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Introduction: Intracranial fungal infections' (IcFIs) varying clinical manifestations lead to difficulties in diagnosis and treatment. African populations are disproportionately affected by the high burden of the disease. There is a lack of clarity as to the diagnostic and treatment modalities employed across the continent. In this review, we aim to detail the management, and outcome of IcFIs across Africa. Methods: This scoping review was conducted using the Arksey and O'Malley framework. MEDLINE, EMBASE, Cochrane Library, African Index Medicus, and African Journals Online were searched for relevant articles from database inception to August 10th, 2021. The Preferred Reporting Items for Systematic Review and Meta-Analysis extension for Scoping Reviews guidelines were used to report the findings of the review. Results: Of the 5,779 records identified, 131 articles were included. The mean age was 35.6 years, and the majority (56.4%) were males. The majority (n = 8,433/8,693, 97.0%) of IcFIs presented as a meningitis, the most common communicable predisposing factor of IcFIs was HIV/AIDS (n = 7,815/8,693, 89.9%), and the most common non-communicable risk factor was diabetes mellitus (n = 32/8,693, 0.4%). Cryptococcus species was the most common (n = 8,428/8,693, 97.0%) causative organism. The most commonly used diagnostic modality was cerebrospinal (CSF) cultures (n = 4,390/6,830, 64.3%) for diffuse IcFIs, and MRI imaging (n = 12/30, 40%) for focal IcFIs. The most common treatment modality was medical management with antifungals only (n = 4,481/8,693, 51.6%). The most commonly used antifungal agent in paediatric, and adult patients was amphotericin B and fluconazole dual therapy (51.5% vs 44.9%). The overall mortality rate was high (n = 3,475/7,493, 46.3%), and similar for both adult and paediatric patients (47.8% vs 42.1%). Conclusion: Most IcFIs occurred in immunosuppressed individuals, and despite the new diagnostic techniques, CSF culture was mostly used in Africa. Antifungals regimens used was similar between children and adults. The outcome of IcFIs in Africa was poor for both paediatric and adult patients. [ABSTRACT FROM AUTHOR]

The emergence of deadly fungal infections in Africa is primarily driven by a disproportionately high burden of human immunodeficiency virus (HIV) infections, lack of access to quality health care, and the unavailability of effective antifungal drugs. Immunocompromised people in Africa are therefore at high risk of infection from opportunistic fungal pathogens such as Cryptococcus neoformans and Pneumocystis jirovecii, which are associated with high morbidity, mortality, and related socioeconomic impacts. Other emerging fungal threats include Emergomyces spp., Histoplasma spp., Blastomyces spp., and healthcare‐associated multi‐drug resistant Candida auris. Socioeconomic development and the Covid‐19 pandemic may influence shifts in epidemiology of invasive fungal diseases on the continent. This review discusses the epidemiology, clinical manifestations, and current management strategies available for these emerging fungal diseases in Africa. We also discuss gaps in knowledge, policy, and research to inform future efforts at managing these fungal threats. [ABSTRACT FROM AUTHOR]

Cryptococcal meningoencephalitis, a disease with poor patient outcomes, remains the most prevalent invasive fungal infection worldwide, accounting for approximately 180,000 deaths each year. In several areas of sub-Saharan Africa with the highest HIV prevalence, cryptococcal meningitis is the leading cause of community-acquired meningitis, with a high mortality among HIV-infected individuals. Recent studies show that patient disease outcomes are impacted by the genetics of the infecting isolate. Yet, there is still limited knowledge of how these genotypic variations contribute to clinical disease outcome. Further, it is unclear how the genetic heterogeneity of C. neoformans and the extensive phenotypic variation observed between and within isolates affects infection and disease. In this review, we discuss current knowledge of how various genotypes impact disease progression and patient outcome in HIV-positive populations in sub-Saharan African, a setting with a high burden of cryptococcosis. [ABSTRACT FROM AUTHOR]

Our understanding of the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii has been greatly enhanced by use of genome sequencing technologies. Found ubiquitously as saprotrophs in the environment, inhalation of infectious spores from these pathogens can lead to the disease cryptococcosis. Individuals with compromised immune systems are at particular risk, most notably those living with HIV/AIDS. Genome sequencing in combination with laboratory and clinical studies has revealed diverse lineages with important differences in their observed frequency, virulence and clinical outcomes. However, to date, genomic analyses have focused primarily on clinical isolates that represent only a subset of the diversity in the environment. Enhanced genomic surveillance of these yeasts in their native environments is needed in order to understand their ecology, biology and evolution and how these influence the epidemiology and pathophysiology of clinical disease. This is particularly relevant on the African continent from where global cryptococcal diversity may have originated, yet where environmental sampling and sequencing has been sparse despite harbouring the largest population at risk from cryptococcosis. Here, we review what scientifically and clinically relevant insights have been provided by analysis of environmental Cryptococcus isolates to date and argue that with further sampling, particularly in Africa, many more important discoveries await. [ABSTRACT FROM AUTHOR]

Background Mortality from cryptococcal meningitis remains very high in Africa. In the Advancing Cryptococcal Meningitis Treatment for Africa (ACTA) trial, 2 weeks of fluconazole (FLU) plus flucytosine (5FC) was as effective and less costly than 2 weeks of amphotericin-based regimens. However, many African settings treat with FLU monotherapy, and the cost-effectiveness of adding 5FC to FLU is uncertain. Methods The effectiveness and costs of FLU+5FC were taken from ACTA, which included a costing analysis at the Zambian site. The effectiveness of FLU was derived from cohorts of consecutively enrolled patients, managed in respects other than drug therapy, as were participants in ACTA. FLU costs were derived from costs of FLU+5FC in ACTA, by subtracting 5FC drug and monitoring costs. The cost-effectiveness of FLU+5FC vs FLU alone was measured as the incremental cost-effectiveness ratio (ICER). A probabilistic sensitivity analysis assessed uncertainties and a bivariate deterministic sensitivity analysis examined the impact of varying mortality and 5FC drug costs on the ICER. Results The mean costs per patient were US $847 (95% confidence interval [CI] $776–927) for FLU+5FC, and US $628 (95% CI $557–709) for FLU. The 10-week mortality rate was 35.1% (95% CI 28.9–41.7%) with FLU+5FC and 53.8% (95% CI 43.1–64.1%) with FLU. At the current 5FC price of US $1.30 per 500 mg tablet, the ICER of 5FC+FLU versus FLU alone was US $65 (95% CI $28–208) per life-year saved. Reducing the 5FC cost to between US $0.80 and US $0.40 per 500 mg resulted in an ICER between US $44 and US $28 per life-year saved. Conclusions The addition of 5FC to FLU is cost-effective for cryptococcal meningitis treatment in Africa and, if made available widely, could substantially reduce mortality rates among human immunodeficiency virus–infected persons in Africa. [ABSTRACT FROM AUTHOR]

Genetic diversity analyses were performed by sero-genotyping and multi-locus sequence typing on 252 cryptococcal isolates from 13 HIV-positive Ivorian patients followed-up for cryptococcal meningitis. Antifungal susceptibility analyses were performed according to the CLSI M27A3 method. The majority (67.8%) of the isolates belonged to the Cryptococcus neoformans (serotype A) species complex, with 91.9% being VNI and 7.1% being VNII. Cryptococcus deuterogattii VGII (serotype B) represented 16.7% of the strains, while C. neoformans/C. deneoformans VNIII (serotype AD) hybrids accounted for 15.1% of the strains. One strain (0.4%) was not identifiable. Nine different sequence types (STs 5, 6, 23, 40, 93, 207, 311, and a new ST; 555) were identified in the C. neoformans population, while the C. deuterogattii population comprised the single ST 173. The distribution of the strains showed that, while the majority of patients (9/13) harboured a single sequence type, 4 patients showed mixed infections. These patients experienced up to 4 shifts in strain content either at the species and/or ST level during their follow-up. This evolution of diversity over time led to the co-existence of up to 3 different Cryptococcus species and 4 different ST within the same individual during the course of infection. Susceptibility testing showed that all strains were susceptible to amphotericin B while 3.6% of them had a none-wild type phenotype to 5-flucytosine. Concerning fluconazole, 2.9% of C.neoformans serotype A strains and 2.4% of C. deuterogattii had also respectively a none-wild type phenotype to this molecule. All C. neoformans x C. deneoformans serotype AD hybrids had however a wild type phenotype to fluconazole. The present study showed that mixed infections exist and could be of particular importance for care outcomes. Indeed, (i) the different Cryptococcus species are known to exhibit different virulence and different susceptibility patterns to antifungal drugs and (ii) the strains genetic diversity within the samples may influence the susceptibility to antifungal treatment. Author summary: Cryptococcal meningitis is a neglected fungal disease responsible for 181 000 deaths worldwide in 2014, with 75% of deaths occurring in sub-Saharan Africa. Cryptococcal meningitis is caused by environmental yeasts belonging to the Cryptococcus neoformans/Cryptococcus gattii species complexes. The evolution of the diversity of the yeast populations within the patients and during the course of treatment is poorly understood. Indeed, it was believed for a long time that infections were of a single strain type. It was only recently that the complexity of the yeast diversity during infection began to be assessed. Here, the researchers evaluated the diversity of the Cryptococcus population within Ivoirian patients. The purpose was to generate data about the overall diversity of such yeast in Western Africa where the data are scarce and to better understand the evolution of the pathogen populations during patient follow-up. This last point is particularly important because some species are more virulent or naturally more resistant to antifungal treatments and could be an issue in the case of relapses during care protocols. [ABSTRACT FROM AUTHOR]

Combretum molle occurs widely in Africa and is used traditionally to treat many different ailments including microbial infections. Some work has been done on the antimicrobial activity of bark extracts, but not on leaf extracts, a sustainable resource. Dried ground leaves were extracted with methanol, butanol, acetone, ethyl acetate, chloroform, dichloromethane and n-hexane. The antibacterial and antifungal activities were determined by using a serial microplate dilution method and the number of antimicrobial compounds were determined by bioautography. Both animal (Candida albicans , Cryptococcus neoformans , Aspergillus fumigatus) and plant (Penicillium janthinellum , Aspergillus niger , Aspergillus parasiticus , Fusarium oxysporum , Rhizoctonia solani) pathogenic fungal species were examined. Four important nosocomial bacterial species (Staphylococcus aureus , Escherichia coli , Enterococcus faecalis and Pseudomonas aeruginosa) were also examined. Butanol extracted the highest mass of plant material (41 mg) and hexane and dichloromethane extracted the lowest masses, 8 and 9 mgl, respectively. In bioautograms developed with BEA sprayed with Aspergillus fumigatus , all the extracts had clear zones of inhibition at R values of c. 0.12, 0.23, and 0.40 for the different fungi. The MIC values of the extracts ranged from 0.04 to 0.77 mg/ml after 12 h incubation. The acetone leaf extract was the most active with an MIC of 0.04 mg/ml against P. janthinellum , an important plant fungal pathogen. The total activity of 775 ml/g (indicating that the extract obtained from 1 g of leaves can be diluted to 775 ml and will still inhibit the growth) means that the acetone leaf extract could be used to control P. janthinellum infections on plants. • Combretum molle extracts are widely used for many different indications in Africa. • Phytochemical work to date was done mainly on bark extracts. • There was reasonable to good activity against several fungal or bacterial pathogens. • Extracts contained three to five antimicrobial compounds based on bioautography. • Promising application extract against plant pathogen Penicillium janthinellum. [ABSTRACT FROM AUTHOR]

The article presents a study testing two treatment strategies for cryptococcal meningitis among a population of HIV-infected adults in Africa. Details are provided on the use of fluconazole and flucytosine or amphotericin B. The authors go on to explain the differences in these treatment strategies compared to the standard use of amphotericin B plus flucytosine as well as the fluconazole monotherapy.

Cryptococcosis is a neglected tropical disease and the main cause of fungal-related deaths in HIV-positive persons in Africa. It is an AIDS-defining illness that has almost surpassed tuberculosis (TB) in mortality despite wide coverage with antiretroviral therapy. What is known about the cryptococcosis burden in Africa is from estimations based on data from a few studies on the infection burden and associated complications. Consequently, the projected implications of cryptococcosis in Africa have been based on these estimations. This systematic review is aimed at providing unique and up-to-date data on the burden of cryptococcosis in Africa using published hospital-based research data on cryptococcosis in HIV infected and uninfected persons. The review also focused on providing temporal data on the availability of diagnostic and therapeutic options for cryptococcosis in Africa. From our results, about 40 948 cases of cryptococcosis were reported in Africa from 1969 to 2021, and the highest prevalence of cryptococcosis was from southern Africa. The most isolated species was Cryptococcus neoformans 42.4% (17 710/41 801) and only 1.3% (549/41 801) isolates were C. gattii. C. neoformans (serotype A) VN I 64.5% (918/1522) was the most prevalent serotype in Africa, while C. gattii (serotype C) VG IV was thought to pose a huge danger. However, C. neoformans (serotype A) VN I continued to be the major threat in Africa. Due to the limited availability of molecular typing methods and the widespread use of culture, direct microscopy, and serological techniques for diagnosis, 23 542 isolates were uncharacterised. Amphotericin B and flucytosine combination therapy is highly recommended for treatment of cryptococcal meningitis. However, these drugs are expensive and remain largely unavailable in most African countries. Amphotericin B requires laboratory facilities to monitor for toxicity. Although fluconazole monotherapy is the readily available treatment option for cryptococcosis, drug resistance, and high mortality have been recorded in majority of cases in Africa. The lack of awareness and paucity of published data on cryptococcosis are likely to have contributed to the underestimation of cases in Africa and led to underprioritisation of this important disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Summary: HIV-associated pulmonary cryptococcosis is under diagnosed, and may progress to fatal meningoencephalitis. We present a case of HIV-associated pulmonary Cryptococcus neoformans infection, initially mis-diagnosed as smear-negative pulmonary TB, which progressed to fatal cryptococcal meningitis. Autopsy series suggest that pulmonary cryptococcosis is common in African AIDS patients, and, due to limited diagnostic capacity, often mis-diagnosed as smear negative TB. Serum cryptococcal antigen testing may facilitate diagnosis in such cases. [ABSTRACT FROM AUTHOR]

Background:  Cryptococcal meningitis (CM) is a leading cause of death in individuals infected with human immunodeficiency virus (HIV). Identifying factors associated with mortality informs strategies to improve outcomes., Methods:  Five hundred one patients with HIV-associated CM were followed prospectively for 10 weeks during trials in Thailand, Uganda, Malawi, and South Africa. South African patients (n = 266) were followed for 1 year. Similar inclusion/exclusion criteria were applied at all sites. Logistic regression identified baseline variables independently associated with mortality., Results:  Mortality was 17% at 2 weeks and 34% at 10 weeks. Altered mental status (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.7-5.9), high cerebrospinal fluid (CSF) fungal burden (OR, 1.4 per log10 colony-forming units/mL increase; 95% CI, 1.0-1.8), older age (>50 years; OR, 3.9; 95% CI, 1.4-11.1), high peripheral white blood cell count (>10 × 10(9) cells/L; OR, 8.7; 95% CI, 2.5-30.2), fluconazole-based induction treatment, and slow clearance of CSF infection were independently associated with 2-week mortality. Low body weight, anemia (hemoglobin <7.5 g/dL), and low CSF opening pressure were independently associated with mortality at 10 weeks in addition to altered mental status, high fungal burden, high peripheral white cell count, and older age. In those followed for 1 year, overall mortality was 41%. Immune reconstitution inflammatory syndrome occurred in 13% of patients and was associated with 2-week CSF fungal burden (P = .007), but not with time to initiation of antiretroviral therapy (ART)., Conclusions:  CSF fungal burden, altered mental status, and rate of clearance of infection predict acute mortality in HIV-associated CM. The results suggest that earlier diagnosis, more rapidly fungicidal amphotericin-based regimens, and prompt immune reconstitution with ART are priorities for improving outcomes.