COVID-19-associated fungal infections

Abstract

Coronavirus disease 2019 (COVID-19)-associated invasive fungal infections are an important complication in a substantial number of critically ill, hospitalized patients with COVID-19. Three groups of fungal pathogens cause co-infections in COVID-19: Aspergillus, Mucorales and Candida species, including Candida auris. Here we review the incidence of COVID-19-associated invasive fungal infections caused by these fungi in low-, middle- and high-income countries. By evaluating the epidemiology, clinical risk factors, predisposing features of the host environment and immunological mechanisms that underlie the pathogenesis of these co-infections, we set the scene for future research and development of clinical guidance.

Fig. 1. Timeline of key events of COVID-19, CAPA, CAM and CAC.

*Not specified if in patients with COVID-19/unclear reported numbers. IMV, invasive mechanical ventilation.

Fig. 2. Distribution of CAPA, CAM and CAC.

The CAPA (a), CAM (b) and CAC (c) distributions, including C. auris infections for countries that reported respective cases. References can be found in Supplementary Table 1. a,b, The dots represent cities where cases occurred (yellow, single case; blue, at least two cases at one site; red, multicentre studies/multiple sites per city/national reports). The colour of countries and the size of the dots are proportional to the number of cases per million population of the respective country. c, The dots represent cities where cases occurred (red, C. auris; yellow, C. auris and Candida non-auris cases; blue, Candida non-auris cases). The colour of countries and size of the dots are proportional to the number of cases per million population of the respective country (cut-off at 10 million population: El Salvador, Lebanon, Panama, Qatar and United Arab Emirates).

Fig. 3. Risk factors for CAPA, CAM and CAC.

References can be found in Supplementary Table 2.

Fig. 4. Immunological pathways and factors involved in CAPA and CAM.

SARS-CoV-2 infects alveolar epithelial cells by binding to the ACE2 receptor with the help of TMPRSS2. The virus represses type I IFN responses by blocking the transcription of IFN-stimulated genes and pre-existing genetic variants; type I IFN autoantibodies add further to this effect, preventing signalling through the IFNAR1/2 receptor complex. Delayed type I IFN responses favour the release of proinflammatory cytokines and chemokines, leading to the recruitment of monocyte-derived macrophages and neutrophils into the lungs that further contribute to cytokine and chemokine production. This general dysregulation of the immune response underlies a hyperinflammatory state that results in a ‘cytokine storm’ and ARDS that ultimately favours the development of fungal co-infections. During COVID-19, virus-induced cell lysis favours the invasion of the tissue by fungi; the release of DAMPs from damaged or dying cells further potentiates the hyperinflammatory phenotype. Conditions such as hyperglycaemia, steroid overuse and high levels of iron and ketone bodies upregulate the expression of GRP78, which, besides acting as a cofactor in viral entry, binds to spore-coating CotH3 invasin on the fungal surface and favours invasion of nasal epithelial cells by Mucorales. Similarly, the interaction of CotH7 with integrin α3β1 in alveolar epithelial cells contributes to the progression of pulmonary mucormycosis. The production of mucoricin by Mucorales hyphae promotes vascular damage that allows the enhanced recruitment of leucocytes from the bloodstream into the tissue, thereby favouring the hyperinflammatory state.