Oropharyngeal and intestinal concentrations of opportunistic pathogens are independently associated with death of SARS-CoV-2 critically ill adults
Authors: Patrier Juliette , Villageois-Tran Khanh , Szychowiak Piotr , Ruckly Stéphane , Gschwind Rémi , Wicky Paul-Henri , Gueye Signara , Armand-Lefevre Laurence , Marzouk Mehdi , Sonneville Romain , Bouadma Lila , Petitjean Marie , Lamara Fariza , de Montmollin Etienne , Timsit Jean-Francois , Ruppé Etienne ,   The French COVID Cohort Study Group, Abel Laurent , Abrous Amal , Andrejak Claire , Angoulvant François , Bachelet Delphine , Bartoli Marie , Behilill Sylvie , Beluze Marine , Bhavsar Krishna , Bouadma Lila , Cervantes-Gonzalez Minerva , Chair Anissa , Charpentier Charlotte , Chenard Léo , Chirouze Catherine , Couffin-Cadiergues Sandrine , Couffignal Camille , Debray Marie-Pierre , Deplanque Dominique , Descamps Diane , Diallo Alpha , da Silva Fernanda Dias , Dorival Céline , Duval Xavier , Eloy Philippine , Enouf Vincent , Esperou Hélène , Esposito-Farese Marina , Etienne Manuel , Florence Aline-Marie , Gaymard Alexandre , Ghosn Jade , Gigante Tristan , Gilg Morgane , Goehringer François , Guedj Jérémie , Houas Ikram , Hoffmann Isabelle , Hulot Jean-Sébastien , Jaafoura Salma , Kafif Ouifiya , Khalil Antoine , Lafhej Nadhem , Laouénan Cédric , Laribi Samira , Le Minh , Le Hingrat Quentin , Le Mestre Soizic , Letrou Sophie , Levy Yves , Lina Bruno , Lingas Guillaume , Malvy Denis , Mentré France , Mouquet Hugo , Neant Nadège , Paul Christelle , Papadopoulos Aurélie , Paul Christelle , Petrov-Sanchez Ventzislava , Peytavin Gilles , Piquard Valentine , Picone Olivier , Rosa-Calatrava Manuel , Rossignol Bénédicte , Rossignol Patrick , Roy Carine , Schneider Marion , Su Richa , Tardivon Coralie , Timsit Jean-François , Tubiana Sarah , Van Der Werf Sylvie , Visseaux Benoit , Wiedemann Aurélie 
Published: October 2022

Abstract
Background
The composition of the digestive microbiota may be associated with outcome and infections in patients admitted to the intensive care unit (ICU). The dominance by opportunistic pathogens (such as Enterococcus) has been associated with death. However, whether this association remains all throughout the hospitalization are lacking.

Methods
We performed a single-center observational prospective cohort study in critically ill patients admitted with severe SARS-CoV-2 infection. Oropharyngeal and rectal swabs were collected at admission and then twice weekly until discharge or death. Quantitative cultures for opportunistic pathogens were performed on oropharyngeal and rectal swabs. The composition of the intestinal microbiota was assessed by 16S rDNA sequencing. Oropharyngeal and intestinal concentrations of opportunistic pathogens, intestinal richness and diversity were entered into a multivariable Cox model as time-dependent covariates. The primary outcome was death at day 90.

Results
From March to September 2020, 95 patients (765 samples) were included. The Simplified Acute Physiology Score 2 (SAPS 2) at admission was 33 [24; 50] and a Sequential Organ Failure Assessment score (SOFA score) at 6 [4; 8]. Day 90 all-cause mortality was 44.2% (42/95). We observed that the oropharyngeal and rectal concentrations of Enterococcus spp., Staphylococcus aureus and Candida spp. were associated with a higher risk of death. This association remained significant after adjustment for prognostic covariates (age, chronic disease, daily antimicrobial agent use and daily SOFA score). A one-log increase in Enterococcus spp., S. aureus and Candida spp. in oropharyngeal or rectal swabs was associated with a 17% or greater increase in the risk of death.

Conclusion
We found that elevated oropharyngeal/intestinal Enterococcus spp. S. aureus and Candida spp. concentrations, assessed by culture, are associated with mortality, independent of age, organ failure, and antibiotic therapy, opening prospects for simple and inexpensive microbiota-based markers for the prognosis of critically ill SARS-CoV-2 patients.