Clustering COVID-19 ARDS patients through the first days of ICU admission. An analysis of the CIBERESUCICOVID Cohort
Authors: Ceccato Adrian , Forne Carles , Bos Lieuwe D. , Camprubí-Rimblas Marta , Areny-Balagueró Aina , Campaña-Duel Elena , Quero Sara , Diaz Emili , Roca Oriol , De Gonzalo-Calvo David , Fernández-Barat Laia , Motos Anna , Ferrer Ricard , Riera Jordi , Lorente Jose A. , Peñuelas Oscar , Menendez Rosario , Amaya-Villar Rosario , Añón José M. , Balan-Mariño Ana , Barberà Carme , Barberán José , Blandino-Ortiz Aaron , Boado Maria Victoria , Bustamante-Munguira Elena , Caballero Jesús , Carbajales Cristina , Carbonell Nieves , Catalán-González Mercedes , Franco Nieves , Galbán Cristóbal , Gumucio-Sanguino Víctor D. , de la Torre Maria del Carmen , Estella Ángel , Gallego Elena , García-Garmendia José Luis , Garnacho-Montero José , Gómez José M. , Huerta Arturo , Jorge-García Ruth Noemí , Loza-Vázquez Ana , Marin-Corral Judith , Martínez de la Gándara Amalia , Martin-Delgado María Cruz , Martínez-Varela Ignacio , Messa Juan Lopez , Muñiz-Albaiceta Guillermo , Nieto María Teresa , Novo Mariana Andrea , Peñasco Yhivian , Pozo-Laderas Juan Carlos , Pérez-García Felipe , Ricart Pilar , Roche-Campo Ferran , Rodríguez Alejandro , Sagredo Victor , Sánchez-Miralles Angel , Sancho-Chinesta Susana , Socias Lorenzo , Solé-Violan Jordi , Suarez-Sipmann Fernando , Tamayo-Lomas Luis , Trenado José , Úbeda Alejandro , Valdivia Luis Jorge , Vidal Pablo , Bermejo Jesus , Gonzalez Jesica , Barbe Ferran , Calfee Carolyn S. , Artigas Antonio , Torres Antoni ,   CIBERESUCICOVID Project, Adell-Serrano Berta , Cabello María Aguilar , Aguilera Luciano , Alcaraz-Serrano Victoria , Aldecoa Cesar , Alegre Cynthia , Almansa Raquel , Álvarez Sergio , Ruiz Antonio Álvarez , Villar Rosario Amaya , Andrea Ruth , Novo Mariana Andrea , Ángel José , Añon Jose Manuel , Arrieta Marta , Ayestarán JIgnacio , Badia Joan Ramon , Badía Mariona , Pravia Orville Báez , Mariño Ana Balan , Balsera Begoña , Barberà Carme , Barberán José , Barbena Laura , Barbeta Enric , Bardi Tommaso , Segade Patricia Barral , Barroso Marta , García José Ángel Berezo , Bermejo-Martin Jesús F. , Beteré Belén , Bigas Judit , Ortiz Aaron Blandino , Blancas Rafael , Cortés María Luisa Blasco , Boado María , Saera María Bodi , Bofill Neus , Vieiro María Teresa Bouza , Bueno Leticia , Bustamante-Munguira Elena , Bustamante-Munguira Juan , del Busto Martínez Cecilia , Caballero Jesús , Hermoso David Campi , Fernández Sandra Campos , Carbajales Cristina , Cano Iosune , Cantón-Bulnes Maria Luisa , Carbonell Nieves , Fernández Pablo Cardina , García Laura Carrión , Carvalho Sulamita , Casacuberta-Barberà Núria , Castellà Manuel , Castellví Andrea , Castro Pedro , Catalán-González Mercedes , Ávila Ramon Cicuendez , Cillóniz Catia , Clar Luisa , Climent Cristina , Codina Jordi , Conde Pamela , Contreras Sofía , Martin María Cruz , de Pablo Sánchez Raul , De Mendoza Diego , Díaz Emili , Díaz Yolanda , Vilas María Digna Rivas , Moreno Cristina Dólera , Dot Irene , Giraudo Pedro Enríquez , Arijón Inés Esmorís , Estella Angel , Monjo Teresa Farre , Fernández Javier , Ferrando Carlos , Figueras Albert , Forcadell-Ferreres Eva , Espina Lorena Forcelledo , Franco Nieves , Franquesa Enric , Furro Àngels , Gabarrus Albert , Galbán Cristóbal , Gallego Elena , García Felipe , García Beatriz , Garmendia José Luis García , Garcia-Gasulla Dario , Prieto Emilio García , Redruello Carlos García , Sagastume Amaia García , Garnacho-Montero José , Castillo Maria Luisa Gascón , Gomà Gemma , Gómez José M. , Casal Vanesa Gómez , Gómez Silvia , Gonzalez Carmen Gómez , de Gonzalo-Calvo David , González Jessica , Gordo Federico , Gracia Maria Pilar , Gumucio-Sanguino Víctor D. , Herraiz Alba , Herrán-Monge Rubén , Huerta Arturo , Ibarz Mercedes , Iglesias Silvia , Janer Maria Teresa , Jiménez Gabriel , García Ruth Noemí Jorge , Díaz Mar Juan , Kiarostami Karsa , Álvarez Juan ILazo , León Miguel , López-Gavín Alexandre , Lago Ana López , Messa Juan Lopez , López-Ramos Esther , Loza-Vázquez Ana , Guerrero Desire Macias , Herrera Nuria Mamolar , Mendiluce Rafael Mañez , Mantellini Cecilia L. , Naya Gregorio Marco , Marcos Pilar , Marin-Corral Judith , Peis Enrique Marmol , Vicente Paula Martín , Martínez María , Fernández Carmen Eulalia Martínez , de la Gándara Amalia Martínez , Juan Maria Dolores Martínez , Palacios Basilisa Martínez , Varela Ignacio Martínez , Jimenez Juan Fernando Masa , Masclans Joan Ramon , Maseda Emilio , Fernández Eva María Menor , Miralbés Mar , Monclou Josman , Montejo-González Juan Carlos , Montserrat Neus , Aznar María Mora , Morales Dulce , Cano Sara Guadalupe Moreno , Rodríguez David Mosquera , Muñoz-Bermúdez Rosana , Albaiceta Guillermo Muñiz , Nicolás José María , NIeto Maria Teresa , Bou Ramon Nogue , Salinas Rafaela Nogueras , Ocón Marta , Ortega Ana , Ossa Sergio , Pagliarani Pablo , Parrilla Francisco , Pedregosa-Díaz Jose , Peñasco Yhivian , Peñuelas Oscar , Bastida Leire Pérez , Pérez Purificación , Pérez-García Felipe , Planelles Gloria Pérez , Rubio Eva Pérez , Laguna David Pestaña , Piñol-Tena Àngels , Prados Javier , Pujol Andrés , Pozo Juan Carlos , Coll Núria Ramon , Sanchez-Giron Gloria Renedo , Riera Jordi , Ricart Pilar , Roche-Campo Ferran , Rodríguez Alejandro , Rodriguez Laura , de Castro Felipe Rodríguez , Rodríguez Silvia , Ruiz Covadonga Rodríguez , Rubio Jorge , López Alberto Rubio , Ruiz-García Ángela Leonor , Miralles Miriam Ruiz , Murúa Pablo Ryan , Paz Eva Saborido , Sagredo Victor , Degracia Ana Salazar , Salvador-Adell Inmaculada , Sanchez Miguel , Sánchez Ana , Sánchez-Miralles Angel , Chinesta Susana Sancho , Santacoloma Bitor , Sanchez Miguel , Sariñena Maria Teresa , Pensado Marta Segura , Serra Lidia , Serra-Fortuny Mireia , Lázaro Ainhoa Serrano , Servià Lluís , Socias Lorenzo , Soliva Laura , Solé-Violan Jordi , Sipmann Fernando Suarez , Speziale Carla , Lomas Luis Tamayo , Tormos Adrián , de la Torre Maria del Carmen , Torres Gerard , Torres Mateu , Trefler Sandra , Trenado Josep , Trujillano Javier , Úbeda Alejandro , Urrelo-Cerrón Luis , Val Estela , Valledor Manuel , Ruiz Luis Valdivia , Vallverdú Montserrat , Van der Hofstadt Martin-Montalvo Maria , Adrio Sabela Vara , Vázquez Nil , Vengoechea Javier , Vidal Pablo , Vilà-Vilardel Clara , Vilanova Judit , Warrington Tatiana Villada , Yang Hua , Yang Minlan , Zapatero Ana 
Published: March 2024

Abstract
Background
Acute respiratory distress syndrome (ARDS) can be classified into sub-phenotypes according to different inflammatory/clinical status. Prognostic enrichment was achieved by grouping patients into hypoinflammatory or hyperinflammatory sub-phenotypes, even though the time of analysis may change the classification according to treatment response or disease evolution. We aimed to evaluate when patients can be clustered in more than 1 group, and how they may change the clustering of patients using data of baseline or day 3, and the prognosis of patients according to their evolution by changing or not the cluster.

Methods
Multicenter, observational prospective, and retrospective study of patients admitted due to ARDS related to COVID-19 infection in Spain. Patients were grouped according to a clustering mixed-type data algorithm (k-prototypes) using continuous and categorical readily available variables at baseline and day 3.

Results
Of 6205 patients, 3743 (60%) were included in the study. According to silhouette analysis, patients were grouped in two clusters. At baseline, 1402 (37%) patients were included in cluster 1 and 2341(63%) in cluster 2. On day 3, 1557(42%) patients were included in cluster 1 and 2086 (57%) in cluster 2. The patients included in cluster 2 were older and more frequently hypertensive and had a higher prevalence of shock, organ dysfunction, inflammatory biomarkers, and worst respiratory indexes at both time points. The 90-day mortality was higher in cluster 2 at both clustering processes (43.8% [n = 1025] versus 27.3% [n = 383] at baseline, and 49% [n = 1023] versus 20.6% [n = 321] on day 3). Four hundred and fifty-eight (33%) patients clustered in the first group were clustered in the second group on day 3. In contrast, 638 (27%) patients clustered in the second group were clustered in the first group on day 3.

Conclusions
During the first days, patients can be clustered into two groups and the process of clustering patients may change as they continue to evolve. This means that despite a vast majority of patients remaining in the same cluster, a minority reaching 33% of patients analyzed may be re-categorized into different clusters based on their progress. Such changes can significantly impact their prognosis.