Invasive Fungal Infections Complicating COVID-19: A Narrative Review

Abstract

Invasive fungal infections (IFIs) can complicate the clinical course of COVID-19 and are associated with a significant increase in mortality, especially in critically ill patients admitted to an intensive care unit (ICU). This narrative review concerns 4099 cases of IFIs in 58,784 COVID-19 patients involved in 168 studies. COVID-19-associated invasive pulmonary aspergillosis (CAPA) is a diagnostic challenge because its non-specific clinical/imaging features and the fact that the proposed clinically diagnostic algorithms do not really apply to COVID-19 patients. Forty-seven observational studies and 41 case reports have described a total of 478 CAPA cases that were mainly diagnosed on the basis of cultured respiratory specimens and/or biomarkers/molecular biology, usually without histopathological confirmation. Candidemia is a widely described secondary infection in critically ill patients undergoing prolonged hospitalisation, and the case reports and observational studies of 401 cases indicate high crude mortality rates of 56.1% and 74.8%, respectively. COVID-19 patients are often characterised by the presence of known risk factors for candidemia such as in-dwelling vascular catheters, mechanical ventilation, and broad-spectrum antibiotics. We also describe 3185 cases of mucormycosis (including 1549 cases of rhino-orbital mucormycosis (48.6%)), for which the main risk factor is a history of poorly controlled diabetes mellitus (>76%). Its diagnosis involves a histopathological examination of tissue biopsies, and its treatment requires anti-fungal therapy combined with aggressive surgical resection/debridement, but crude mortality rates are again high: 50.8% in case reports and 16% in observational studies. The presence of other secondary IFIs usually diagnosed in severely immunocompromised patients show that SARS-CoV-2 is capable of stunning the host immune system: 20 cases of Pneumocystis jirovecii pneumonia, 5 cases of cryptococcosis, 4 cases of histoplasmosis, 1 case of coccidioides infection, 1 case of pulmonary infection due to Fusarium spp., and 1 case of pulmonary infection due to Scedosporium.

Changing Trends of Candida Species and Antifungal Susceptibility Profile of Candida Bloodstream Isolates: A 5-Year Retrospective Survey

“…However, the increase in the frequency of C. parapsilosis in NAC species continued. It has been shown that the use of broad-spectrum antibiotics, the presence or prolonged use of central venous catheters, and immunosuppressive treatments increase fungal infections in the COVID-19 period (35,36).…”

Fungal Colonization and Infections—Interactions with Other Human Diseases

“…While COVID vaccination has tremendously improved the morbidity and mortality of the disease, secondary fungal infections were common and had worsened the morbidity during the full-blown pandemic until 2021 [114,118]. SARS-CoV-2 triggers host immune dysregulation, which has been postulated to contribute to fungal co-infections increasing the morbidity and mortality associated with COVID-19 [119].…”

SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale

“…In health, the first point of contact of inhaled conidia will be the airway epithelium, which is a ciliated stratified epithelium capable of eliminating conidia through secreted mucus by goblet cells; the coordinated beating of cilia and the mucociliary escalator lead to either their swallowing or expectoration [ 10 , 19 , 45 ]. Importantly however, A. fumigatus can circumvent these mechanisms through toxin production and in the setting of concurrent disease, can enter the lower airways.…”

“…The European Organization for the Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSGERC) algorithm, only validated in haematological patients, requires the presence of host risk factors that can be absent in SARS-CoV-2 patients and does not recognise aspergillus colonisation [ 19 ].…”

“…A key difficulty, however, as highlighted is distinguishing between Aspergillus colonisation and invasive infection given the ubiquity of these fungi in clinical samples such as throat swab, tracheal aspirate, etc. Current diagnostic algorithms for Invasive Fungal Infection (IFI) including CAPA struggle in this regard although a newer diagnostic guideline (AspICU) algorithm categorises colonisation separately but at the expense of fungal biomarkers [ 19 ]. Therefore, CAPA requires strong clinical suspicion and the integration of clinical, radiological and biomarker correlates to correctly make the diagnosis, all of which individually can be difficult to intepret and may be confounded by comorbidities and implemented therapies.…”