since 2000. We then reviewed recent updates on the diagnosis and antifungal treatment of cryptococcal infections. Finally, we summarized knowledge regarding the resistance and tolerance of C. neoformans to approved antifungal drugs. RESULTS: There has been a general reduction in the estimated global burden of HIV-associated cryptococcal meningitis since 2009, probably due to improvements in highly active antiretroviral therapies. However, cryptococcal meningitis still accounts for 19% of AIDS-related deaths annually. The incidences of CM in Europe and North America and the Latin America region have increased by approximately two-fold since 2009, while other regions showed either reduced or stable numbers of cases. Unfortunately, diagnostic and treatment options for cryptococcal infections are limited, and emerging antifungal resistance exacerbates the public health burden. CONCLUSION: The rising threat of C. neoformans is compounded by accumulating evidence for its ability to infect immunocompetent individuals and the emergence of antifungal-resistant variants. Emphasis should be placed on further understanding the mechanisms of pathogenicity and of antifungal resistance and tolerance. The development of novel management strategies through the identification of new drug targets and the discovery and optimization of new and existing diagnostics and therapeutics are key to reducing the health burden.

Modelling the impact of CD4 testing on mortality from TB and cryptococcal meningitis among patients with advanced HIV disease in nine countries.

INTRODUCTION: Despite antiretroviral therapy (ART) scale-up among people living with HIV (PLHIV), those with advanced HIV disease (AHD) (defined in adults as CD4 count <200 cells/mm3 or clinical stage 3 or 4), remain at high risk of death from opportunistic infections. The shift from routine baseline CD4 testing towards viral load testing in conjunction with "Test and Treat" has limited AHD identification. METHODS: We used official estimates and existing epidemiological data to project deaths from tuberculosis (TB) and cryptococcal meningitis (CM) among PLHIV-initiating ART with CD4 <200 cells/mm3 , in the absence of select World Health Organization recommended diagnostic or therapeutic protocols for patients with AHD. We modelled the reduction in deaths, based on the performance of screening/diagnostic testing and the coverage and efficacy of treatment/preventive therapies for TB and CM. We compared projected TB and CM deaths in the first year of ART from 2019 to 2024, with and without CD4 testing. The analysis was performed for nine countries: South Africa, Kenya, Lesotho, Mozambique, Nigeria, Uganda, Zambia, Zimbabwe and the Democratic Republic of Congo. RESULTS: The effect of CD4 testing comes through increased identification of AHD and consequent eligibility for protocols for AHD prevention, diagnosis and management; algorithms for CD4 testing avert between 31% and 38% of deaths from TB and CM in the first year of ART. The number of CD4 tests required per death averted varies widely by country from approximately 101 for South Africa to 917 for Kenya. CONCLUSIONS: This analysis supports retaining baseline CD4 testing to avert deaths from TB and CM, the two most deadly opportunistic infections among patients with AHD. However, national programmes will need to weigh the cost of increasing CD4 access against other HIV-related priorities and allocate resources accordingly.

Cryptococcal Meningitis and Clinical Outcomes in Persons With Human Immunodeficiency Virus: A Global View.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of morbidity and mortality in persons with human immunodeficiency virus (HIV; PWH). Little is known about CM outcomes and availability of diagnostic and treatment modalities globally. METHODS: In this retrospective cohort study, we investigated CM incidence and all-cause mortality in PWH in the International Epidemiology Databases to Evaluate AIDS cohort from 1996 to 2017. We estimated incidence using quasi-Poisson models adjusted for sex, age, calendar year, CD4 cell count (CD4), and antiretroviral therapy (ART) status. Mortality after CM diagnosis was examined using multivariable Cox models. A site survey from 2017 assessed availability of CM diagnostic and treatment modalities. RESULTS: Among 518 852 PWH, there were 3857 cases of CM with an estimated incidence of 1.54 per 1000 person-years. Mortality over a median of 2.6 years of post-CM diagnosis follow-up was 31.6%, with 29% lost to follow-up. In total, 2478 (64%) were diagnosed with CM after ART start with a median of 253 days from ART start to CM diagnosis. Older age (hazard [HR], 1.31 for 50 vs 35 years), lower CD4 (HR, 1.15 for 200 vs 350 cells/mm3), and earlier year of CM diagnosis (HR, 0.51 for 2015 vs 2000) were associated with higher mortality. Of 89 sites, 34% reported access to amphotericin B; 12% had access to flucytosine. CONCLUSIONS: Mortality after CM diagnosis was high. A substantial portion of CM cases occurred after ART start, though incidence and mortality may be higher than reported due to ascertainment bias. Many sites lacked access to recommended CM treatment.

Cryptococcal Meningitis in a Mexican Neurological Center.

BACKGROUND: Cryptococcal meningitis, one of the most severe infections affecting the central nervous system, often involves severe neurological sequels and high mortality. METHODS: A retrospective review was performed, including 76 cases admitted in a 10-year period at a neurological referral center in Mexico City. From 68 isolates, 52 fungal specimens were identified as part of the Cryptococcus neoformans var. neoformans complex, 15 as C. neoformans var gattii complex, and one as Cryptococcus non- neoformans/gattii . RESULTS: Higher cryptococcal meningitis incidence and severity were found in HIV-infected men; other risk factors frequently observed were diabetes mellitus and labor exposure to poultry. The main clinical manifestations were subacute headache, cognitive alterations, and photophobia (exclusively in HIV patients). MRI was highly sensitive for pathologic findings such as meningeal enhancements and cryptococcomas, most of them associated to C. neoformans complex. Eleven patients developed severe brain vasculitis, as observed by transcranial Doppler. Hydrocephalus with intracranial hypertension was the most frequent complication. CONCLUSIONS: One-half of the population died, and the rest had neurological sequels, mainly neuropsychiatric manifestations and secondary headaches. These patients developed severe functional limitations in performing daily activities in an independent manner.

Cryptococcal meningitis in people living with human immunodeficiency virus in Nepal: Perspectives from resource limited setting.

Early diagnosis of cryptococcal meningitis among people living with HIV (PLHIV) is crucial for its therapeutic success. The objective of this study was to diagnose cryptococcal meningitis in PLHIV cases using the available laboratory techniques for its confirmation in resource limited setting. This cross-sectional prospective study was conducted among 72 PLHIV with clinical suspicion of meningitis. Each cerebrospinal fluid (CSF) sample received at the National Public Health Laboratory, Kathmandu was processed for India ink staining, cryptococcal antigen lateral flow assay, and fungal culture following standard protocols. The laboratory-confirmed cryptococcal meningitis cases were between 24 and 69 years of age (median age 39 years) with 87.5% (12/14) of cases being male. Cryptococcus was detected in 22.22% (16/72) by any of the three tests, 19.44% (14/72) by cryptococcal antigen lateral flow assay, 16.66% (12/72) by India ink staining, and 8.33% (6/72) by culture. High percentage of cryptococcal meningitis among PLHIV warrants early microbiological diagnosis for better case management. Cryptococcal antigen detection immunoassay should be the priority test for laboratory diagnosis of cryptococcal meningitis in PLHIV. Alternatively, very simple and economic India ink staining of CSF specimens could be used in resource limited settings.

Cryptococcal Antigenemia in Advanced Human Immunodeficiency Virus Disease: Pathophysiology, Epidemiology, and Clinical Implications.

Cryptococcal antigen (CrAg) is detectable in blood prior to the onset of symptomatic cryptococcal meningitis (CM), a leading cause of death among people with advanced human immunodeficiency virus (HIV) disease globally. Highly sensitive assays can detect CrAg in blood, and screening people with HIV with low CD4 counts, followed by preemptive antifungal treatment, is recommended and widely implemented as part of a global strategy to prevent CM and end cryptococcal-related deaths. Cryptococcal antigenemia encompasses a spectrum of conditions from preclinical asymptomatic infection (cerebrospinal fluid [CSF] CrAg-negative) through subclinical (CSF CrAg-positive without overt meningism) to clinical symptomatic cryptococcal disease, usually manifesting as CM. In this review, we summarize current understanding of the pathophysiology, risk factors for, and clinical implications of cryptococcal antigenemia within this spectrum. We also provide an update on global prevalence, recommended screening and treatment strategies, and future considerations for improving outcomes among patients with cryptococcal antigenemia.

Cryptococcal antigenemia in people living with HIV and AIDS.

AIM: To assess the prevalence of cryptococcal antigenemia among people living with HIV/AIDS (PLHA) with CD4 ≤100/mm3. DESIGN: This observational study was performed on PLHA with laboratory-confirmed CD4 ≤100/mm3. All PLHA were recruited irrespective of their duration of HIV diagnosis, antiretroviral therapy (ART) naïve, or ART failure. METHODS: The prevalence of cryptococcal antigen (CrAg) was assessed in 102 PLHA, with CD4 ≤100/mm3, using a latex agglutination test on serum samples. All the subjects were followed up for 3 months. RESULTS: Amongst 102 PLHA, 62 (60.8%) and 40 (39.2%) patients were ART-naïve and ART failures, respectively, with 2.9% (n = 3) having clinical features of meningitis and 6.8% (n = 7) patients being asymptomatic CrAg-positive. At the 3 month follow-up, total mortality was 10.8%, of which 33.3% and 8.8% were among CrAg-positive and negative patients (p = 0.05). Mortality in asymptomatic and meningitis symptomatic CrAg-positive patients was 1.03% (n = 1) and 2.06% (n = 2), respectively. Of note, five patients were lost to follow-up. CONCLUSION: Cryptococcal antigenemia is common among patients with CD4 ≤100/mm3 who were either ART naïve or had treatment failure. Asymptomatic patients who underwent pre-emptive therapy demonstrated good clinical outcomes.

High concordance in plasma and CSF HIV-1 drug resistance mutations despite high cases of CSF viral escape in individuals with HIV-associated cryptococcal meningitis in Botswana.

OBJECTIVES: We compared the patterns of HIV-1 drug resistance mutations between the CSF and plasma of individuals with HIV-associated cryptococcal meningitis. METHODS: This is a cross-sectional study of archived CSF and plasma samples collected from ART-exposed participants recruited in the Phase 3 AmBisome Therapy Induction Optimisation randomized controlled trial (ISRCTN72509687) conducted in Botswana between 2018 and 2021. HIV-1 RT and protease genes were genotyped using next-generation sequencing and HIV-1 drug resistance mutations were compared between the CSF and plasma compartments stratified by thresholds of ≥20% and <20%. RESULTS: Overall, 66.7% (16/24) of participants had at least one HIV-1 drug resistance mutation in the CSF and/or plasma. A total of 15/22 (68.2%) participants had HIV-1 drug resistance mutations at ≥20% threshold in the plasma and of those, 11 (73.3%) had been on ART longer than 6 months. HIV-1 drug resistance mutations were highly concordant between the CSF and plasma at ≥20% threshold despite a substantial number of individuals experiencing CSF viral escape and with only 54.5% with CSF WBC count ≥20 cells/mm3. Minority HIV-1 drug resistance mutations were detected in 20.8% (5/24) of participants. There were no mutations in the CSF that were not detected in the plasma. CONCLUSIONS: There was high concordance in HIV-1 drug resistance mutations in the CSF and plasma, suggesting intercompartmental mixing and possibly a lack of compartmentalization. Some individuals harboured minority HIV-1 drug resistance mutations, demonstrating the need to employ more sensitive genotyping methods such as next-generation sequencing for the detection of low-abundance mutations.