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      Prognostic Impact of Bronchoalveolar Lavage Fluid Galactomannan and Aspergillus Culture Results on Survival in COVID-19 Intensive Care Unit Patients: a Post Hoc Analysis from the European Confederation of Medical Mycology (ECMM) COVID-19-Associated Pulmonary Aspergillosis Study

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          ABSTRACT

          Critically ill patients with coronavirus disease 2019 (COVID-19) may develop COVID-19-associated pulmonary aspergillosis (CAPA), which impacts their chances of survival. Whether positive bronchoalveolar lavage fluid (BALF) mycological tests can be used as a survival proxy remains unknown. We conducted a post hoc analysis of a previous multicenter, multinational observational study with the aim of assessing the differential prognostic impact of BALF mycological tests, namely, positive (optical density index of ≥1.0) BALF galactomannan (GM) and positive BALF Aspergillus culture alone or in combination for critically ill patients with COVID-19. Of the 592 critically ill patients with COVID-19 enrolled in the main study, 218 were included in this post hoc analysis, as they had both test results available. CAPA was diagnosed in 56/218 patients (26%). Most cases were probable CAPA (51/56 [91%]) and fewer were proven CAPA (5/56 [9%]). In the final multivariable model adjusted for between-center heterogeneity, an independent association with 90-day mortality was observed for the combination of positive BALF GM and positive BALF Aspergillus culture in comparison with both tests negative (hazard ratio, 2.53; 95% CI confidence interval [CI], 1.28 to 5.02; P = 0.008). The other independent predictors of 90-day mortality were increasing age and active malignant disease. In conclusion, the combination of positive BALF GM and positive BALF Aspergillus culture was associated with increased 90-day mortality in critically ill patients with COVID-19. Additional study is needed to explore the possible prognostic value of other BALF markers.

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          Most cited references16

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          Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance

          Severe 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. COVID-19-associated pulmonary aspergillosis is proposed to be defined as possible, probable, or proven on the basis of sample validity and thus diagnostic certainty. Recommended first-line therapy is either voriconazole or isavuconazole. If azole resistance is a concern, then liposomal amphotericin B is the drug of choice. Our aim is to provide definitions for clinical research and up-to-date recommendations for clinical management of the diagnosis and treatment of COVID-19-associated pulmonary aspergillosis.
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            Epidemiology of invasive pulmonary aspergillosis among COVID-19 intubated patients: a prospective study

            ABSTRACT Background In this study we evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical coronavirus disease 2019 (COVID-19) and evaluated different case definitions of invasive aspergillosis. Methods Prospective, multicentre study on adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA). Results A total of 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) of patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significant higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, p= 0.002) or PIPA (74% vs 26%, p<0.001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA [OR 3.53 (95%CI 1.29-9.67), P=0.014] or PIPA [OR 11.60 (95%CI 3.24-41.29) p<0.001] with 30-day mortality from ICU admission was confirmed even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients, 43%) A trend toward lower mortality (46% vs 59% p=0.30) and reduction of galactomannan index in consecutive samples was observed. Conclusion We found a high incidence of CAPA among critically ill COVID-19 patients and that its occurrence seems to change the natural history of disease
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              COVID-19–Associated Pulmonary Aspergillosis, March–August 2020

              Pneumonia caused by severe acute respiratory syndrome coronavirus 2 emerged in China at the end of 2019. Because of the severe immunomodulation and lymphocyte depletion caused by this virus and the subsequent administration of drugs directed at the immune system, we anticipated that patients might experience fungal superinfection. We collected data from 186 patients who had coronavirus disease–associated pulmonary aspergillosis (CAPA) worldwide during March–August 2020. Overall, 182 patients were admitted to the intensive care unit (ICU), including 180 with acute respiratory distress syndrome and 175 who received mechanical ventilation. CAPA was diagnosed a median of 10 days after coronavirus disease diagnosis. Aspergillus fumigatus was identified in 80.3% of patient cultures, 4 of which were azole-resistant. Most (52.7%) patients received voriconazole. In total, 52.2% of patients died; of the deaths, 33.0% were attributed to CAPA. We found that the cumulative incidence of CAPA in the ICU ranged from 1.0% to 39.1%.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                J Clin Microbiol
                J Clin Microbiol
                jcm
                Journal of Clinical Microbiology
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0095-1137
                1098-660X
                24 March 2022
                April 2022
                24 March 2022
                : 60
                : 4
                : e02298-21
                Affiliations
                [a ] Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
                [b ] Clinica Malattie Infettive, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
                [c ] Medical University of Grazgrid.11598.34, , Division of Infectious Diseases, Excellence Centre for Medical Mycology (ECMM), Graz, Austria
                [d ] Universitair Ziekenhuis Leuven, Leuven, Belgium
                [e ] Section of Biostatistics, Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy
                [f ] University of Cologne, Medical Faculty and University Hospital Cologne, Department I of Internal Medicine, Excellence Centre for Medical Mycology (ECMM), Cologne, Germany
                [g ] University of Cologne, Medical Faculty and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
                [h ] Algemeen Ziekenhuis Sint-Jan Brugge-Oostende, Bruges, Belgium
                [i ] Ziekenhusnetwerk Antwerp, Antwerp, Belgium
                [j ] Algemeen Ziekenhuis Delta, Roeselare, Belgium
                [k ] I.I. Mechnikov North-Western State Medical University, St. Petersburg, Russian Federation
                [l ] University of Cologne, Medical Faculty and University Hospital Cologne, Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany
                [m ] University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), Cologne, Germany
                [n ] German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
                [o ] Mycology Reference Centre Manchester and Department of Infectious Diseases, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom
                [p ] Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom
                [q ] Department of Laboratory Medicine, University Hospitals Leuven, Leuven, Belgium
                [r ] Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
                [s ] Division of Infectious Diseases and Global Public Health, University of California San Diego, San Diego, California, USA
                [t ] Clinical and Translational Fungal-Working Group, University of California San Diego, San Diego, California, USA
                University of Utah
                Author notes

                Daniele Roberto Giacobbe and Juergen Prattes are co-first authors. Author order was determined alphabetically.

                Matteo Bassetti and Martin Hoenigl are co-senior authors. Author order was determined alphabetically.

                The authors declare a conflict of interest. Outside the submitted work, D.R.G. reports an unconditional grant from Correvio Italia, and investigator-initiated grants from Pfizer Inc and Gilead Italia. J.P. has received personal fees from Gilead Sciences and Pfizer, research funding from MSD outside of the submitted work and is stakeholder of AbbVie and Novo Nordisk. J.W. reports grants and personal fees from Gilead and Pfizer: investigator-initiated grants, personal fees and also non-financial support from MSD, outside the submitted work. J.M. reports grants, personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Pfizer Inc., grants, personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from Astellas Pharma, personal fees and non-financial support from Cidara, personal fees and non-financial support from F2G, personal fees and non-financial support from Mundipharma, personal fees and non-financial support from Takeda/Shire, outside of the submitted work. O.A.C reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley, outside the submitted work. J.S.-G. has received lecture honoraria from Gilead and Pfizer, outside the submitted work. M. Bassetti has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, Astellas, Bayer, BioMèrieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer and Shionogi. R.R.-R. has received speaker honoraria from Astellas Pharma, Gilead Sciences, Pfizer, and research funding from Associates of Cape Cod. P.K. reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. K.L. received consultancy fees from SMB Laboratoires Brussels, MSD and Gilead, travel support from Pfizer, speaker fees from FUJIFILM WAKO, Pfizer and Gilead and a service fee from Thermo Fisher Scientific. M.H. received research funding from Gilead Sciences, Astellas, Scynexis, F2G, MSD, and Pfizer, all outside the submitted work. All other authors declare no conflict of interest for this study.

                Author information
                https://orcid.org/0000-0003-2385-1759
                https://orcid.org/0000-0002-7516-9471
                https://orcid.org/0000-0002-1653-2824
                Article
                02298-21 jcm.02298-21
                10.1128/jcm.02298-21
                9020339
                35321555
                3e628f43-ee96-434a-b362-bd73f2c2fdc9
                Copyright © 2022 American Society for Microbiology.

                All Rights Reserved.

                This article is made available via the PMC Open Access Subset for unrestricted noncommercial re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 16 November 2021
                : 3 January 2022
                : 14 February 2022
                Page count
                Figures: 1, Tables: 3, Equations: 0, References: 16, Pages: 9, Words: 5885
                Categories
                Mycology
                clinical-microbiology, Clinical Microbiology
                Custom metadata
                April 2022

                Microbiology & Virology
                capa,gm,biomarker,galactomannan,aspergillus,covid-19,balf
                Microbiology & Virology
                capa, gm, biomarker, galactomannan, aspergillus, covid-19, balf

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