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Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis – Authors' reply

2021; Elsevier BV; Volume: 21; Issue: 6 Linguagem: Inglês

10.1016/s1473-3099(21)00123-7

1474-4457

Philipp Koehler, P. Lewis White, Paul E. Verweij, Oliver A. Cornely,

Infectious Diseases and Mycology

We 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).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. 2020; (published online Dec 14.)https://doi.org/10.1016/S1473-3099(20)30847-1Summary Full Text Full Text PDF PubMed Scopus (551) Google Scholar 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 standardisation2Salmanton-García J Sprute R Stemler J et al.COVID-19–associated pulmonary aspergillosis, March–August 2020.Emerg Infect Dis. 2021; (published online Feb 4.)https://doi.org/10.3201/eid2704.204895Crossref PubMed Scopus (181) Google Scholar and recognition of secondary fungal infections as an issue in future WHO COVID-19 clinical research recommendations.3WHO 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 (1064) Google Scholar Despite reservations during the first COVID-19 wave about doing bronchoscopy, this procedure remains the cornerstone of invasive aspergillosis diagnosis as it is a well validated procedure, it enables diagnosis of invasive tracheobronchitis, and bronchoalveolar lavage (BAL) fluid is validated for detection of galactomannan. During the first wave, bronchoscopy was already recommended in patients with COVID-19 to diagnose secondary infection, and the procedure can be done safely using WHO-style checklists, team timeouts, and safety precautions, including adequate personal protective equipment.4Koehler P Cornely OA Kochanek M Bronchoscopy safety precautions for diagnosing COVID-19 associated pulmonary aspergillosis—a simulation study.Mycoses. 2021; 64: 55-59Crossref PubMed Scopus (21) Google Scholar There is increasing evidence that infectious risk associated with bronchoscopy on intubated COVID-19 patients is indeed manageable.5Gao CA Bailey JI Walter JM et al.Bronchoscopy on intubated COVID-19 patients is associated with low infectious risk to operators.Ann Am Thorac Soc. 2021; (published online Jan 15.)https://doi.org/10.1513/annalsats.202009-1225rlCrossref Scopus (35) Google Scholar We agree that data are limited in relation to galactomannan performance and thresholds for the diagnosis of CAPA. However, thresholds identifying the optimal performance of galactomannan-EIA have been described in detailed studies across diverse populations, and consistent optimal thresholds have been determined, irrespective of patient population. Meta-analyses involving various patient populations have confirmed a high specificity (≥90%) when galactomannan-EIA is done with a threshold of ≥1·0, and on the basis of excellent meta-analytical performance (sensitivity 90%, specificity 94%) the 2019 American Thoracic Society guidelines support the use of galactomannan-EIA on BAL fluid in patients with suspected invasive fungal disease.6Haydour Q Hage CA Carmona EM et al.Diagnosis of fungal infections. A systematic review and meta-analysis supporting American Thoracic Society practice guideline.Ann Am Thorac Soc. 2019; 16: 1179-1188Crossref PubMed Scopus (53) Google Scholar Furthermore, the thresholds provided are in line with those for the diagnosis of IAPA. The CAPA consensus definitions accept non-directed bronchial lavage (NBL) galactomannan as a diagnostic criterion as NBL offers an opportunity to obtain material from the lower respiratory tract, with limited aerosolisation risk. Although NBL has not been validated for galactomannan detection, the thresholds we provided were based on existing evidence.7Van Biesen S Kwa D Bosman RJ Juffermans NP Detection of invasive pulmonary aspergillosis in COVID-19 with non-directed bronchoalveolar lavage.Am J Respir Crit Care Med. 2020; 202: 1171-1173Crossref PubMed Scopus (63) Google Scholar, 8White PL Dhillon R Cordey A et al.A national strategy to diagnose COVID-19 associated invasive fungal disease in the ICU.Clin Infect Dis. 2020; (https://dx.doi.org/10.1093%2Fcid%2Fciaa1298 published online Aug 29.)Google Scholar Furthermore, to acknowledge the scarcity of supporting evidence, we classified patients diagnosed through NBL galactomannan as possible CAPA, which highlights the reservation in relation to enrolling patients in clinical trials or registries but permits earlier therapy in the clinic through ease of sampling. The diagnosis of CAPA remains challenging, and the comments by Jabeen and colleagues highlight the diagnostic difficulties encountered in resource-limited settings. The authors propose more flexible diagnostic criteria and advocate the use of endotracheal aspirates to diagnose CAPA. We believe that testing of upper respiratory tract specimens is insufficient to discriminate between aspergillus colonisation and invasive infection, and this specimen was therefore not considered a diagnostic criterion to classify CAPA cases. The positive predictive value of aspergillus culture of endotracheal aspirates was 20% in a study involving 56 CAPA cases and 156 controls (unpublished). Furthermore, our definition of CAPA relies not only on potentially restricted biomarkers, but also on conventional mycology, including microscopy and aspergillus culture, to fulfil microbiological diagnostic criteria, provided that lower respiratory tract specimens are obtained. As highlighted by the conflicting opinions raised by Permpalung and colleagues and Jabeen and colleagues, we believe that the 2020 ECMM/ISHAM consensus definitions provide a solid base to standardise clinical CAPA research and enhance comparability of surveillance studies, in response to an urgent clinical need. As further evidence becomes available, our understanding of performance characteristics of diagnostic tests in various sample types will increase and will help to further refine the case definitions. Given the diagnostic challenges we encounter in CAPA, histopathological validation of diagnostic tests and the CAPA case definition is a crucial next step. PK is supported by the German Federal Ministry of Research and Education, has received non-financial scientific grants from Miltenyi Biotec and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, and has received lecture honoraria from, or is advisor to, Akademie für Infektionsmedizin, Ambu, Astellas Pharma, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, MSD, Noxxon, and University Hospital of Munich, outside the submitted work. PLW did diagnostic evaluations for, and received meeting sponsorship from, Bruker, Dynamiker, and Launch Diagnostics. PLW reports speakers fees, expert advice fees, and meeting sponsorship from Gilead Sciences; speaker and expert advice fees from F2G; and speaker fees from MSD and Pfizer. PLW is a founding member of the European Aspergillus PCR Initiative. PEV reports grants from Mundipharma, F2G, Pfizer, Thermofisher, Gilead Sciences, and Cidara, and non-financial support from IMMY, outside the submitted work. OAC is supported by the German Federal Ministry of Research and Education; is funded by the Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy (CECAD, EXC 2030—390661388; and has received research grants from, is an advisor to, or has received lecture honoraria from Actelion, Allecra Therapeutics, Al-Jazeera Pharmaceuticals, Amplyx, Astellas, Basilea, Biosys, Cidara, Da Volterra, Entasis, F2G, Gilead Sciences, Grupo Biotoscana, IQVIA, Janssen, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini, MSD, Mylan, Nabriva, Noxxon, Octapharma, Paratek, Pfizer, PSI, Roche Diagnostics, Scynexis, and Shionogi. 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 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 Diagnostic dilemma in COVID-19-associated pulmonary aspergillosisWe 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,1–3 Philipp Koehler and colleagues4 propose new definitions for CAPA and provide management recommendations. We have questions and concerns for feedback. Full-Text PDF