Diagnosis of Invasive Fungal Disease in Coronavirus Disease 2019

Approaches and Pitfalls

P. Lewis White


Curr Opin Infect Dis. 2021;34(6):573-580. 

In This Article

Abstract and Introduction


Purpose of Review: This review will comment on the current knowledge for the diagnosis of the main causes of COVID-19-associated invasive fungal disease (IFD); it will discuss the optimal strategies and limitations and wherever available, will describe international recommendations.

Recent Findings: A range of secondary IFDs complicating COVID-19 infection have been described and while COVID-19-associated pulmonary aspergillosis was predicted, the presentation of significant numbers of COVID-19-associated candidosis and COVID-19-associated mucormycosis was somewhat unexpected. Given the range of IFDs and prolonged duration of risk, diagnostic strategies need to involve multiple tests for detecting and differentiating various causes of IFD. Although performance data for a range of tests to diagnose COVID-19-associated pulmonary aspergillosis is emerging, the performance of tests to diagnose other IFD is unknown or based on pre-COVID performance data.

Summary: Because of the vast numbers of COVID-19 infections, IFD in COVID-19 critical-care patients represents a significant burden of disease, even if incidences are less than 5%. Optimal diagnosis of COVID-19-associated IFD requires a strategic approach. The pandemic has highlighted the potential impact of IFD outside of the typical high-risk clinical cohorts, given the ever-increasing population at risk of IFD and enhanced surveillance of fungal infections is required.


The onset of the coronavirus disease 2019 (COVID-19) pandemic raised considerable concern regarding secondary invasive fungal disease (IFD) in the critical-care patient.[1] Given the clinical interventions utilized in the critical-care setting, the risk of invasive candidal disease is significant in patients receiving antibacterials, haemodialysis or parenteral nutrition or with central venous catheters, mechanical ventilation, renal insufficiency or diabetes mellitus, all of which are common in the COVID-19 critical-care patient.[2] The considerable, unavoidable pressures on critical-care during peaks of the pandemic can limit the ability to implement sufficient infection control measures and outbreaks of Candida auris have been documented.[3] Although there is evidence confirming the increased incidence of invasive candidosis during the COVID-19 pandemic, it is not clear whether this is directly associated with COVID-19 disease pathogenicity or the difficulty in maintaining infection control processes.[4,5]

With the recent enhanced awareness of influenza-associated pulmonary aspergillosis, there was significant anxiety that a similar manifestation would arise in the critical-care COVID-19 patient.[1,6,7] Despite differences in the pathogenicity of COVID-19 and influenza, COVID-19-associated pulmonary aspergillosis (CAPA) has been diagnosed in significant numbers, although incidences vary considerably, dependent on various factors but it remains a significant secondary complication in the critical-care COVID-19 patient associated with increased mortality.[8–10] Lymphopenia is a common manifestation of COVID-19 infection, potentially associated with poor prognosis, which itself is a documented risk factor for IFD.[11,12] Although infections, such as CAPA have been regularly diagnosed, other IFD associated with lymphopenia, such as Pneumocystis jirovecii pneumonia (PcP), have only been diagnosed in low numbers and generally in patients with other underlying conditions that increase the risk of PcP (e.g. HIV).[13] The use of trimethoprim/sulfamethoxazole to empirically treat ventilator-associated pneumonia may be inadvertently lowering the incidence of PcP.

A less expected, but equally concerning complication of COVID-19 infection are the significant rates of COVID-19-associated mucormycosis (CAM), particularly in patients with poorly or uncontrolled diabetes mellitus, in geographical regions with higher background incidences of mucormycosis (e.g. India).[14] With severe COVID-19 infection, frequently associated with obese patients with type 2 diabetes mellitus (T2DM), the considerable rates of T2DM in certain countries, the capacity of COVID-19 to cause, or worsen hyperglycaemia and given the use of corticosteroids to manage COVID-19, there is a considerable population at risk of CAM, which can also occur postrecovery from COVID-19 infection.[14] Other forms of IFD have been documented (e.g. Rhodotorula fungaemia, Fusarium and Trichosporon infections) but remain rare, likely a result of the low pre-COVID-19 incidence combined with limited diagnostics.[10,15,16]

This review will comment on the current knowledge for the diagnosis of the main causes of COVID-19-associated IFD (Figure 1), it will discuss the optimal strategies and limitations and wherever available will describe international recommendations for diagnosing/defining IFD. Currently, rates of COVID-19-associated IFD vary considerably between centres, likely influenced by the diagnostic strategy employed by individual centres.[8] Although some reports consider the rates of secondary IFD to be low, it is important to remember the number of patients infected by COVID-19 requiring critical-care management, subsequently at enhanced risk of IFD and when these are compared with estimates for IFD outside the setting of the pandemic it highlights the significant impact of COVID-19 (Table 1).[19] Given the established treatments for the management of COVID-19 (e.g. Dexamethasone and/or Tocilizumab) result in suppression of the patient's innate immune response, the risk of secondary opportunistic infection, including IFD will likely be increased and subsequent accurate diagnosis is critical to patient management.

Figure 1.

The range of mycology options for diagnosing various invasive fungal disease (with the exception of endemic fungi) in the coronavirus disease 2019 patient according to sample type.