Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis
Authors: Nitipong Permpalung, Johan Maertens, Kieren A Marr
Journal: The Lancet Infectious Diseases (2021)

We thank the community for rapid recognition and characterisation of COVID-19-associated pulmonary aspergillosis (CAPA), increasingly observed in people with severe SARS-CoV-2 infection. Consistent with previous efforts to standardise definitions for invasive fungal infections,1De Pauw B Walsh TJ Donnelly JP et al.Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.Clin Infect Dis. 2008; 46: 1813-1821Crossref PubMed Scopus (4258) Google Scholar, 2Donnelly JP Chen SC Kauffman CA et al.Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.Clin Infect Dis. 2019; 71: 1367-1376Crossref Scopus (1374) Google Scholar, 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 Philipp Koehler and colleagues4Koehler 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. 2020; (published online Dec 14.)https://doi.org/10.1016/S1473-3099(20)30847-1Summary Full Text Full Text PDF PubMed Scopus (533) Google Scholar propose new definitions for CAPA and provide management recommendations. We have questions and concerns for feedback. Although we agree that standardised definitions are necessary to facilitate enrolment into clinical trials, consensus definitions for invasive fungal infections were historically supported by observational studies and not intended to guide clinical care.1De Pauw B Walsh TJ Donnelly JP et al.Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.Clin Infect Dis. 2008; 46: 1813-1821Crossref PubMed Scopus (4258) Google Scholar, 2Donnelly JP Chen SC Kauffman CA et al.Revision and update of the consensus definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium.Clin Infect Dis. 2019; 71: 1367-1376Crossref Scopus (1374) Google Scholar As a newly recognised syndrome, we worry that the proposed definitions for CAPA are not adequately supported by evidence; premature confidence in definitions risks biasing outcomes of future research and directing inappropriate management, without first establishing a requisite level of evidence. The proposed CAPA definitions are highly reliant on bronchoscopy, which is variably used, especially in surge conditions with strained infection control. A bronchoscopy-driven approach will inevitably underestimate the burden of CAPA and potentially skew trial enrolment towards people with more invasive disease. Also, we have concerns with the biomarker cutoffs proposed. Whereas investigators have done detailed studies to determine cutoffs for galactomannan enzyme immunoassays using appropriate measures (ie, receiver operating characteristic curves) in other populations,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, 5Maertens J Theunissen K Verbeken E et al.Prospective clinical evaluation of lower cut-offs for galactomannan detection in adult neutropenic cancer patients and haematological stem cell transplant recipients.Br J Haematol. 2004; 126: 852-860Crossref PubMed Scopus (161) Google Scholar we are not aware of similar data to support recommendations for positivity at the multiple levels proposed by Koehler and colleagues, combined with requirements for repeated testing. This expert proposal is particularly problematic when cutoffs are not aligned with local regulatory recommendations. Should clinicians and investigators ignore their regulatory-cleared biomarker cutoffs in the absence of supportive evidence? Moreover, Koehler and colleagues proposed various cutoffs for non-bronchoalveolar lavage biomarkers, which have not been cleared or validated. Although this proposal is reasonable to generate data in early research settings, one can hardly say that we have enough evidence to derive consensus. Multiple issues arise with using definitions in different clinical and research contexts. For instance, conservative definitions are not actionable for clinical care or prevention studies—settings where the earliest therapy is essential to improve clinical outcomes. We thank our colleagues for early efforts to understand and define this new entity, but fear that more caution is needed to acknowledge critical gaps in data. We believe that establishing consensus definitions for CAPA requires more efforts, especially those directed towards deriving biomarker performance characteristics. NP reports grants from Health System Research Institute and Cystic Fibrosis Foundation, and personal fees from Shionogi, outside the submitted work. JM reports personal fees and non-financial support from MSD, Pfizer, Gilead, Cidara, F2G, Scynexis, and Bio-Rad, and grants from Pfizer and Gilead, outside the submitted work. KAM reports personal fees from Cidara, Sfunga, and MSD, outside the submitted work, and patents on fungal diagnostics with royalties paid by MycoMed Technologies. Diagnostic dilemma in COVID-19-associated pulmonary aspergillosisWe read with interest the ECMM/ISHAM consensus criteria for COVID-19-associated pulmonary aspergillosis (CAPA), but noted with concern its limited applicability to resource-limited settings.1 Multiple studies indicate that approximately 20% of severely ill patients with COVID-19 develop invasive aspergillosis if a diagnosis is actively sought.2 Pakistan was among the first countries to report CAPA in critically ill patients with COVID-19 using AspICU criteria.3 After an initial report of five putative CAPA cases from March to April, 2020, at our institute, within 2 months 12 more putative CAPA cases were identified. Full-Text PDF Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidanceSevere acute respiratory syndrome coronavirus 2 causes direct damage to the airway epithelium, enabling aspergillus invasion. Reports of COVID-19-associated pulmonary aspergillosis have raised concerns about it worsening the disease course of COVID-19 and increasing mortality. Additionally, the first cases of COVID-19-associated pulmonary aspergillosis caused by azole-resistant aspergillus have been reported. This article constitutes a consensus statement on defining and managing COVID-19-associated pulmonary aspergillosis, prepared by experts and endorsed by medical mycology societies. Full-Text PDF Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis – Authors' replyWe thank Nitipong Permpalung and colleagues and Kauser Jabeen and colleagues for their thoughtful remarks on the 2020 ECMM/ISHAM consensus criteria on COVID-19-associated pulmonary aspergillosis (CAPA).1 We acknowledge that the proposed definitions have shortcomings due to the recent and rapid emergence of CAPA limiting validation studies in this patient population. However, up to publication of these consensus definitions, CAPA cohort studies had used numerous case definitions, including EORTC/MSGERC (for immunocompromised patients), AspICU, modified AspICU, modified Influenza-Associated Pulmonary Aspergillosis (IAPA), and modified IAPA expert case definition, illustrating the urgent need for standardisation2 and recognition of secondary fungal infections as an issue in future WHO COVID-19 clinical research recommendations. Full-Text PDF