Antifungal Prophylaxis for Prevention of COVID-19-Associated Pulmonary Aspergillosis in Critically Ill Patients

An Observational Study

Stefan Hatzl; Alexander C. Reisinger; Florian Posch; Juergen Prattes; Martin Stradner; Stefan Pilz; Philipp Eller; Michael Schoerghuber; Wolfgang Toller; Gregor Gorkiewicz; Philipp Metnitz; Martin Rief; Florian Prüller; Alexander R. Rosenkranz; Thomas Valentin; Robert Krause; Martin Hoenigl; Gernot Schilcher


Crit Care. 2021;25(335) 

In This Article

Abstract and Introduction


Background: Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far.

Methods: In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria.

Results: We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2–9.7) in the MAFP group and 17.5% (95% CI 9.6–31.4) in the group without MAFP (p = 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01–0.63; p = 0.017).

Conclusion: In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease 2019 (COVID-19)-associated acute respiratory failure contributes to a highly permissive inflammatory environment. This in turn favours fungal pathogenesis due to the release of danger-associated molecular patterns and collateral effects of host recognition pathways required for the activation of antiviral immunity.[1] In this context, COVID-19-associated pulmonary aspergillosis (CAPA) has been emerging as an important fungal complication of COVID-19,[1] affecting an average of 3.1% (range 0.7–7.7%)[2–5] of patients hospitalized with COVID-19, 8.9% (range 2.5–39%) of patients admitted to the intensive care unit (ICU),[3,6–11] and an average of 20.1% (range 3.2–38%) of those requiring invasive ventilation.[6,7,12–14]

Diagnosis of CAPA is challenging in patients with COVID-19-associated ARDS, as clinical picture and radiological findings of CAPA resemble those of severe COVID-19,[15,16] and blood tests lack sensitivity due to the primarily airway invasive growth of Aspergillus in non-neutropenic patients.[15–17] Testing of bronchoalveolar lavage (BAL) with fungal culture, galactomannan (GM), Aspergillus polymerase chain reaction (PCR), or the Aspergillus GM lateral flow assay (LFA) is therefore preferred,[18,19] but due to the presumed risk of COVID-19 transmission through bronchoscopies, sampling of the primary infection site is still not performed consistently across ICUs.

The high prevalence rates of CAPA in critically ill patients requiring invasive ventilation together with the difficulties in diagnosis and the devastating overall mortality rates of over 50%[2–4,6,9–12,14,15,20,21] could justify clinical trials evaluating antifungal prophylaxis in COVID-19 patients with acute respiratory failure. One retrospective single-centre case series from Belgium has reported the successful use of prophylaxis in terms of CAPA case reduction with inhaled liposomal Amphotericin B in a cohort of ICU patients with severe COVID-19;[6] however, studies evaluating systemic antifungal prophylaxis are lacking.

The objective of this observational single-centre study was to evaluate the effectiveness of mould-active antifungal prophylaxis in preventing CAPA in critical care patients with COVID-19-associated acute respiratory failure. Secondary objectives included the evaluation of a potential survival benefit associated with antifungal prophylaxis as well as the impact of CAPA on overall survival.