Fungal infections should be part of the core outcome set for COVID-19
Authors: Paul E Verweij, Alexandre Alanio
Journal: The Lancet Infectious Diseases (2020)

In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium published a minimum set of common outcome measures for studies of COVID-19.1WHO Working Group on the Clinical Characterisation and Management of COVID-19 infectionA minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis. 2020; 20: e192-e197Summary Full Text Full Text PDF PubMed Scopus (1038) Google Scholar A core outcome set is crucial in the setting of an evolving research response to the COVID-19 pandemic and will greatly facilitate pooling of data across cohort studies and clinical trials.1WHO Working Group on the Clinical Characterisation and Management of COVID-19 infectionA minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis. 2020; 20: e192-e197Summary Full Text Full Text PDF PubMed Scopus (1038) Google Scholar The proposed minimal outcome set involves a broad range of parameters, including organ dysfunction, biochemical parameters, radiological findings, secondary infections, duration of intervention, quality of life, pregnancy outcomes, and resource use.1WHO Working Group on the Clinical Characterisation and Management of COVID-19 infectionA minimal common outcome measure set for COVID-19 clinical research.Lancet Infect Dis. 2020; 20: e192-e197Summary Full Text Full Text PDF PubMed Scopus (1038) Google Scholar It is surprising that only bacterial and viral secondary infections are considered in the proposed set, without mention of fungal coinfections. There are indications that the frequency of bacterial coinfections in patients with COVID-19 might be low, whereas up to 30% of patients admitted to the intensive care unit (ICU) were reported to develop invasive pulmonary aspergillosis.2Alanio 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 (320) Google Scholar Secondary infections with Aspergillus spp have emerged in association with influenza infection. Severe influenza was found to be an independent risk factor for invasive pulmonary aspergillosis.3Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study.Lancet Respir Med. 2018; 6: 782-792Summary Full Text Full Text PDF PubMed Scopus (611) Google Scholar All-cause mortality of patients in the ICU with influenza-associated pulmonary aspergillosis was notably higher than in patients in the ICU with influenza only (51% vs 28%, p<0·001),3Schauwvlieghe AFAD Rijnders BJA Philips N et al.Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study.Lancet Respir Med. 2018; 6: 782-792Summary Full Text Full Text PDF PubMed Scopus (611) Google Scholar and some manifestations of influenza-associated pulmonary aspergillosis, such as invasive aspergillus tracheobronchitis, have been reported to have a mortality rate as high as 90%.4Nyga R Maizel J Nseir S et al.Invasive tracheobronchial aspergillosis in critically ill patients with severe influenza.Am J Respir Crit Care Med. 2020; (published online May 14.)https://doi.org/10.1164/rccm.201.910.1931OCCrossref PubMed Scopus (39) Google Scholar The first data collected indicate that aspergillus disease manifestations are more heterogeneous in patients with COVID-19 than in those with influenza,5Verweij PE Rijnders BJA Brüggemann RJM et al.Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion.Intensive Care Med. 2020; (published online June 22.)https://doi.org/10.1007/s00134.020.06091-6Crossref PubMed Scopus (267) Google Scholar which might be due to differences in the pathophysiology of the viral infection. Notably, serum galactomannan was frequently negative in patients with COVID-19-associated pulmonary aspergillosis (CAPA), whereas respiratory samples were aspergillus positive. Distinguishing between airway colonisation and invasive disease might prove difficult. Indeed, whereas patients with presumed CAPA can survive without antifungal therapy, cases of proven CAPA have been reported that were serum galactomannan negative.6Rutsaert L Steinfort N Van Hunsel T et al.COVID-19-associated invasive pulmonary aspergillosis.Ann Intensive Care. 2020; 10: 71Crossref PubMed Scopus (177) Google Scholar Given these diagnostic challenges and the lack of a CAPA case definition, clinical studies are urgently needed to gain more insight into the pathophysiology of CAPA, to identify host and risk factors, and to design diagnostic and treatment strategies. To benefit from data collected through international clinical research studies of COVID-19, we believe that fungal infections should be part of the proposed core outcome set. PEV reports grants from Mundipharma, F2G, Pfizer, Thermo Fisher Scientific, Gilead Sciences, and Cidara, and non-financial support from IMMY, outside this work. AA reports personal fees from Gilead Sciences and non-financial support from Astellas, outside this work. Fungal infections should be part of the core outcome set for COVID-19 – Authors' replyWe thank Paul E Verweij and Alexandre Alanio for their interest in our minimal common outcomes set for studies of COVID-19,1 which we developed in collaboration with a broad group of clinical researchers. We agree with Verweij and Alanio that fungi are important nosocomial pathogens that merit evaluation in addition to bacterial and viral infections as potential complications of some interventions against COVID-19. However, the evidence that fungal coinfections are more common in patients with COVID-19 than bacterial or viral coinfections is limited. Full-Text PDF A minimal common outcome measure set for COVID-19 clinical researchClinical research is necessary for an effective response to an emerging infectious disease outbreak. However, research efforts are often hastily organised and done using various research tools, with the result that pooling data across studies is challenging. In response to the needs of the rapidly evolving COVID-19 outbreak, the Clinical Characterisation and Management Working Group of the WHO Research and Development Blueprint programme, the International Forum for Acute Care Trialists, and the International Severe Acute Respiratory and Emerging Infections Consortium have developed a minimum set of common outcome measures for studies of COVID-19. Full-Text PDF