Mucormycosis in 2023: an update on pathogenesis and management

Abstract

Mucormycosis (MCR) is an emerging and frequently lethal fungal infection caused by the Mucorales family, with Rhizopus, Mucor, and Lichtheimia, accounting for > 90% of all cases. MCR is seen in patients with severe immunosuppression such as those with hematologic malignancy or transplantation, Diabetes Mellitus (DM) and diabetic ketoacidosis (DKA) and immunocompetent patients with severe wounds. The recent SARS COV2 epidemy in India has resulted in a tremendous increase in MCR cases, typically seen in the setting of uncontrolled DM and corticosteroid use. In addition to the diversity of affected hosts, MCR has pleiotropic clinical presentations, with rhino-orbital/rhino-cerebral, sino-pulmonary and necrotizing cutaneous forms being the predominant manifestations. Major insights in MCR pathogenesis have brought into focus the host receptors (GRP78) and signaling pathways (EGFR activation cascade) as well as the adhesins used by Mucorales for invasion. Furthermore, studies have expanded on the importance of iron availability and the complex regulation of iron homeostasis, as well as the pivotal role of mycotoxins as key factors for tissue invasion. The molecular toolbox to study Mucorales pathogenesis remains underdeveloped, but promise is brought by RNAi and CRISPR/Cas9 approaches. Important recent advancements have been made in early, culture-independent molecular diagnosis of MCR. However, development of new potent antifungals against Mucorales remains an unmet need. Therapy of MCR is multidisciplinary and requires a high index of suspicion for initiation of early Mucorales-active antifungals. Reversal of underlying immunosuppression, if feasible, rapid DKA correction and in selected patients, surgical debulking are crucial for improved outcomes.

Keywords: COVID-19-associated mucormycosis; DKA; Mucorales; immunosuppression; invasive fungal infections; mucormycosis; pathogenicity; rhizopus.

Figure 1

Frequency of mucormycosis manifestation in susceptible hosts and the etiologic agents of the disease. (A) Frequency of mucormycosis by underlaying predisposing host condition. (B) Etiological agents of mucormycosis. (C) Frequency of different types of mucormycosis reported. * Data adapted from Roden M et al. CID 2005 (Roden et al., 2005).

Figure 2

(A) Morphology of Rhizopus delemar. Sporangia form at the apices of sporangiophores and contain the asexual sporangiospores. Germinated spores seen in the sporangium magnified box can be an overlay of the sporangium on released and germinated spores. (B) Under normal circumstance, alveolar macrophages (AMS) are able to phagocytize fungi and killing through LC3-associated phagocytosis (LAP+). While AMS are able to phagocytize Mucorales spores, spore melanin is able to arrest LAP to prevent phagosome maturation. However, spores are unable to grow and germinate due to iron restriction (Frąc et al., 2018). In the presence of abnormal nutritional immunity (i.e. excessive iron) spores are able to germinate and kill Ams (Andrianaki et al., 2018). Courtesy of Dr. Georgios Chamilos. “Created with BioRender.com”.

Figure 3

Postulated events that lead to adhesion and invasion and host cell death. 1) Inhaled spores bind to epithelial via CotH/integrin a3β1 followed by germination. Germlings produce mucoricin. 2) Considerable disruption of the epithelium due to invasion of the spores within hours of infection. 3) Mucoricin causes host cell death within 48 h of infection. 4) Angioinvasion of hyphae and sporulated cells occur via CotH and endothelial cell GRP78 interactions, 5) endothelial cell injury occurs after infection with R. delemar spores resulting in tissue necrosis. 6) Hematogenous dissemination results in organ seeding. Tissue edema and organ failure are the results of excessive vascular leak. “Created with BioRender.com”.

Figure 4

An Algorithm for Mucormycosis Treatment.