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. 2020 Aug;46(8):1524-1535.
doi: 10.1007/s00134-020-06091-6. Epub 2020 Jun 22.

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Paul E Verweij  1   2 , Bart J A Rijnders  3 , Roger J M Brüggemann  4   5 , Elie Azoulay  6 , Matteo Bassetti  7   8 , Stijn Blot  9   10 , Thierry Calandra  11 , Cornelius J Clancy  12   13 , Oliver A Cornely  14   15   16 , Tom Chiller  17 , Pieter Depuydt  18 , Daniele Roberto Giacobbe  7   19 , Nico A F Janssen  4   20 , Bart-Jan Kullberg  4   20 , Katrien Lagrou  21   22 , Cornelia Lass-Flörl  23 , Russell E Lewis  24 , Peter Wei-Lun Liu  25   26 , Olivier Lortholary  27   28 , Johan Maertens  21   29 , Ignacio Martin-Loeches  30   31 , M Hong Nguyen  12   13 , Thomas F Patterson  32   33 , Thomas R Rogers  34 , Jeroen A Schouten  35   36 , Isabel Spriet  37 , Lore Vanderbeke  21   38 , Joost Wauters  38 , Frank L van de Veerdonk  4   20
Affiliations

Review of influenza-associated pulmonary aspergillosis in ICU patients and proposal for a case definition: an expert opinion

Paul E Verweij et al. Intensive Care Med. 2020 Aug.

Abstract

Purpose: Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies.

Methods: A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus.

Results: Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for Aspergillus. Probable IAPA required the detection of galactomannan or positive Aspergillus culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between Aspergillus and the SARS-CoV-2-infected lung.

Conclusion: A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe Aspergillus disease, and may be of use to study CAPA.

Keywords: COVID-19; ICU; Influenza; Invasive aspergillosis; Viral pneumonia.

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Conflict of interest statement

PE Verweij reported grants from Gilead Sciences, MSD, Pfizer and F2G, and non-financial support from OLM and IMMY, outside the submitted work. BJA Rijnders was the investigator for studies supported by Gilead Sciences, Janssen-Cilag, MSD, Pfizer, ViiV; has received research grants from Gilead and MSD; was an invited speaker for Gilead, MSD, Pfizer, Jansen-Cilag, BMS; and an advisory board member for BMS, Abbvie, MSD, Gilead, Jansen-Cilag; he received travel support from BMS, Abbvie, MSD, Gilead, Jansen-Cilag. RJM Brüggemann served as a consultant to Astellas Pharma, Inc., F2G, Amplyx, Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc., and has received unrestricted and research grants from Astellas Pharma, Inc., Gilead Sciences, Merck Sharp & Dohme Corp., and Pfizer, Inc. All contracts were through Radboudumc, and all payments were invoiced by Radboudumc. E Azoulay has received fees for lectures from Pfizer, Gilead, MSD, Alexion and Baxter. His institution received research support from Fisher&Payckle, Jazz pharma and Gilead. M Bassetti has received funding for scientific advisory boards, travel and speaker honoraria from Angelini, Astellas, AstraZeneca, Basilea, Bayer, BioMèrieux, Cidara, Correvio, Cubist, Menarini, Molteni, MSD, Nabriva, Paratek, Pfizer, Roche, Shionogi, Tetraphase, Thermo Fisher and The Medicine Company. S Blot received research funding from Pfizer and MSD, travel support from Pfizer, MSD and Gilead, and is an invited speaker for Pfizer and Gilead. T Calandra reported advisory board membership from Astellas, Basilea, Cidara, MSD, Sobi, ThermoFisher and GE Healthcare and data monitoring board membership from Novartis, all outside the submitted work. Fees are paid to its institution. CJ Clancy has been awarded investigator-initiated research grants from Astellas, Merck, Melinta and Cidara for projects unrelated to this project, served on advisory boards or consulted for Astellas, Merck, the Medicines Company, Cidara, Scynexis, Shionogi, Qpex and Needham & Company, and spoken at symposia sponsored by Merck and T2Biosystems. OA Cornely is supported by the German Federal Ministry of Research and Education and the European Commission, and has received research grants from, is an advisor to, or received lecture honoraria from Actelion, Allecra Therapeutics, Amplyx, Astellas, Basilea, Biosys UK Limited, Cidara, Da Volterra, Entasis, F2G, Gilead, Grupo Biotoscana, Janssen Pharmaceuticals, Matinas, Medicines Company, MedPace, Melinta Therapeutics, Menarini Ricerche, Merck/MSD, Octapharma, Paratek Pharmaceuticals, Pfizer, PSI, Rempex, Scynexis, Seres Therapeutics, Tetraphase, Vical. T Chiller reported no conflicts of interest. P Depuydt reported no conflicts of interest. DR Giacobbe reported honoraria from Stepstone Pharma GmbH and an unconditional grant from MSD Italia. NAF Janssen reported no conflicts of interest. BJ Kullberg has been a scientific advisor for Amplyx, Cidara and Scynexis. K Lagrou received consultancy fees from MSD, SMB Laboratoires Brussels and Gilead, travel support from Pfizer and MSD and speaker fees from Gilead, MSD, FUJIFILM WAKO. C Lass-Florl received research funding from Pfizer, Gilead and Egger, travel support from Pfizer, MSD, and Gilead, and is an invited speaker for Pfizer and Gilead. RE Lewis has received research support from Merck and has served as an invited speaker for Gilead, Cidara. P Wei-Lun Liu has received research grants from MSD, Pfizer, and has served as an invited speaker for Gilead, MSD, Pfizer, Astellas Pharma, and is an advisor to Pfizer, Gilead. O Lortholary has served as an invited speaker for Gilead, MSD, Pfizer, Astellas Pharma, and is a consultant for Gilead, Novartis and F2G. J Maertens reported personal fees and non-financial support from Basilea Pharmaceuticals, Bio-Rad Laboratories, Cidara, F2G Ltd., Gilead Sciences, Merck, Astellas, Scynexis, and Pfizer Inc. and grants from Gilead Sciences, IMMY and OLM. I Martin-Loeches reported no conflicts of interest. MH Nguyen has been awarded investigator-initiated research grants from Astellas, Merck, Melinta and Cidara for projects unrelated to this study and served on advisory boards for Astellas, Merck, the Medicines Company, Scynexis and Shionogi. TF Patterson reported grants from Cidara to UT Health San Antonio; personal fees from Basilea, Gilead, Mayne, Merck, Pfizer, Scynexis, Sfunga, Toyama and United Medical outside the submitted work. TR Rogers has received grants from Gilead Sciences, lecture honoraria from Gilead Sciences and Pfizer Healthcare Ireland, and advisory board membership with Menarini Pharma. JA Schouten has received unrestricted educational and research grants from MSD and has been an advisor to Pfizer. All contracts were through Radboudumc, and all payments were invoiced by Radboudumc. I Spriet has received unrestricted research grants, speaker fees and travel grants from MSD, Pfizer, Gilead and Cidara. She has served in the advisory board for Cidara. L Vanderbeke is supported by the Flanders Research Foundation (FWO Vlaanderen) through a doctoral fellowship. J Wauters reported grants from Gilead Sciences, MSD and Pfizer, and non-financial support from MSD, outside the submitted work. FL van de Veerdonk has served as an invited speaker for Gilead.

Figures

Fig. 1
Fig. 1
Flowchart of probable IAPA classification. (*)If hyphae consistent with Aspergillus are documented in a biopsy of an airway lesion AND Aspergillus is grown from sputum or a tracheal aspirate, the case fulfills the definition of proven IAPA
See this image and copyright information in PMC

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