The epidemiology of fungal infections in Eritrea is unknown. Most cases are under-reported due to a lack of diagnostics. This study estimates the burden of serious fungal infections and highlights treatment and diagnostic gaps in the country. All publications related to fungal infections were identified by searches using PubMed/Medline and Google Scholar. Where no data were available, data from neighbouring countries, then sub-Saharan African countries, then other parts of the world were considered for deriving estimates. The Eritrea population was 3,546,427 in 2020. In 2020, HIV/AIDS patients numbered 1400 and TB incidence were 2875. The five-year adult prevalence of asthma (2016-2020) was 41,390, and the total prevalence estimate of chronic obstructive pulmonary disease (COPD) was 308,328. The annual incidence of cryptococcal meningitis and Pneumocystis jirovecii pneumonia in AIDS patients was estimated at 96 and 205 cases. Oesophageal candidiasis incidence is 715 HIV-infected patients. Chronic pulmonary aspergillosis prevalence, including post-tuberculosis cases, was estimated at 1399 (39/100,000). Fungal asthma has a prevalence of 1035 and 1366 in adults. The estimated prevalence of recurrent vulvovaginal candidiasis and tinea capitis is 59,391 and 342,585, respectively. There are no data on candidaemia, but it is estimated at 5/100,000 (177 cases annually). Invasive aspergillosis in leukaemia, lung cancer, COPD and HIV is estimated at 540 cases and fungal keratitis in 514 cases annually. Serious fungal infections are prevalent in Eritrea with approximately 408,164 people (11.5%) affected annually. Studies on fungal diseases to improve diagnosis and treatment are required with the implementation of a national surveillance program.

For the first time, we aimed to estimate the burden of serious fungal infections or diseases (SFD) and highlight national epidemiological features in Serbia. Data on population and underlining conditions were extracted from the Statistical Office of the Republic of Serbia, World Bank, the Institute of Public Health of Serbia, the World Health Organization, National reference laboratory for medical mycology, the national registries of Serbian professional societies, and relevant publications. The population structure/inhabitants in 2016 (not including the autonomous region Kosovo & Metohija) was 7,058,322; with 6,041,743 adults (85.6%). The populations at risk (total cases per year) were: HIV infected 2441; acute myeloid leukemia 212; stem cell transplantation 151; solid organ transplants 59; chronic obstructive pulmonary disease 250,302; adult asthmatics 311,806; adult cystic fibrosis 65; pulmonary tuberculosis 898; lung cancer 7260; intensive care unit admissions 19,821; and renal support 520. Annual fungal disease cases estimated are: candidemia 518; invasive aspergillosis 619; Candida peritonitis 187; Pneumocystis jirovecii pneumonia 62; cryptococcosis 5; mucormycosis or fusariosis 23; severe asthma with fungal sensitization 10,393; allergic bronchopulmonary aspergillosis 9094; chronic pulmonary aspergillosis 448, recurrent Candida vaginitis 135,303; oral candidiasis 208,489; esophageal candidiasis 173, fungal keratitis 70; tinea capitis 300; and onychomycosis 342,721. We expect that 156,825 people suffer from serious SFD each year (2221/100,000), and 409 dies annually. Additionally, the prevalence of superficial infections exceeds 1,008,995 cases (14,295/100,000). The first Rhinosporidium outbreak in Europe was associated with Serbian Silver Lake. The plant pathogen Fusarium seems to be emerging in Serbian pediatric haematooncology settings. Candida auris and endemic mycoses have not been observed to date. These general estimates provide a primer for further efforts to study fungal epidemiology in Serbia.

To explore the characteristics of invasive pulmonary fungal disease and the spectrum of pathogens causing invasive pulmonary fungal disease diagnosed by pathological examination using fungal stains.

Scedosporium fungi are found in various natural and host-associated environments, including the lungs of cystic fibrosis patients. However, their role in infection development remains underexplored. Here the attachment of conidia of a virulent S. aurantiacum strain WM 06.482 onto the human lung epithelial A549 cells in vitro was visualized using microscopy to examine the initial steps of infection. We showed that 75-80% of fungal conidia were bound to the A549 cells within four hours of co-incubation, and started to produce germ tubes. The germinating conidia seemed to invade the cells through the intercellular space, no intracellular uptake of fungal conidia by the airway epithelial cells after conidial attachment. Transcriptomic analysis of the A549 cells revealed that the up-regulated genes were mainly associated with cell repair and inflammatory processes indicating a protective response against S. aurantiacum infection. Network analysis of the differentially expressed genes showed activation of the innate immune system (NF-kB pathway) leading to the release of pro-inflammatory cytokines. We believe this is the first report showing the transcriptomic response of human alveolar epithelial cells exposed to S. aurantiacum conidia paving a way for better understanding of the mechanism of the infection process.

Fungal infections (FIs) are one of the leading causes of morbidity and mortality within the first year of lung transplant (LT) in LT recipients (LTRs). Their prompt identification and treatment are crucial for a favorable LTR outcome. The objectives of our study were to assess (i) the FI incidence and colonization during the first year after a bilateral LT, (ii) the risk factors associated with FI and colonization, and (iii) the differences in fungal incidence according to the different prophylactic strategies. All bilateral LTRs admitted to the intensive care unit of Padua University Hospital were retrospectively screened, excluding patients <18 years of age, those who had been re-transplanted, and those who had received ventilation and/or extracorporeal membrane oxygenation before LT. Overall, 157 patients were included. A total of 13 (8%) patients developed FI, and 36 (23%) developed colonization, which was mostly due to Aspergillus spp. We did not identify independent risk factors for FI. Groups of patients receiving different prophylactic strategies reported a similar incidence of both FI and colonization. The incidence of FI and fungal colonization was 8% and 23%, respectively, with no differences between different antifungal prophylaxes or identified predisposing factors. Further studies with larger numbers are needed to confirm our results.

Fungi are abundant in the environment, causing our lungs to be constantly exposed to a diverse range of species. While the majority of these are cleared effectively in healthy individuals, constant exposure to spores (especially Aspergillus spp.) can lead to the development of allergic inflammation that underpins and worsen diseases such as asthma. Despite this, the precise mechanisms that underpin the development of fungal allergic disease are poorly understood. Innate immune cells, such as macrophages (MΦs) and dendritic cells (DCs), have been shown to be critical for mediating allergic inflammation to a range of different allergens. This review will focus on the crucial role of MΦ and DCs in mediating antifungal immunity, evaluating how these immune cells mediate allergic inflammation within the context of the lung environment. Ultimately, we aim to highlight important future research questions that will lead to novel therapeutic strategies for fungal allergic diseases.

Patients with chronic obstructive pulmonary disease (COPD) develop acute exacerbations (AE), with varying natural history. The exacerbation is triggered by infection, leading to increased morbidity and mortality. The study on infectious aetiology of AECOPD is largely restricted to only viral or only bacterial aetiology. There are no studies from India that have investigated multiple viral, bacterial, and fungal associations from the same group of patients. This prospective study was conducted over 2 years to estimate the incidence and profile of viral infections in AECOPD patients, their coinfection with other bacterial and fungal agents, and association of the type and pattern of infective agent with the clinical severity.

Metagenomic next-generation sequencing (mNGS) is widely used for pulmonary infection; nonetheless, the experience from its clinical use in diagnosing pulmonary fungal infections is sparse. This study aimed to compare mNGS results from lung biopsy and bronchoalveolar lavage fluid (BALF) and determine their clinical diagnostic efficacy.

Lungs balance threat from primary viral infection, secondary infection, and inflammatory damage. Severe pulmonary inflammation induces vascular permeability, edema, and organ dysfunction. We previously demonstrated that poly(I:C) (pICLC) induced type 1 interferon (t1IFN) protected mice from Cryptococcus gattii (Cg) via local iron restriction. Here we show pICLC increased serum protein and intravenously injected FITC-dextran in the lung airspace suggesting pICLC induces vascular permeability. Interestingly, pICLC induced a pro-inflammatory signature with significant expression of IL-1 and IL-6 which depended on MDA5 and t1IFN. Vascular permeability depended on MDA5, t1IFN, IL-1, and IL-6. T1IFN also induced MDA5 and other MDA5 signaling components suggesting that positive feedback contributes to t1IFN dependent expression of the pro-inflammatory signature. Vascular permeability, induced by pICLC or another compound, inhibited Cg by limiting iron. These data suggest that pICLC induces t1IFN which potentiates pICLC-MDA5 signaling increasing IL-1 and IL-6 resulting in leakage of antimicrobial serum factors into lung airspace. Thus, induced vascular permeability may act as an innate defense mechanism against opportunistic fungal infection, such as cryptococcosis, and may be exploited as a host-directed therapeutic target.

The COVID-19 pandemic has intensified interest in how the infection affects the lung microbiome of critically ill patients and how it contributes to acute respiratory distress syndrome (ARDS). We aimed to characterize the lower respiratory tract mycobiome of critically ill patients with COVID-19 in comparison to patients without COVID-19.

Asthma is a group of inflammatory conditions that compromises the airways of a continuously increasing number of people around the globe. Its complex etiology comprises both genetic and environmental aspects, with the intestinal and lung microbiomes emerging as newly implicated factors that can drive and aggravate asthma. Longitudinal infant cohort studies combined with mechanistic studies in animal models have identified microbial signatures causally associated with subsequent asthma risk. The recent inclusion of fungi in human microbiome surveys has revealed that microbiome signatures associated with asthma risk are not limited to bacteria, and that fungi are also implicated in asthma development in susceptible individuals. In this review, we examine the unique properties of human-associated and environmental fungi, which confer them the ability to influence immune development and allergic responses. The important contribution of fungi to asthma development and exacerbations prompts for their inclusion in current and future asthma studies in humans and animal models.

Invasive fungal infections are an increasingly important cause of human morbidity and mortality. We generated a next-generation sequencing (NGS)-based method designed to detect a wide range of fungi and applied it to analysis of the fungal microbiome (mycobiome) of the lung during fungal infection. Internal transcribed spacer 1 (ITS1) amplicon sequencing and a custom analysis pipeline detected 96% of species from three mock communities comprised of potential fungal lung pathogens with good recapitulation of the expected species distributions (Pearson correlation coefficients r = 0.63, p = 0.004; r = 0.71, p < 0.001; r = 0.62, p = 0.002). We used this pipeline to analyze mycobiomes of bronchoalveolar lavage (BAL) specimens classified as culture-negative (n = 50) or culture-positive (n = 39) for Blastomyces dermatitidis/gilchristii, the causative agent of North America blastomycosis. Detected in 91.4% of the culture-positive samples, Blastomyces dominated (>50% relative abundance) the mycobiome in 68.6% of these culture-positive samples but was absent in culture-negative samples. To overcome any bias in relative abundance due to between-sample variation in fungal biomass, an abundance-weighting calculation was used to normalize the data by accounting for sample-specific PCR cycle number and PCR product concentration data utilized during sample preparation. After normalization, there was a statistically significant greater overall abundance of ITS1 amplicon in the Blastomyces-culture-positive samples versus culture-negative samples. Moreover, the normalization revealed a greater biomass of yeast and environmental fungi in several Blastomyces-culture-positive samples than in the culture-negative samples. Successful detection of Coccidioides, Scedosporium, Phaeoacremonium, and Aspergillus in 6 additional culture-positive BALs by ITS1 amplicon sequencing demonstrates the ability of this method to detect a broad range of fungi from clinical specimens, suggesting that it may be a potentially useful adjunct to traditional fungal microbiological testing for the diagnosis of respiratory mycoses.

For many years, fungi have emerged as significant and frequent opportunistic pathogens and nosocomial infections in many different populations at risk. Fungal infections include disease that varies from superficial to disseminated infections which are often fatal. No fungal disease is reportable in Oman. Many cases are admitted with underlying pathology, and fungal infection is often not documented. The burden of fungal infections in Oman is still unknown. Using disease frequencies from heterogeneous and robust data sources, we provide an estimation of the incidence and prevalence of Oman's fungal diseases. An estimated 79,520 people in Oman are affected by a serious fungal infection each year, 1.7% of the population, not including fungal skin infections, chronic fungal rhinosinusitis or otitis externa. These figures are dominated by vaginal candidiasis, followed by allergic respiratory disease (fungal asthma). An estimated 244 patients develop invasive aspergillosis and at least 230 candidemia annually (5.4 and 5.0 per 100,000). Only culture and microscopy are currently available for diagnosis, so case detection is suboptimal. Uncertainty surrounds these figures that trigger the need for urgent local epidemiological studies with more sensitive diagnostics.

Fungal infections are frequent in Cameroon, and invasive fungal infections are sometimes detected, usually in HIV-infected patients. For these reasons, we have estimated the burden of fungal infections. Using published literature and population estimates for the at-risk group, we used deterministic modelling to derive national incidence and prevalence estimates for the most serious fungal diseases. HIV infection is common and an estimated 120,000 have CD4 counts <200 × 10⁶/mL and commonly present with opportunistic infection. Oesophageal candidiasis in HIV is common, and in poorly controlled diabetics. We estimate 6720 cases of cryptococcal meningitis, 9000 of Pneumocystis pneumonia, 1800 of disseminated histoplasmosis annually complicating AIDS, and 1200 deaths from invasive aspergillosis in AIDS, but there are no data. We found that 2.4% of adults have chronic obstructive pulmonary disease (COPD) and 2.65% have asthma, with "fungal asthma" affecting 20,000. Chronic pulmonary aspergillosis probably affects about 5000 people, predominantly after tuberculosis but also with COPD and other lung diseases. Also, tinea capitis in schoolchildren is frequent. Overall, an estimated 1,235,775 people are affected by a serious fungal infection. There is an urgent need for government and clinician attention, improved laboratory facilities, fungal diagnostic tests, and competent laboratory technicians, as well as all World Health Organization (WHO)-endorsed essential antifungal drugs to be made available, as only fluconazole is registered and available in the country.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Clinical trial registries may allow for producing a global mapping of health research. However, health conditions are not described with standardized taxonomies in registries. Previous work analyzed clinical trial registries to improve the retrieval of relevant clinical trials for patients. However, no previous work has classified clinical trials across diseases using a standardized taxonomy allowing a comparison between global health research and global burden across diseases. We developed a knowledge-based classifier of health conditions studied in registered clinical trials towards categories of diseases and injuries from the Global Burden of Diseases (GBD) 2010 study. The classifier relies on the UMLS® knowledge source (Unified Medical Language System®) and on heuristic algorithms for parsing data. It maps trial records to a 28-class grouping of the GBD categories by automatically extracting UMLS concepts from text fields and by projecting concepts between medical terminologies. The classifier allows deriving pathways between the clinical trial record and candidate GBD categories using natural language processing and links between knowledge sources, and selects the relevant GBD classification based on rules of prioritization across the pathways found. We compared automatic and manual classifications for an external test set of 2,763 trials. We automatically classified 109,603 interventional trials registered before February 2014 at WHO ICTRP.

Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.

Asthma, a common disorder that affects >250 million people worldwide, is defined by exaggerated bronchoconstriction to inflammatory mediators including acetylcholine (ACh), bradykinin and histamine-also termed airway hyper-responsiveness. Nearly 10% of people with asthma have severe, treatment-resistant disease, which is frequently associated with immunoglobulin-E sensitization to ubiquitous fungi, typically Aspergillus fumigatus (Af). Here we show that a major Af allergen, Asp f13, which is a serine protease, alkaline protease 1 (Alp 1), promotes airway hyper-responsiveness by infiltrating the bronchial submucosa and disrupting airway smooth muscle (ASM) cell-extracellular matrix (ECM) interactions. Alp 1-mediated ECM degradation evokes pathophysiological RhoA-dependent Ca(2+) sensitivity and bronchoconstriction. These findings support a pathogenic mechanism in asthma and other lung diseases associated with epithelial barrier impairment, whereby ASM cells respond directly to inhaled environmental allergens to generate airway hyper-responsiveness.

Colitis is characterized by colonic inflammation and impaired gut health. Both features aggravate obesity and insulin resistance. Host defense peptides (HDPs) are key regulators of gut homeostasis and generally malfunctioning in above-mentioned conditions. We aimed here to improve bowel function in diet-induced obesity and chemically induced colitis through daily oral administration of lysozyme, a well-characterized HDP, derived from Acremonium alcalophilum.C57BL6/J mice were fed either low-fat reference diet or HFD ± daily gavage of lysozyme for 12 weeks, followed by metabolic assessment and evaluation of colonic microbiota encroachment. To further evaluate the efficacy of intestinal inflammation, we next supplemented chow-fed BALB/c mice with lysozyme during Dextran Sulfate Sodium (DSS)-induced colitis in either conventional or microbiota-depleted mice. We assessed longitudinal microbiome alterations by 16S amplicon sequencing in both models.Lysozyme dose-dependently alleviated intestinal inflammation in DSS-challenged mice and further protected against HFD-induced microbiota encroachment and fasting hyperinsulinemia. Observed improvements of intestinal health relied on a complex gut flora, with the observation that microbiota depletion abrogated lysozyme's capacity to mitigate DSS-induced colitis.Akkermansia muciniphila associated with impaired gut health in both models, a trajectory that was mitigated by lysozyme administration. In agreement with this notion, PICRUSt2 analysis revealed specific pathways consistently affected by lysozyme administration, independent of vivarium, disease model and mouse strain.Taking together, lysozyme leveraged the gut microbiota to curb DSS-induced inflammation, alleviated HFD-induced gastrointestinal disturbances and lowered fasting insulin levels in obese mice. Collectively, these data present A. alcalophilum-derived lysozyme as a promising candidate to enhance gut health.

Asthma is one of the neglected diseases in Africa with a high prevalence. Allergic fungal diseases have been reported to complicate asthma progression and treatment outcomes. However, data about fungal asthma and its associated complications are limited in Africa. We aimed to estimate the burden of fungal asthma among adults and children in Africa using a systematic review.