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SAMJ: South African Medical Journal

On-line version ISSN 2078-5135
Print version ISSN 0256-9574

SAMJ, S. Afr. med. j. vol.110 n.11 Pretoria Nov. 2020 



Opportunistic pathogenic fungal co-infections are prevalent in critically ill COVID-19 patients: Are they risk factors for disease severity?



O T Ezeokoli; C H Pohl

PhD; Pathogenic Yeast Research Group, Department of Microbial, Biochemical and Food Biotechnology, Faculty of Natural and Agricultural Sciences, University of the Free State, Bloemfontein, South Africa





Fungal co-infections, especially with Aspergillus and Candida species, are prevalent in hospitalised COVID-19 patients, and could influence patient outcomes and hamper treatment efforts. However, information about and elucidation of the causal relationship between fungal co-infections and COVID-19 disease outcomes or severity in patients are still lacking. Such information, if and when available, will help facilitate appropriate case management.



The novel severe-acute respiratory coronavirus 2 (SARS-CoV-2) is the cause of COVID-19, a condition that was declared a global pandemic by the World Health Organization on 30 January 2020. As of 20 August, a total of 213 countries and territories were affected by the pandemic, with >22 256 219 confirmed cases globally.[1] The prognosis of the disease in patients with underlying conditions is dire, with comorbidities reported in a large number of hospitalised and severe cases.[2] Based on initial reports, older individuals and individuals with pre-existing conditions such as diabetes, heart disease, chronic obstructive pulmonary disease and cancer are more predisposed than others to severe COVID-19.[2,3] While the mechanistic links between the aforementioned pre-existing conditions and COVID-19 severity are being unravelled, reasons for severe COVID-19 in individuals without a known history of comorbidities (otherwise healthy individuals) are somewhat puzzling and may be compounded by genetics, such as the ABO blood group, and androgens, which may predispose a person to adverse COVID-19 outcomes.[4-6] While there is much we have yet to learn about the disease, it is therefore clear that an immunocompromising condition places the patient at a disadvantage against SARS-CoV-2.

The high incidence of severe infection and mortality in COVID-19 is thought to be due in part to a lack of natural immunity and to viral replication in the lower respiratory tract, as well as superinfections, secondary infections or co-infections (these terms are often used interchangeably), leading to severe lung injury and acute respiratory distress syndrome (ARDS).[7] Co-infections with respiratory viruses (other than SARS-CoV-2), bacteria and fungi have been reported in COVID-19 patients in Wuhan, China,[8-10] and secondary infections were identified as one of the predictors of a fatal outcome in COVID-19 cases.[11] An earlier report from China suggests that the mortality rate for COVID-19 patients on ventilators in intensive care units (ICUs) is ~60%, and indicated that invasive fungal co-infections may contribute to this high mortality.[2]

Invasive fungal infections, including aspergillosis and candi-diasis,[12-14] are prevalent in hospitalised patients, and it is commonly established that acute respiratory disease, including invasive pulmonary aspergillosis (IPA), is frequent in ICUs and among immunocompromised populations.[15-18] In addition, in some patients without a well-defined underlying immunocompromising disease, there is a high risk of secondary complications with IPA in ARDS due to viral infection.[19-22] However, few such co-infections are being reported in the current COVID-19 pandemic, especially in South Africa (SA).


Fungal co-infections are prevalent in critically ill COVID-19 patients: Are they risk factors for severe outcomes?

Fungal infections, either pre or post COVID-19 exposure, can complicate diagnosis, treatment and progression of COVID-19.[10,23-25] At this stage, data on pre-existing fungal infections are mostly not reported. This is in part due to the likelihood of undiagnosed fungal infections in healthy individuals pre COVID-19 exposure, a lack of comprehensive descriptions of patients' clinical characteristics, and prioritisation of COVID-19 diagnosis over fungal infection diagnosis.[24,26-28] However, a retrospective study by Gao et al.[29] in China showed that the presence of a coexisting medical condition was the only independent risk factor for the ARDS in influenza A (H7N9) patients during the spring of 2013, with secondary bacterial or fungal infection being the cause of death in 3 out of 30 patients (10%) who died. Shortly before the outbreak of SARS-CoV-2, Gao et al.[29] showed that 25 of 528 patients (4.8%) with viral pneumonia had fungal co-infections. Of these patients, 12 survived while 13 died.[29] In addition, data from previous coronavirus outbreaks (SARS (severe acute respiratory syndrome)-CoV and MERS (Middle East respiratory syndrome)) have indicated that invasive aspergillosis and other systemic fungal infections contributed to severe outcomes for patients in ICUs.[19,30,31]

With regard to secondary infections or co-infection, data from several countries show prevalence of fungal co-infections in COVID-19 patients (Table 1). From these data, it is evident that the majority of these infections are caused by Aspergillus (mostly A. fumigatus) and Candida species. These infections are not COVID-19 exclusive, but are often observed in patients admitted to ICUs.[32] This finding complicates establishment of a causal relationship between fungal co-infection and COVID-19 disease severity, as there may be underlying conditions that predispose a patient to both infections. Interestingly, Zuo et al.[33] reported that the gastrointestinal mycobiomes of hospitalised COVID-19 patients were more heterogeneous, more enriched for C. albicans and contained higher levels of C. auris and A. flavus compared with controls, even after resolution of symptoms. This finding highlights the question whether fungal colonisation contributes to or results from SARS-CoV-2 infection.


An SA perspective

Studies conducted before the current COVID-19 pandemic showed that fungal infections are highly prevalent in the SA population, partly owing to the high incidence of HIV.[34-36] It was observed that the Candida carrier rate is higher in the SA population than elsewhere and that HIV-positive patients carry more and a greater variety of pathogenic yeasts compared with HIV-negative subjects.[35,36] Similarly, cryptococcal meningitis, caused by Cryptococcus neoformans species complex, is one of the leading causes of HIV-related deaths in SA, with >135 900 deaths estimated for sub-Saharan Africa in 2014.[34,35,37] Other fungal infections, including invasive aspergillosis, Pneumocystis pneumonia and endemic mycoses, are also prevalent in SA.[34] Given the high prevalence of HIV/AIDS in SA as well as the high number of persons undergoing immunosuppressive therapies for other illnesses, co-infections with opportunistic fungal species may be affecting the current COVID-19 disease statistics in SA. Unfortunately, information on microbial co-infections in COVID-19 patients is lacking in currently published epidemiological and clinical reports on COVID-19 patients in SA.[38,39] The extent and contribution of such fungal co-infections (either pre-existing or nosocomial) on COVID-19 patient outcomes in SA are therefore unclear. In time, meta-analyses of case reports from COVID-19 patients may help provide such answers. However, this requires that patients' histories, disease characteristics and prognosis must be well documented and accessible for meta-analyses, both globally and in SA. Such information is vital for the full appreciation of factors contributing to the current COVID-19 statistics in SA.

Declaration. None.

Acknowledgements. None.

Author contributions. OTE wrote the initial draft of the manuscript. CHP conceptualised the article, added recently published information and edited the manuscript.

Funding. The work was financially supported by the National Research Foundation (NRF). CHP holds an NRF SARChI Research Chair in Pathogenic Yeasts (grant no. 115566).

Conflicts of interest. None.



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C H Pohl

Accepted 27 September 2020

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