Co-infection and ICU-acquired infection in COVID-19 ICU patients: a secondary analysis of the UNITE-COVID data set
Authors: Conway Morris Andrew , Kohler Katharina , De Corte Thomas , Ercole Ari , De Grooth Harm-Jan , Elbers Paul W. G. , Povoa Pedro , Morais Rui , Koulenti Despoina , Jog Sameer , Nielsen Nathan , Jubb Alasdair , Cecconi Maurizio , De Waele Jan ,   for the ESICM UNITE COVID investigators, Bezzi Marco , Gira Alicia , Eller Philipp , Hamid Tarikul , Haque Injamam Ull , De Buyser Wim , Cudia Antonella , De Backer Daniel , Foulon Pierre , Collin Vincent , De Waele Jan , Van Hecke Jolien , De Waele Elisabeth , Van Malderen Claire , Mesland Jean-Baptiste , Piagnerelli Michael , Haentjens Lionel , De Schryver Nicolas , Van Leemput Jan , Vanhove Philippe , Bulpa Pierre , Ilieva Viktoria , Katz David , Geagea Anna , Binnie Alexandra , Tirapegui Fernando , Lago Gustavo , Graf Jerónimo , Perez-Araos Rodrigo , Vargas Patricio , Martinez Felipe , Labarca Eduardo , Franco Daniel Molano , Parra-Tanoux Daniela , Reyes Luis Felipe , Yepes David , Periš Filip , Stipić Sanda Stojanović , Burgos Cynthia Vanessa Campozano , Boada Paulo Roberto Navas , Brun Jose Luis Barberan , Ballesteros Juan Pablo Paredes , Hammouda Ahmed , Elmandouh Omar , Azzam Ahmed , Hussein Aliae Mohamed , Galal Islam , Awad Ahmed K. , Azab Mohammed A. , Abdalla Maged , Assal Hebatallah , Alfishawy Mostafa , Ghozy Sherief , Tharwat Samar , Eldaly Abdullah , Reinhard Veronika , Chrisment Anne , Poyat Chrystelle , Badie Julio , Ferrari Fernando Berdaguer , Weiss Björn , Kuhn Karl Friedrich , Grunow Julius J. , Lorenz Marco , Schaller Stefan , Spieth Peter , Bota Marc , Fichtner Falk , Fuest Kristina , Lahmer Tobias , Herrmann Johannes , Meybohm Patrick , Markou Nikolaos , Vasileiadou Georgia , Chrysanthopoulou Evangelia , Papamichalis Panagiotis , Soultati Ioanna , Jog Sameer , Kalvit Kushal , Myatra Sheila Nainan , Krupa Ivan , Tharwat Aisa , Nichol Alistair , McCarthy Aine , Mahmoodpoor Ata , Tonetti Tommaso , Isoni Paolo , Spadaro Savino , Volta Carlo Alberto , Mirabella Lucia , Noto Alberto , Florio Gaetano , Guzzardella Amedeo , Paleari Chiara , Baccanelli Federica , Savi Marzia , Antonelli Massimo , Vaccarini Barbara , Montrucchio Giorgia , Sales Gabriele , Donadello Katia , Gottin Leonardo , Polati Enrico , De Rosa Silvia , Sulemanji Demet , Abusalama Abdurraouf , Elhadi Muhammed , De Jesus Montelongo Felipe , Gonzalez Daniel Rodriguez , Canedo Nancy , Chavez Alejandro Esquivel , Dendane Tarek , Grady Bart , de Jong Ben , van der Heiden Eveline , Thoral Patrick , van den Bogaard Bas , Spronk Peter E. , Achterberg Sefanja , Groeneveld Melanie , So Ralph K. L. , de Wijs Calvin , Scholten Harm , Beishuizen Albertus , Cornet Alexander D. , Reidinga Auke C. , Kranen Hetty , Mensink Roos , Boer Sylvia den , de Groot Marcel , Beck Oliver , Bethlehem Carina , van Bussel Bas , Frenzel Tim , de Jong Celestine , Wilting Rob , Kesecioglu Jozef , Mehagnoul-Schipper Jannet , Alasia Datonye , Kumar Ashok , Qayyum Ahad , Rana Muhammad , Jayyab Mustafa Abu , Sierra Rosario Quispe , Hernandez Aaron Mark , Taborda Lúcia , Ramires Tiago , Silva Catarina , Roriz Carolina , Póvoa Pedro , Patricio Patricia , Santos Maria Lurdes , Costa Vasco , Cunha Pedro , Gonçalves Celina , Nunes Sandra , Camões João , Adrião Diana , Oliveira Ana , Omrani Ali , Al Maslamani Muna , elbuzidi Abdurrahmaan Suei , Al qudah Bara Mahmoud , Akkari Abdel Rauof , Alkhatteb Mohamed , Baiou Anas , Husain Ahmed , Alwraidat Mohamed , Saif Ibrahim Abdulsalam , Bakdach Dana , Ahmed Amna , Aleef Mohamed , Bintaher Awadh , Petrisor Cristina , Popov Evgeniy , Popova Ksenia , Dementienko Mariia , Teplykh Boris , Pyregov Alexey , Davydova Liubov , Vladislav Belskii , Neporada Elena , Zverev Ivan , Meshchaninova Svetlana , Sokolov Dmitry , Gavrilova Elena , Shlyk Irena , Poliakov Igor , Bлacoвa Mapинa , Aljuhani Ohoud , Alkhalaf Amina , Humaid Felwa Bin , Arabi Yaseen , Kuhail Ahmed , Elrabi Omar , Alghnam Madihah , Kansal Amit , Ho Vui Kian , Ng Jensen , García Raquel Rodrígez , Fraga Xiana Taboada , del Pilar García-Bonillo Mª , Padilla-Serrano Antonio , Cuadrado Marta Martin , Ferrando Carlos , Catalan-Monzon Ignacio , Galarza Laura , Frutos-Vivar Fernando , Jimenez Jorge , Rodríguez-Solis Carmen , Franquesa-Gonzalez Enric , Acosta Guillermo Pérez , Cabrera Luciano Santana , Parra Juan Pablo Aviles , Gonzalez Francisco Muñoyerro , del Carmen Lorente Conesa Maria , Varela Ignacio Yago Martinez , Pravia Orville Victoriano Baez , Delgado Maria Cruz Martin , de Cabo Carlos Munoz , Ioan Ana-Maria , Perez-Calvo Cesar , Santos Arnoldo , Abad-Motos Ane , Ripolles-Melchor Javier , Martin Belén Civantos , Teruel Santiago Yus , Lucas Juan Higuera , Ortiz Aaron Blandino , de Pablo Sánchez Raúl , Barrueco-Francioni Jesús Emilio , Espina Lorena Forcelledo , Bonell-Goytisolo José M. , Salaverria Iñigo , Mir Antonia Socias , Rodriguez-Ruiz Emilio , Valverde Virginia Hidalgo , Cubero Patricia Jimeno , Linde Francisca Arbol , Leganes Nieves Cruza , Romeu Juan Maria , Concha Pablo , Berezo-Garcia José Angel , Fraile Virginia , Cuenca-Rubio Cristina , Perez-Torres David , Serrano Ainhoa , Valero Clara Martínez , Suner Andrea Ortiz , Larrañaga Leire , Legaristi Noemi , Ferrigno Gerardo , Khlafalla Safa , Bihariesingh-Sanchit Rosita , Zoerner Frank , Grip Jonathan , Kilsand Kristina , Österlind Jonas , von Seth Magnus , Berkius Johan , Ceruti Samuele , Glotta Andrea , Izdes Seval , Turan Işıl Özkoçak , Cosar Ahmet , Halacli Burcin , Dereli Necla , Yilmaz Mehmet , Akbas Türkay , Elay Gülseren , Eyüpoğlu Selin , Bílír Yelíz , Saraçoğlu Kemal Tolga , Kaya Ebru , Sahin Ayca Sultan , Ekren Pervin Korkmaz , Mengi Tuğçe , Suner Kezban Ozmen , Tomak Yakup , Eroglu Ahmet , Alsabbah Asad , Hanlon Katie , Gervin Kevin , McMahon Sean , Hagan Samantha , Higenbottam Caroline V. , Mullhi Randeep , Poulton Lottie , Torlinski Tomasz , Gareth Allen , Truman Nick , Vijayakumar Gopal , Hall Chris , Jubb Alasdair , Cagova Lenka , Jones Nicola , Graham Sam , Robin Nicole , Cowton Amanda , Donnelly Adrian , Singatullina Natalia , Kent Melanie , Boulanger Carole , Campbell Zoë , Potter Elizabeth , Duric Natalie , Szakmany Tamas , Kviatkovske Orinta , Marczin Nandor , Ellis Caroline , Saha Rajnish , Sri-Chandana Chunda , Allan John , Mumelj Lana , Venkatesh Harish , Gotz Vera Nina , Cochrane Anthony , Lumlertgul Nuttha , Ficial Barbara , Jain Susan , Crapelli Giulia Beatrice , Vlachou Aikaterini , Golden David , Garrioch Sweyn , Henning Jeremy , Loveleena Gupta , Davey Miriam , Grauslyte Lina , Salciute-Simene Erika , Cook Martin , Barling Danny , Broadhurst Phil , Purvis Sarah , Michael Spivey , Shuker Benjamin , Grecu Irina , Harding Daniel , Singatullina Natalia , Dean James T. , Nielsen Nathan D. , Al-Bayati Sama , Al-Sadawi Mohammed , Charron Mariane , Stubenrauch Peter , Santanilla Jairo , Wentowski Catherine , Rosenberger Dorothea , Eksarko Polikseni , Jawa Randeep 
Published: August 2022

Abstract
Background
The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.

Methods
This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson’s Chi-squared and continuous variables by Mann–Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the “full” matching method.

Results
Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.

Conclusions
In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids.
Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021).

Graphical abstract