Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic: a matched analysis

Background: The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. Methods: This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Results: Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. Conclusions: In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannula.Financial support was provided by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII), Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", and the Centro de Investigación Biomedica En Red – Enfermedades Respiratorias (CIBERES). DdGC has received financial support from the Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by European Social Fund (ESF)/”Investing in your future”.Peer ReviewedArticle signat per 70 autors/es: Jordi Riera*1,2; Enric Barbeta*2,3,4; Adrián Tormos5; Ricard Mellado-Artigas2,3; Adrián Ceccato6; Anna Motos4; Laia Fernández-Barat4; Ricard Ferrer1; Darío García-Gasulla5; Oscar Peñuelas7; José Ángel Lorente7; Rosario Menéndez8; Oriol Roca1,2; Andrea Palomeque4,9; Carlos Ferrando2,3; Jordi SoléViolán10; Mariana Novo11; María Victoria Boado12; Luis Tamayo13; Ángel Estella14, Cristóbal Galban15; Josep Trenado16; Arturo Huerta17; Ana Loza18; Luciano Aguilera19; José Luís García Garmendia20; Carme Barberà21; Víctor Gumucio22; Lorenzo Socias23; Nieves Franco24; Luis Jorge Valdivia25; Pablo Vidal26; Víctor Sagredo27; Ángela Leonor Ruiz-García28; Ignacio Martínez Varela29; Juan López30; Juan Carlos Pozo31; Maite Nieto32; José M Gómez33; Aaron Blandino34; Manuel Valledor35; Elena Bustamante-Munguira36; Ángel Sánchez-Miralles37; Yhivian Peñasco38; José Barberán39; Alejandro Ubeda40; Rosario Amaya-Villar41; María Cruz Martín42; Ruth Jorge43; Jesús Caballero44; Judith Marin45; José Manuel Añón46; Fernando Suárez Sipmann47; Guillermo Muñiz2,48;Álvaro Castellanos-Ortega49; Berta Adell-Serrano50; Mercedes Catalán51; Amalia Martínez de la Gándara52; Pilar Ricart53; Cristina Carbajales54; Alejandro Rodríguez55; Emili Díaz6; Mari C de la Torre56; Elena Gallego57; Luisa Cantón-Bulnes58; Nieves Carbonell59, Jessica González60, David de Gonzalo-Calvo60, Ferran Barbé60 and Antoni Torres2,4,9 on behalf of the CiberesUCICOVID Consortium. // 1. Critical Care Department, Hospital Universitari Vall d’Hebron; SODIR, Vall d’Hebron Institut de Recerca, Barcelona, Spain. 2. CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain. 3.Surgical Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain. 4. Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. 5. Barcelona Supercomputing Center (BSC), Barcelona, Spain. 6. Critical Care Center, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Sabadell, Spain. Universitat Autonoma de Barcelona (UAB), Spain. 7. Hospital Universitario de Getafe, Universidad Europea, Madrid, Spain. 8. Pneumology Department, Hospital Universitario y Politécnico La Fe/Instituto de Investigación Sanitaria (IIS) La Fe, 46026 Valencia, Spain; Pneumology Department, Hospital Universitario y Politécnico La Fe, Avda, Fernando Abril Martorell 106, 46026 Valencia, Spain. 9.Respiratory Intensive Care Unit, Hospital Clínic de Barcelona, Barcelona, Spain. 10. Critical Care Department, Hospital Dr. Negrín Gran Canaria. Universidad Fernando Pessoa. Las Palmas, Gran Canaria, Spain. 11. Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, Illes Balears, Spain. 12. Hospital Universitario de Cruces, Barakaldo, Spain. 13. Critical Care Department, Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain. 14. Departamento Medicina Facultad Medicina Universidad de Cádiz. Hospital Universitario de Jerez, Jerez de la Frontera, Spain. 15. Department of Medicine, CHUS, Complejo Hospitalario Universitario de Santiago, Santiago de Compostela, Spain. 16. Servicio de Medicina Intensiva, Hospital Universitario Mútua de Terrassa, Terrassa, Barcelona, Spain. 17. Pulmonary and Critical Care Division; Emergency Department, Clínica Sagrada Família, Barcelona, Spain. 18. Hospital Virgen de Valme, Sevilla, Spain. 19. Hospital de Basurto, Bilbao, Spain. 20. Intensive Care Unit, Hospital San Juan de Dios del Aljarafe, Bormujos, Sevilla, Spain. 21. Hospital Santa Maria; IRBLleida, Lleida, Spain. 22. Department of Intensive Care. Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain. Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. 23. Intensive Care Unit, Hospital Son Llàtzer, Palma de Mallorca, Illes Balears, Spain. 24. Hospital Universitario de Móstoles, Madrid, Spain. 25. Hospital Universitario de León, León, Spain. 26. Complexo Hospitalario Universitario de Ourense, Ourense, Spain. 27. Hospital Universitario de Salamanca, Salamanca, Spain. 28. Servicio de Microbiología Clínica, Hospital Universitario Príncipe de Asturias – Departamento de Biomedicina y Biotecnología, Universidad de Alcalá de Henares, Madrid, Spain. 29. Critical Care Department, Hospital Universitario Lucus Augusti, Lugo, Spain. 30. Complejo Asistencial Universitario de Palencia, Palencia, Spain. 31. UGC-Medicina Intensiva, Hospital Universitario Reina Sofia, Instituto Maimonides IMIBIC, Córdoba, Spain. 32. Hospital Universitario de Segovia, Segovia, Spain. 33. Hospital General Universitario Gregorio Marañón, Madrid, Spain. 34. Servicio de Medicina Intensiva, Hospital Universitario Ramón y Cajal, Madrid, Spain. 35. Hospital Universitario "San Agustín", Avilés, Spain. 36. Department of Intensive Care Medicine, Hospital Clínico Universitario Valladolid, Valladolid, Spain. 37. Servicio de Medicina Intensiva. Hospital Universitario Sant Joan d´Alacant, Alicante, Spain. 38. Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, Santander, Spain. 39. Hospital Universitario HM Montepríncipe, Universidad San Pablo-CEU, Madrid, Spain. 40. Servicio de Medicina Intensiva, Hospital Punta de Europa, Algeciras, Spain. 41. Intensive Care Clinical Unit, Hospital Universitario Virgen de Rocío, Sevilla, Spain. 42. Hospital Universitario Torrejón- Universidad Francisco de Vitoria, Madrid, Spain. 43. Intensive Care Department, Hospital Nuestra Señora de Gracia, Zaragoza, Spain. 44. Critical Care Department, Hospital Universitari Arnau de Vilanova; IRBLleida, Lleida, Spain. 45. Critical Care Department, Hospital del Mar-IMIM, Barcelona, Spain. 46. Hospital Universitario la Paz, Madrid, Spain. 47. Intensive Care Unit, Hospital Universitario La Princesa, Madrid, Spain. 48. Departamento de Biología Funcional. Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo; Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Central de Asturias, Oviedo, Spain. 49. Hospital Universitario y Politécnico la Fe, Valencia, Spain. 50. Hospital de Tortosa Verge de la Cinta, Tortosa, Tarragona, Spain. 51. Department of Intensive Care Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain. 52. Hospital Universitario Infanta Leonor, Madrid, Spain. 53. Servei de Medicina Intensiva, Hospital Universitari Germans Trias, Badalona, Spain. 54. Intensive Care Unit, Hospital Álvaro Cunqueiro, Vigo, Spain. 55. Hospital Universitari Joan XXIII de Tarragona, Tarragona, Spain. 56. Hospital de Mataró de Barcelona, Spain. 57. Unidad de Cuidados Intensivos, Hospital Universitario San Pedro de Alcántara, Cáceres, Spain. 58. Unidad de Cuidados Intensivos, Hospital Virgen Macarena, Sevilla, Spain. 59. Intensive Care Unit, Hospital Clínico y Universitario de Valencia, Valencia, Spain. 60. Translational Research in Respiratory Medicine, Respiratory Department, Hospital Universitari Aranu de Vilanova and Santa Maria, IRBLleida, Lleida, Spain.Postprint (published version

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profle of hepatocellular carcinoma (HCC) cells that show diferences in TGF-β expression. Oxygen consumption rate (OCR), extracellular acidifcation rate (ECAR), metabolomics and transcriptomics were performed. Results indicated that the switch from an epithelial to a mesenchymal/migratory phenotype in HCC cells is characterized by reduced mitochondrial respiration, without signifcant diferences in glycolytic activity. Concomitantly, enhanced glutamine anaplerosis and biosynthetic use of TCA metabolites were proved through analysis of metabolite levels, as well as metabolic fuxes from U-13C6-Glucose and U-13C5-Glutamine. This correlated with increase in glutaminase 1 (GLS1) expression, whose inhibition reduced cell migration. Experiments where TGF-β function was activated with extracellular TGF-β1 or inhibited through TGF-β receptor I silencing showed that TGF-β induces a switch from oxidative metabolism, coincident with a decrease in OCR and the upregulation of glutamine transporter Solute Carrier Family 7 Member 5 (SLC7A5) and GLS1. TGF-β also regulated the expression of key genes involved in the fux of glycolytic intermediates and fatty acid metabolism. Together, these results indicate that autocrine activation of the TGF-β pathway regulates oxidative metabolism in HCC cells

Risk factors associated with mortality among elderly patients with COVID-19: Data from 55 intensive care units in Spain

On behalf of CIBERESUCICOVID Project (COV20/00110ISCIII).Introduction and objectives: Critically-ill elderly ICU patients with COVID-19 have poor outcomes. We aimed to compare the rates of in-hospital mortality between non-elderly and elderly critically-ill COVID-19 ventilated patients, as well as to analyze the characteristics, secondary outcomes and independent risk factors associated with in-hospital mortality of elderly ventilated patients. Patients and Methods: We conducted a multicentre, observational cohort study including consecutive critically-ill patients admitted to 55 Spanish ICUs due to severe COVID-19 requiring mechanical ventilation (non-invasive respiratory support [NIRS; include non-invasive mechanical ventilation and high-flow nasal cannula] and invasive mechanical ventilation [IMV]) between February 2020 and October 2021. Results: Out of 5,090 critically-ill ventilated patients, 1,525 (27%) were aged =70 years (554 [36%] received NIRS and 971 [64%] received IMV. In the elderly group, median age was 74 years (interquartile range 72–77) and 68% were male. Overall in-hospital mortality was 31% (23% in patients <70 years and 50% in those =70 years; p<0.001). In-hospital mortality in the group =70 years significantly varied according to the modality of ventilation (40% in NIRS vs. 55% in IMV group; p<0.001). Factors independently associated with in-hospital mortality in elderly ventilated patients were age (sHR 1.07 [95%CI 1.05–1.10], p<0.001); previous admission within the last 30 days (sHR 1.40 [95%CI 1.04–1.89], p = 0.027); chronic heart disease (sHR 1.21 [95%CI 1.01–1.44], p = 0.041); chronic renal failure (sHR 1.43 [95%CI 1.12- 1.82], p = 0.005); platelet count (sHR 0.98 [95% CI 0.98–0.99], p<0.001); IMV at ICU admission (sHR 1.41 [95% CI 1.16- 1.73], p<0.001); and systemic steroids (sHR 0.61 [95%CI 0.48- 0.77], p<0.001). Conclusions: Amongst critically-ill COVID-19 ventilated patients, those aged =70 years presented significantly higher rates of in-hospital mortality than younger patients. Increasing age, previous admission within the last 30 days, chronic heart disease, chronic renal failure, platelet count, IMV at ICU admission and systemic steroids (protective) all comprised independent factors for in-hospital mortality in elderly patientsThis study was supported by the Instituto de Salud Carlos III de Madrid (COV20/00110, ISCIII); Fondo Europeo de Desarrollo Regional (FEDER); "Una manera de hacer Europa"; and Centro de Investigacion Biomédica En Red - Enfermedades Respiratorias (CIBERES). DdGC has received financial support from the Instituto de Salud Carlos III (Miguel Servet 2020:CP20/00041), co-funded by European Social Fund (ESF)/ “Investing in your future”. CC received a grant from the Fondo de Investigacion Sanitaria ( PI19/00207), Instituto de Salud Carlos III, co-funded by the European Union.Peer ReviewedCIBERESUCICOVID Project Investigators: Víctor D. Gumucio- Sanguino, Rafael Manez: Hospital Universitario de Bellvitge, Barcelona. Jordi Sole-Violan, Felipe Rodríguez de Castro: Hospital Dr. Negrín, Las Palmas. Fernando SuarezSipmann: Hospital Universitario La Princesa, Madrid. Ruth Noemí Jorge García, María Mora Aznar: Hospital Nuestra Senora de Gracia, Zaragoza. Mateu Torres, María Martinez, Cynthia Alegre, Jordi Riera, Sofía Contreras: Hospital Universitari Vall d’Hebron, Barcelona. Jesus Caballero, Javier Trujillano, Montse Vallverdu, Miguel Leon, Mariona Badía, Begona Balsera, Lluís Servia, Judit Vilanova, Silvia Rodríguez, Neus Montserrat, Silvia Iglesias, Javier Prados, Sula Carvalho, Mar Miralbes, Josman Monclou, Gabriel Jimenez, Jordi Codina, Estela Val, Pablo Pagliarani, Jorge Rubio, Dulce Morales, Andres Pujol, Angels Furro, Beatriz García, Gerard Torres, Javier Vengoechea, David de Gonzalo-Calvo, Jessica Gonzalez, Silvia Gomez: Hospital Universitari Arnau de Vilanova, Lleida. Jose M. Gomez: Hospital General Universitario Gregorio Marañon, Madrid. Nieves Franco: Hospital Universitario de Mostoles, Madrid. Jose Barberan: Hospital Universitario HM Montepríncipe. Guillermo M Albaiceta, Lorena Forcelledo Espina, Emilio García Prieto, Paula Martín Vicente, Cecilia del Busto Martínez: Hospital Universitario Central de Asturias, Oviedo. Pablo Vidal: Complexo Hospitalario Universitario de Ourense, Ourense. Jose Luis García Garmendia, María Aguilar Cabello, Carmen Eulalia Martínez Fernandez: Hospital San Juan de Dios del Aljarafe, Sevilla. Nieves Carbonell, María Luisa Blasco Cortes, Ainhoa Serrano Lazaro, Mar Juan Díaz: Hospital Clínic Universitari de Valencia, Valencia. Aaron Blandino Ortiz:Hospital Universitario Ramon y Cajal, Madrid. Rosario Menendez: Hospital La Fe de Valencia. Luis Jorge Valdivia: Hospital Universitario de Leon, Leon. María Victoria Boado: Hospital Universitario de Cruces, Barakaldo. Susana Sancho Chinesta: Hospital Universitario y Politecnico La Fe, Valencia. Maria del Carmen de la Torre: Hospital de Mataro. Ignacio Martínez Varela, María Teresa Bouza Vieiro, Ines Esmorís Arij on: Hospital Universitario Lucus Augusti, Lugo. David Campi Hermoso., Rafaela Nogueras Salinas., Teresa Farre Monjo., Ramon Nogue Bou., Gregorio Marco Naya., Carme Barbera, Nuria Ramon Coll: Hospital Universitari de Santa Maria, Lleida. Mercedes Catalan-Gonzalez, Juan Carlos Montejo-Gonzalez: Hospital Universitario 12 de Octubre, Madrid. Gloria Renedo SanchezGiron, Juan Bustamante-Munguira, Elena Bustamante-Munguira, Ramon Cicuendez Avila, Nuria Mamolar Herrera: Hospital Clínico Universitario, Valladolid. Raquel Almansa: Instituto de Investigacion Biomedica de Salamanca (IBSAL). Víctor Sagredo: Hospital Universitario de Salamanca, Salamanca. Jose Anon, Alexander Agrifoglio, Lucia Cachafeiro, Emilio Maseda: Hospital Universitario La Paz-Carlos III, Madrid. Lorenzo Socias, Mariana Andrea Novo, Albert Figueras, Maria Teresa Janer, Laura Soliva, Marta Ocon, Luisa Clar, J Ignacio Ayestaran: Hospital Universitario Son Espases, Palma de Mallorca. Yhivian Penasco, Sandra Campos Fernandez: Hospital Universitario Marques de Valdecilla, Santander. Mireia Serra-Fortuny, Eva Forcadell-Ferreres, Immaculada Salvador-Adell, Neus Bofill, Berta Adell-Serrano, Josep Pedregosa Díaz, Nuria Casacuberta-Barbera, Luis Urrelo-Cerron, Angels Piñol-Tena, Ferran Roche-Campo: Hospital Verge de la Cinta de Tortosa, Tortosa. Amalia Martínez de la Gandara, Pablo Ryan Murua, Covadonga Rodríguez Ruíz, Laura Carrion García, Juan I Lazo Alvarez: Hospital Universitario Infanta Leonor, Madrid. Jose Angel Lorente: Hospital Universitario de Getafe. Ana Loza-Vazquez, Desire Macias Guerrero: Hospital Universitario Virgen de Valme, Sevilla. Arturo Huerta, Daniel Tognetti: Clinica Sagrada Familia, Barcelona. Carlos García Redruello, David Mosquera Rodríguez, Eva María Menor Fernandez, Sabela Vara Adrio, Vanesa Gomez Casal, Marta Segura Pensado, María Digna Rivas Vilas, Amaia García Sagastume: Hospital de Vigo, Vigo. Raul de Pablo Sanchez, David Pesta na Laguna, Tommaso Bardi: Hospital Universitario Ramon y Cajal, Madrid. Rosario Amaya Villar, Carmen Gomez Gonzalez, Maria Luisa Gascon Castillo: Hospital Universitario Virgen del Rocio, Sevilla. Jose Garnacho-Montero, María Luisa Canton-Bulnes: Hospital Universitario Virgen Macarena, Sevilla. Judith Marin-Corral, Cristina Carbajales Perez: Hospital Alvaro Cunqueiro, Vigo. Joan Ramon Masclans, Ana Salazar Degracia, Judit Bigas, Rosana Munoz-Bermudez, Clara Vila-Vilardel, Francisco Parrilla, Irene Dot, Ana Zapatero, Yolanda Díaz, María Pilar Gracia, Purificacion Perez, Andrea Castellví, Cristina Climent: Hospital del Mar, Barcelona. Lidia Serra, Laura Barbena, Iosune Cano: Consorci Sanitari del Maresme, Barcelona. Pilar Ricart, Alba Herraiz, Pilar Marcos, Laura Rodríguez, Maria Teresa Sarinena, Ana Sanchez: Hospital Universitari Germans Trias i Pujol, Badalona. Alejandro Ubeda: Hospital Punta de Europa, Algeciras. María Cruz Martin Delgado: Hospital Universitario Torrejon-Universidad Francisco de Vitoria, Madrid. Elena Gallego, Juan Fernando Masa Jimenez: Hospital Universitario San Pedro de Alcantara, Caceres. Gemma Goma, Emi Díaz: Hospital Parc Taulí, Sabadell. Mercedes Ibarz, Diego De Mendoza: Hospital Universitari Sagrat Cor, Bacelona. Enric Barbeta, Victoria Alcaraz-Serrano, Joan Ramon Badia, Manuel Castella, Leticia Bueno, Adrian Ceccato, Andrea Palomeque, Laia Fernandez Barat, Catia Cilloniz, Pamela Conde, Javier Fernandez, Albert Gabarrus, Karsa Kiarostami, Alexandre Lopez- Gavín, Cecilia L Mantellini, Carla Speziale, Nil Vazquez, Hua Yang, Minlan Yang, Carlos Ferrando, Pedro Castro, Marta Arrieta, Jose Maria Nicolas, Rut Andrea: Hospital Clinic, Barcelona. Marta Barroso, Raquel Perez, Sergio Alvarez, Dario Garcia-Gasulla, Adrian Tormos: Barcelona supercomputing Center, Barcelona. Luis Tamayo Lomas, Cesar Aldecoa, Ruben Herran-Monge, Jose Angel Berezo García, Pedro Enríquez Giraudo: Hospital Rio Hortega, Valladolid. Pablo Cardinal Fernandez, Alberto Rubio Lopez, Orville Baez Pravia: Hospitales HM, Madrid. Juan Lopez Messa, Leire Perez Bastida, Antonjo Alvarez Ruiz: Complejo Asistencial Universitario de Palencia, Palencia. Jose Trenado, Anna Parera Pous: Hospital Universitari MutuaTerrassa, Terrassa. Cristobal Galban, Ana Lopez Lago, Eva Saborido Paz, Patricia Barral Segade: Hospital de Santiago de Compostela, Santiago. Ana Balan Marino, Manuel Valledor Mendez: Hospital San Agustin, Aviles. Raul de Frutos, Luciano Aguilera: Hospital Basurto, Basurto. Felipe Perez-García, Esther Lopez-Ramos, Angela Leonor Ruiz-García, Belen Betere: Hospital Universitario Principe Asturias, Alcala de Henares. Rafael Blancas: Hospital Universitario del Tajo, Aranjuez. Cristina Dolera, Gloria Perez Planelles, Enrique Marmol Peis, Maria Dolores Martinez Juan, Miriam Ruiz Miralles, Eva Perez Rubio, Maria Van der Hofstadt MartinMontalvo, Angel Sanchez-Miralles, Tatiana Villada Warrington: Hospital Universitario Sant Joan d’Alacant, Alicante. Juan Carlos Pozo-Laderas: Hospital Universitario Reina Sofia. Angel Estella, Sara Guadalupe Moreno Cano: Hospital de Jerez, Jerez. Federico Gordo: Hospital Universitario del Henares, Coslada. Basilisa Martinez Palacios: Hospital Universitario Infanta Cristina, Parla. Maite Nieto, Maria Teresa Nieto: Hospital de Segovia, Segovia. Sergio Ossa: Hospital de Burgos, Burgos. Ana Ortega: Hospital Montecelo, Pontevedra. Miguel Sanchez: Hospital Clinico, Madrid. Bitor Santacoloma: Hospital Galdakao, Galdakao.Postprint (published version

Identification of circulating microRNA profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS

There is a limited understanding of the pathophysiology of postacute pulmonary sequelae in severe COVID-19. The aim of current study was to define the circulating microRNA (miRNA) profiles associated with pulmonary function and radiologic features in survivors of SARS-CoV-2-induced ARDS. The study included patients who developed ARDS secondary to SARS-CoV-2 infection (n = 167) and a group of infected patients who did not develop ARDS (n = 33). Patients were evaluated 3 months after hospital discharge. The follow-up included a complete pulmonary evaluation and chest computed tomography. Plasma miRNA profiling was performed using RT-qPCR. Random forest was used to construct miRNA signatures associated with lung diffusing capacity for carbon monoxide (DLCO) and total severity score (TSS). Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted. DLCO < 80% predicted was observed in 81.8% of the patients. TSS showed a median [P25;P75] of 5 [2;8]. The miRNA model associated with DLCO comprised miR-17-5p, miR-27a-3p, miR-126-3p, miR-146a-5p and miR-495-3p. Concerning radiologic features, a miRNA signature composed by miR-9-5p, miR-21-5p, miR-24-3p and miR-221-3p correlated with TSS values. These associations were not observed in the non-ARDS group. KEGG pathway and GO enrichment analyses provided evidence of molecular mechanisms related not only to profibrotic or anti-inflammatory states but also to cell death, immune response, hypoxia, vascularization, coagulation and viral infection. In conclusion, diffusing capacity and radiological features in survivors from SARS-CoV-2-induced ARDS are associated with specific miRNA profiles. These findings provide novel insights into the possible molecular pathways underlying the pathogenesis of pulmonary sequelae.This work is supported by Instituto de Salud Carlos III (COV20/00110), co-funded by European Regional Development Fund (ERDF)/“A way to make Europe”. CIBERES is an initiative of the Instituto de Salud Carlos III. Suported by: Programa de donaciones “estar preparados” UNESPA (Madrid, Spain) and Fundación Francisco Soria Melguizo (Madrid, Spain). Supported by La Fundació La Marató de TV3, projecte amb codi 202108-30/-31. COVIDPONENT is funded by Institut Català de la Salut and Gestió de Serveis Sanitaris. MM is the recipient of a predoctoral fellowship (PFIS: FI21/00187) from Instituto de Salud Carlos III. MCGH is the recipient of a predoctoral fellowship from “University of Lleida”. DdGC has received financial support from Instituto de Salud Carlos III (Miguel Servet 2020: CP20/00041), co-funded by the European Social Fund (ESF)/“Investing in your future”. AC acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Sara Borrell 2021: CD21/00087). ENL and GL were funded by COVID1005 and ACT210085 from National Agency of Investigation & Development & Development (ANID), Chil

A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study

Background: The identification of critically ill COVID-19 patients at risk of fatal outcomes remains a challenge. Here, we first validated candidate microRNAs (miRNAs) as biomarkers for clinical decision-making in critically ill patients. Second, we constructed a blood miRNA classifier for the early prediction of adverse outcomes in the ICU. Methods: This was a multicenter, observational and retrospective/prospective study including 503 critically ill patients admitted to the ICU from 19 hospitals. qPCR assays were performed in plasma samples collected within the first 48 h upon admission. A 16-miRNA panel was designed based on recently published data from our group. Results: Nine miRNAs were validated as biomarkers of all-cause in-ICU mortality in the independent cohort of critically ill patients (FDR < 0.05). Cox regression analysis revealed that low expression levels of eight miRNAs were associated with a higher risk of death (HR from 1.56 to 2.61). LASSO regression for variable selection was used to construct a miRNA classifier. A 4-blood miRNA signature composed of miR-16-5p, miR-192-5p, miR-323a-3p and miR-451a predicts the risk of all-cause in-ICU mortality (HR 2.5). Kaplan‒Meier analysis confirmed these findings. The miRNA signature provides a significant increase in the prognostic capacity of conventional scores, APACHE-II (C-index 0.71, DeLong test p-value 0.055) and SOFA (C-index 0.67, DeLong test p-value 0.001), and a risk model based on clinical predictors (C-index 0.74, DeLong test-p-value 0.035). For 28-day and 90-day mortality, the classifier also improved the prognostic value of APACHE-II, SOFA and the clinical model. The association between the classifier and mortality persisted even after multivariable adjustment. The functional analysis reported biological pathways involved in SARS-CoV infection and inflammatory, fibrotic and transcriptional pathways. Conclusions: A blood miRNA classifier improves the early prediction of fatal outcomes in critically ill COVID-19 patients.11 página

Effects of intubation timing in patients with COVID-19 throughout the four waves of the pandemic : a matched analysis

The primary aim of our study was to investigate the association between intubation timing and hospital mortality in critically ill patients with COVID-19-associated respiratory failure. We also analysed both the impact of such timing throughout the first four pandemic waves and the influence of prior non-invasive respiratory support on outcomes. This is a secondary analysis of a multicentre, observational and prospective cohort study that included all consecutive patients undergoing invasive mechanical ventilation due to COVID-19 from across 58 Spanish intensive care units (ICU) participating in the CIBERESUCICOVID project. The study period was between 29 February 2020 and 31 August 2021. Early intubation was defined as that occurring within the first 24 h of intensive care unit (ICU) admission. Propensity score (PS) matching was used to achieve balance across baseline variables between the early intubation cohort and those patients who were intubated after the first 24 h of ICU admission. Differences in outcomes between early and delayed intubation were also assessed. We performed sensitivity analyses to consider a different timepoint (48 h from ICU admission) for early and delayed intubation. Of the 2725 patients who received invasive mechanical ventilation, a total of 614 matched patients were included in the analysis (307 for each group). In the unmatched population, there were no differences in mortality between the early and delayed groups. After PS matching, patients with delayed intubation presented higher hospital mortality (27.3% versus 37.1%, p =0.01), ICU mortality (25.7% versus 36.1%, p=0.007) and 90-day mortality (30.9% versus 40.2%, p=0.02) when compared to the early intubation group. Very similar findings were observed when we used a 48-hour timepoint for early or delayed intubation. The use of early intubation decreased after the first wave of the pandemic (72%, 49%, 46% and 45% in the first, second, third and fourth wave, respectively; first versus second, third and fourth waves p<0.001). In both the main and sensitivity analyses, hospital mortality was lower in patients receiving high-flow nasal cannula (n=294) who were intubated earlier. The subgroup of patients undergoing NIV (n=214) before intubation showed higher mortality when delayed intubation was set as that occurring after 48 h from ICU admission, but not when after 24 h. In patients with COVID-19 requiring invasive mechanical ventilation, delayed intubation was associated with a higher risk of hospital mortality. The use of early intubation significantly decreased throughout the course of the pandemic. Benefits of such an approach occurred more notably in patients who had received high-flow nasal cannul

Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study

Background The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Methods Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Findings Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p<0.01). Interpretation Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd