Managing secondary fungal infections in severe COVID-19: how to move forward?
Authors: Paul E Verweij, Frank L van de Veerdonk
Journal: The Lancet Respiratory Medicine (2021)

The recent literature has been confusing regarding the frequency and clinical implications of COVID-19-associated pulmonary aspergillosis (CAPA).1Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.Lancet Infect Dis. 2021; 21: e149-e162Summary Full Text Full Text PDF PubMed Scopus (538) Google Scholar This confusion has been due to the use of variable case definitions, infrequent histopathological confirmation of CAPA,2Kula BE Clancy CJ Hong Nguyen M Schwartz IS Invasive mould disease in fatal COVID-19: a systematic review of autopsies.Lancet Microbe. 2021; 2: e405-e414Summary Full Text Full Text PDF PubMed Scopus (60) Google Scholar and reports of patients with CAPA surviving without receiving antifungal therapy.3Alanio A Dellière S Fodil S Bretagne S Mégarbane B Prevalence of putative invasive pulmonary aspergillosis in critically ill patients with COVID-19.Lancet Respir Med. 2020; 8: e48-e49Summary Full Text Full Text PDF PubMed Scopus (323) Google Scholar Using the 2020 CAPA consensus criteria of the European Confederation of Medical Mycology and International Society for Human and Animal Mycology (ECMM/ISHAM),1Koehler P Bassetti M Chakrabarti A et al.Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance.Lancet Infect Dis. 2021; 21: e149-e162Summary Full Text Full Text PDF PubMed Scopus (538) Google Scholar Jean-Pierre Gangneux and colleagues show that CAPA is a frequent and clinically relevant complication of severe COVID-19.4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar In their study in The Lancet Respiratory Medicine, 76 (15%) of 509 mechanically ventilated patients with COVID-19 fulfilled the ECMM/ISHAM criteria for proven or probable CAPA. In addition, 38 (7%) patients developed other fungal infections including invasive candidiasis (32 patients), mucormycosis (six patients), or fusariosis (one patient), or infection or colonisation with Pneumocystis jirovecii (four patients). Among secondary infections, only fungal co-infection (ie, pulmonary aspergillosis) was significantly associated with mortality, with patients with CAPA showing a significantly higher mortality (61·8% [95% CI 50·0–72·8]) than those without CAPA (32·1% [27·7–36·7]; p<0·0001).4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar Antifungal therapy did not modify mortality and was not associated with improved survival. An important question is how best to manage secondary fungal infections in patients with severe COVID-19 in the intensive care unit (ICU). The 15% CAPA incidence and high mortality might justify antifungal prophylaxis, but no antifungal drugs are currently licensed for prophylaxis in the ICU. A recent study evaluated posaconazole prophylaxis in patients admitted to the ICU with severe influenza, with the aim of preventing cases of influenza-associated pulmonary aspergillosis (IAPA).5Vanderbeke L Janssen NAF Bergmans DCJJ et al.Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.Intensive Care Med. 2021; 47: 674-686Crossref PubMed Scopus (45) Google Scholar The study was unsuccessful because 15 (71%) of 21 IAPA cases were diagnosed at ICU admission, and required immediate antifungal therapy and were excluded. As a consequence, the study was underpowered to show a beneficial effect of posaconazole prophylaxis, although no IAPA cases were observed in patients on posaconazole.5Vanderbeke L Janssen NAF Bergmans DCJJ et al.Posaconazole for prevention of invasive pulmonary aspergillosis in critically ill influenza patients (POSA-FLU): a randomised, open-label, proof-of-concept trial.Intensive Care Med. 2021; 47: 674-686Crossref PubMed Scopus (45) Google Scholar Compared with IAPA, CAPA develops later in the course of ICU admission. Gangneux and colleagues report a median time to CAPA diagnosis of 8·0 days (IQR 4·0–14·0), which is in line with other studies.4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar This delay in onset might provide a period to allow patients with COVID-19 to benefit from antifungal prophylaxis. A small observational study involving 132 patients, of whom 75 (57%) received antifungal prophylaxis, predominantly posaconazole, showed a greater than 90% reduction in 30-day CAPA incidence estimates, from 17·5% (95% CI 9·6–31·4) in the group without prophylaxis to 1·4% (95% CI 0·2–9·7) in those patients receiving antifungal prophylaxis (p=0·002).6Hatzl S Reisinger AC Posch F et al.Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study.Crit Care. 2021; 25: 335Crossref PubMed Scopus (61) Google Scholar However, a survival benefit was not observed, which would require a randomised controlled trial. Posaconazole is regarded as the standard treatment for antimould prophylaxis in patients with haematological malignancy and might also help to prevent secondary fungal infections due to other fungi such as mucormycetes. However, primary prophylaxis depends on the anticipated frequency of secondary fungal infections. Although reported CAPA incidence is 10–17%,4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 6Hatzl S Reisinger AC Posch F et al.Antifungal prophylaxis for prevention of COVID-19-associated pulmonary aspergillosis in critically ill patients: an observational study.Crit Care. 2021; 25: 335Crossref PubMed Scopus (61) Google Scholar, 7Janssen NAF Nyga R Vanderbeke L et al.Multinational observational cohort study of COVID-19-associated pulmonary aspergillosis.Emerg Infect Dis. 2021; 27: 2892-2898Crossref PubMed Scopus (82) Google Scholar most of these studies were performed during the first wave of COVID-19, whereas the current epidemiology is likely to have changed. Factors that might increase invasive fungal infection frequency include the standard use of dexamethasone combined with anti-IL-6 in severe COVID-19, emergence of new (more virulent) SARS-CoV-2 variants,8Veneti L Seppälä E Larsdatter Storm M et al.Increased risk of hospitalization and intensive care admission associated with reported cases of SARS- CoV-2 variants B.1.1.7 and B.1.351 in Norway, December 2020–May 2021.PLoS One. 2021; 16e0258513Crossref PubMed Scopus (27) Google Scholar and a possible shift towards unvaccinated individuals and those who respond less well to vaccination. Conversely, COVID-19 vaccination has been shown to be highly effective in reducing hospitalisation and ICU admission,9Thompson MG Stenehjem E Grannis S et al.Effectiveness of COVID-19 vaccines in ambulatory and inpatient care settings.N Engl J Med. 2021; 385: 1355-1371Crossref PubMed Scopus (291) Google Scholar with increasing vaccine coverages in most countries. The feasibility of a prophylaxis strategy will thus depend on characteristics of the population of patients with severe COVID-19 admitted to the ICU and their probability of developing opportunistic infections. The current recommendation to perform bronchoscopy and bronchoalveolar lavage in patients with COVID-19 who are clinically deteriorating is challenged by the observation of Gangneux and colleagues that any positive Aspergillus culture or PCR from respiratory specimens was associated with increased mortality, regardless of the aspergillosis status.4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar This observation might prompt clinicians to start antifungal therapy as soon as Aspergillus is recovered, which will substantially increase the use of antifungal drugs in patients with COVID-19 in the ICU. Profiling of patients with severe COVID-19 needs to be improved with regard to their risk of developing opportunistic infections. We previously hypothesised that the risk of developing CAPA depends on the accumulation of factors related to the host, including age and risk factors defined by the European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium for invasive fungal diseases, factors related to viral infection, including lytic effects and immune dysregulation, and factors related to treatment interventions, including the administration of dexamethasone and tocilizumab.10van de Veerdonk FL Brüggemann RJM Vos S et al.COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion.Lancet Respir Med. 2021; 9: 795-802Summary Full Text Full Text PDF PubMed Scopus (51) Google Scholar However, the spectrum of secondary infections is broad, also including viral reactivations, such as herpes simplex virus (HSV) and cytomegalovirus (CMV).4Gangneux J-P Dannaoui E Fekkar A et al.Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID study.Lancet Respir Med. 2021; (published online Nov 26.)https://doi.org/10.1016/S2213-2600(21)00442-2Summary Full Text Full Text PDF PubMed Scopus (157) Google Scholar In this respect, CAPA might also be seen as a reflection of a broader immunocompromised status and a sign of the severity of the weakened host status. Integrated risk profiling could involve analysing markers of opportunistic pathogens, including SARS-CoV-2, HSV, and CMV viral loads and biomarkers of opportunistic fungal infections, as well as systemic and local host parameters, including inflammatory cells and cytokines associated with inflammatory pathways, endothelial injury, and alveolar type 1 and 2 injury. Risk profiles could then be correlated with immunosuppressive treatments and outcome. Such an approach might help early identification of patients with severe COVID-19 who might benefit from tailored interventions such as pre-emptive antifungal therapy. PEV reports grants from Mundipharma, F2G, Pfizer, Gilead Sciences, and Cidara Therapeutics, and non-financial support from IMMY, outside of the submitted work. FLvdV declares no competing interests. Fungal infections in mechanically ventilated patients with COVID-19 during the first wave: the French multicentre MYCOVID studyThis study shows the high prevalence of invasive pulmonary aspergillosis and candidaemia and high mortality associated with pr/pb CAPA in mechanically ventilated patients with COVID-19. These findings highlight the need for active surveillance of fungal pathogens in patients with severe COVID-19. Full-Text PDF