Pulmonary herpes simplex virus and cytomegalovirus in patients with acute respiratory distress syndrome related to COVID-19
L.S. Boers, Frank van Someren Gréve, Jarne M. van Hattem, Justin de Brabander, Tom Zwaan, Hugo D.G. van Willigen, Marion Cornelissen, Menno de Jong, Tom van der Poll, JanWillem Duitman, Janke Schinkel, Lieuwe D. J. Bos, Paul E. Verweij, Simone J.C.F.M. Moorlag, Frank L. van de Veerdonk, Lieuwe D. J. Bos, Frank van Someren Gréve, Jeroen J. A. van Kampen, Joost Wauters, Katrien Lagrou, Simon Feys, Jannes Heylen, Michiel A. van Agtmael, Anna Geke Algera, Brent Appelman, Floor van Baarle, Diederik van de Beek, Martijn Beudel, Harm Jan Bogaard, Lieuwe D. J. Bos, Michela Botta, Godelieve de Bree, Matthijs C. Brouwer, Sanne de Bruin, Marianna Bugiani, Esther Bulle, David T.P. Buis, Osoul Chouchane, Alex Cloherty, Mirjam Dijkstra, Dave A. Dongelmans, Romein W. G. Dujardin, Paul Elbers, Lucas M. Fleuren, Suzanne E. Geerlings, Theo Geijtenbeek, Armand R. J. Girbes, Bram Goorhuis, Martin P. Grobusch, Laura A. Hagens, Jörg Hamann, Vanessa Harris, Robert Hemke, Sabine Hermans, Leo Heunks, Markus W. Hollmann, Janneke Horn, Joppe W. Hovius, Menno de Jong, Rutger Koning, Endry H. T. Lim, Niels van Mourik, Jeaninne Nellen, Esther J. Nossent, Frederique Paulus, Edgar Peters, Dan Piña‐Fuentes, Bennedikt Preckel, Jorinde Raasveld, Tom D. Y. Reijnders, Maurits C. F. J. de Rotte, Michiel Schinkel, Marcus J. Schultz, Femke A. P. Schrauwen, Alex R. Schuurman, Jaap Schuurmans, Kim Sigaloff, Marleen A. Slim, Patrick Smeele, Marry R. Smit, Cornelis Stijnis, Willemke Stilma, Charlotte E. Teunissen, Patrick Thoral, Anissa M. Tsonas, Pieter R. Tuinman, Marc van der Valk, Denise P. Veelo, Alexander P. J. Vlaar, Carolien Volleman, Heder de Vries, Lonneke A. van Vught, Michèle van Vugt, W. Joost Wiersinga, Dorien Wouters, Aeilko H. Zwinderman, Matthijs C. Brouwer. E. J. Nossent, Jan Willem Duitman, Anno Saris, Heder de Vries
Abstract
PURPOSE: Human herpesviruses, particularly cytomegalovirus (CMV) and herpes simplex virus (HSV), frequently reactivate in critically ill patients, including those with acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). The clinical interpretation of pulmonary herpesvirus reactivation is challenging and there is ongoing debate about its association with mortality and benefit of antiviral medication. We aimed to quantify the incidence and pathogenicity of pulmonary CMV and HSV reactivations in critically ill COVID-19 patients. METHODS: Mechanically ventilated COVID-19 patients seropositive for CMV or HSV were included in this observational cohort study. Diagnostic bronchoscopy with bronchoalveolar lavage was performed routinely and analyzed for alveolar viral loads and inflammatory biomarkers. Utilizing joint modeling, we explored the dynamic association between viral load trajectories over time and mortality. We explored alveolar inflammatory biomarker dynamics between reactivated and non-reactivated patients. RESULTS: copies/ml) of CMV occurred in 6% of CMV-seropositive patients (9/156), and pulmonary reactivation of HSV in 37% of HSV-seropositive patients (63/172). HSV viral load dynamics prior to or without antiviral treatment were associated with increased 90-day mortality (hazard ratio [HR] 1.24, 95% confidence interval [CI] 1.04-1.47). The alveolar concentration of several inflammatory biomarkers increased with HSV reactivation, including interleukin (IL)-6, IL-1β, granulocyte colony stimulating factor (G-CSF), and tumor necrosis factor (TNF). CONCLUSION: In mechanically ventilated COVID-19 patients, HSV reactivations are common, while CMV reactivations were rare. HSV viral load dynamics prior to or without antiviral treatment are associated with mortality. Alveolar inflammation is elevated after HSV reactivation.