Fungal diseases kill more than 1.5 million and affect over a billion people. However, they are still a neglected topic by public health authorities even though most deaths from fungal diseases are avoidable. Serious fungal infections occur as a consequence of other health problems including asthma, AIDS, cancer, organ transplantation and corticosteroid therapies. Early accurate diagnosis allows prompt antifungal therapy; however this is often delayed or unavailable leading to death, serious chronic illness or blindness. Recent global estimates have found 3,000,000 cases of chronic pulmonary aspergillosis, ~223,100 cases of cryptococcal meningitis complicating HIV/AIDS, ~700,000 cases of invasive candidiasis, ~500,000 cases of Pneumocystis jirovecii pneumonia, ~250,000 cases of invasive aspergillosis, ~100,000 cases of disseminated histoplasmosis, over 10,000,000 cases of fungal asthma and ~1,000,000 cases of fungal keratitis occur annually. Since 2013, the Leading International Fungal Education (LIFE) portal has facilitated the estimation of the burden of serious fungal infections country by country for over 5.7 billion people (>80% of the world’s population). These studies have shown differences in the global burden between countries, within regions of the same country and between at risk populations. Here we interrogate the accuracy of these fungal infection burden estimates in the 43 published papers within the LIFE initiative.

Objectives Coronavirus disease 2019 (COVID-19) associated pulmonary aspergillosis (CAPA) has emerged as a complication in critically ill COVID-19 patients. The objectives of this multinational study were to determine the prevalence of CAPA in patients with COVID-19 in intensive care units (ICU) and to investigate risk factors for CAPA as well as outcome. Methods The European Confederation of Medical Mycology (ECMM) conducted a multinational study including 20 centers from nine different countries to assess epidemiology, risk factors, and outcome of CAPA. CAPA was defined according to the 2020 ECMM/ISHAM consensus definitions. Results A total of 592 patients were included in this study, including 11 (1.9%) patients with histologically proven CAPA, 80 (13.5%) patients with probable CAPA, 18 (3%) with possible CAPA and 483 (81.6%) without CAPA. CAPA was diagnosed a median of 8 days (range 0-31) after ICU admission predominantly in older patients [adjusted hazard ratio (aHR) 1.04 per year; 95%CI 1.02-1.06] with any form of invasive respiratory support (HR 3.4; 95%CI 1.84-6.25) and receiving tocilizumab (HR 2.45; 95%CI 1.41-4.25). Median prevalence of CAPA per center was 10.7% (range 1.7%-26.8%). CAPA was associated with significantly lower 90-day ICU survival rate (29% in patients with CAPA versus 57% in patients without CAPA; Mantel-Byar p<0.001 ) and remained an independent negative prognostic variable after adjusting for other predictors of survival (HR=2.14; 95%CI: 1.59-2.87, p<=0.001 ). Conclusion Prevalence of CAPA varied between centers. CAPA was significantly more prevalent among older patients, patients receiving invasive ventilation and patients receiving tocilizumab, and was an independent strong predictor of ICU mortality.

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity.

Chronic pulmonary aspergillosis (CPA) is a recognized complication of pulmonary tuberculosis (TB). In 2015, the World Health Organization reported 2.2 million new cases of nonbacteriologically confirmed pulmonary TB; some of these patients probably had undiagnosed CPA. In October 2016, the Global Action Fund for Fungal Infections convened an international expert panel to develop a case definition of CPA for resource-constrained settings. This panel defined CPA as illness for >3 months and all of the following: 1) weight loss, persistent cough, and/or hemoptysis; 2) chest images showing progressive cavitary infiltrates and/or a fungal ball and/or pericavitary fibrosis or infiltrates or pleural thickening; and 3) a positive Aspergillus IgG assay result or other evidence of Aspergillus infection. The proposed definition will facilitate advancements in research, practice, and policy in lower- and middle-income countries as well as in resource-constrained settings.

Aspergillus colonization of the lower respiratory airways is common in normal people, and of little clinical significance. However, in some patients, colonization is associated with severe disease including poorly controlled asthma, allergic bronchopulmonary aspergillosis (ABPA) with sputum plugs, worse lung function in chronic obstructive pulmonary aspergillosis (COPD), invasive aspergillosis, and active infection in patients with chronic pulmonary aspergillosis (CPA). Therefore, understanding the pathophysiological mechanisms of fungal colonization in disease is essential to develop strategies to avert or minimise disease. Aspergillus cell components promoting fungal adherence to the host surface, extracellular matrix, or basal lamina are indispensable for pathogen persistence. However, our understanding of individual differences in clearance of A. fumigatus from the lung in susceptible patients is close to zero.

Fluconazole is the most commonly used antifungal agent for both the treatment of cryptococcal meningitis, and for prophylaxis against the disease. However, its prolonged use has the potential to exert selection pressure in favour of fluconazole-resistant strains. We evaluated the prevalence of fluconazole resistance in Cryptococcus spp. clinical isolates in 29 studies from 1988 to May 2017 included in EMBASE and MEDLINE databases. A total of 4995 Cryptococcus isolates from 3210 patients constituted this study; 248 (5.0%) of the isolates from relapsed episodes of cryptococcosis were included in this analysis. Eleven (38%) of the studies used minimum inhibitory concentrations (MICs) breakpoints of ≥64 μg/mL to define fluconazole resistance, 6 (21%) used ≥32 μg/mL, 11 (38%) used ≥16 μg/mL and 1 (3%) used ≤20 μg/mL. Overall, mean prevalence of fluconazole resistance was 12.1% (95% confidence interval [CI]: 6.7-17.6) for all isolates (n = 4995). Mean fluconazole resistance was 10.6% (95% CI: 5.5-15.6) for the incident isolates (n = 4747) and 24.1% (95% CI: -3.1-51.2) for the relapse isolates (n = 248). Of the 4995 isolates, 936 (18.7%) had MICs above the ecological cut-off value. Fluconazole resistance appears to be an issue in Cryptococcus isolates from patients with relapses. It remains unclear whether relapses occur due to resistance or other factors. There is an urgent need to establish antifungal breakpoints for Cryptococcus spp.

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MRT-PCR appears to be a useful test for confirming a diagnosis of IC in critically ill patients, especially in those with deep-seated disease. Its high sensitivity and positive predictive value make it a much more efficient tool for the management of IC than other diagnostic procedures and clinical scores.