ICU-acquired pneumonia is associated with poor health post-COVID-19 syndrome

Some patients previously presenting with COVID-19 have been reported to develop persistent COVID-19 symptoms. While this information has been adequately recognised and extensively published with respect to non-critically ill patients, less is known about the incidence and factors associated with the characteristics of persistent COVID-19. On the other hand, these patients very often have intensive care unit-acquired pneumonia (ICUAP). A second infectious hit after COVID increases the length of ICU stay and mechanical ventilation and could have an influence on poor health post-COVID 19 syndrome in ICU-discharged patients. Methods: This prospective, multicentre, and observational study was carrid out across 40 selected ICUs in Spain. Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated three months after hospital discharge. Results: A total of 1255 ICU patients were scheduled to be followed up at 3 months; however, the final cohort comprised 991 (78.9%) patients. A total of 315 patients developed ICUAP (97% of them had ventilated ICUAP). Patients requiring invasive mechanical ventilation had more persistent post-COVID-19 symptoms than those who did not require mechanical ventilation. Female sex, duration of ICU stay, development of ICUAP, and ARDS were independent factors for persistent poor health post-COVID-19. Conclusions: Persistent post-COVID-19 symptoms occurred in more than two-thirds of patients. Female sex, duration of ICU stay, development of ICUAP, and ARDS all comprised independent factors for persistent poor health post-COVID-19. Prevention of ICUAP could have beneficial effects in poor health post-COVID-19.Financial support was provided by the Instituto Carlos III de Madrid (COV20/00110, ISCIII) and by the Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES). DdGC has received financial support from 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 53 autors/es: Ignacio Martin-Loeches (1,2,3), Anna Motos (1,3), Rosario Menéndez (1,4), Albert Gabarrús (1,4), Jessica González (5,6), Laia Fernández-Barat (1,3), Adrián Ceccato (1,3), Raquel Pérez-Arnal (7), Dario García-Gasulla (7), Ricard Ferrer (1,8), Jordi Riera (1,8), José Ángel Lorente (1,9), Óscar Peñuelas (1,9), Jesús F. Bermejo-Martin (1,10,11), David de Gonzalo-Calvo (5,6), Alejandro Rodríguez (12), Ferran Barbé (5,6), Luciano Aguilera (13), Rosario Amaya-Villar (14), Carme Barberà (15), José Barberán (16), Aaron Blandino Ortiz (17), Elena Bustamante-Munguira (18), Jesús Caballero (19), Cristina Carbajales (20), Nieves Carbonell (21),Mercedes Catalán-González (22), Cristóbal Galbán (23), Víctor D. Gumucio-Sanguino (24), Maria del Carmen de la Torre (25), Emili Díaz (26), Elena Gallego (27), José Luis García Garmendia (28), José Garnacho-Montero (29), José M. Gómez (30), Ruth Noemí Jorge García (31), Ana Loza-Vázquez (32), Judith Marín-Corral (33), Amalia Martínez de la Gándara (34), Ignacio Martínez Varela (35), Juan Lopez Messa (36), Guillermo M. Albaiceta (37,38), Mariana Andrea Novo (39), Yhivian Peñasco (40), Pilar Ricart (41), Luis Urrelo-Cerrón (42), Angel Sánchez-Miralles (43), Susana Sancho Chinesta (44), Lorenzo Socias (45), Jordi Solé-Violan (1,46), Luis Tamayo Lomas (47), Pablo Vidal (48) and Antoni Torres (1,3)*, on behalf of CIBERESUCICOVID Project (COV20/00110 and ISCIII) // (1) CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, 28029 Madrid, Spain; (2) Pulmonary Department, Hospital Clinic, Universitat de Barcelona, IDIBAPS, 08036 Barcelona, Spain; (3) Department of Intensive Care Medicine, St. James’s Hospital, Multidisciplinary Intensive Care Research Organization (MICRO), James’s Street, D08 NHY1 Dublin, Ireland; (4) Pulmonary Department, University and Polytechnic Hospital La Fe, 46026 Valencia, Spain; (5) Translational Research in Respiratory Medicine Group (TRRM), Lleida Biomedical Research Institute (IRBLleida), 25198 Lleida, Spain; (6) Pulmonary Department, Hospital Universitari Arnau de Vilanova and Santa Maria, 25198 Lleida, Spain; (7) Barcelona Supercomputing Centre (BSC), 08034 Barcelona, Spain; (8) Intensive Care Department, Vall d’Hebron Hospital Universitari, SODIR Research Group, Vall d’Hebron Institut de Recerca (VHIR), 08035 Barcelona, Spain; (9) Hospital Universitario de Getafe, 28905 Madrid, Spain; (10) Hospital Universitario Río Hortega de Valladolid, 47012 Valladolid, Spain; (11) Instituto de Investigación Biomédica de Salamanca (IBSAL), Gerencia Regional de Salud de Castilla y León, 47007 Valladolid, Spain; (12) Critical Care Department, Hospital Joan XXIII, 43005 Tarragona, Spain; (13) Anestesia, Reanimación y Terapia del Dolor, Hospital Universitario de Basurto, 48013 Bilbao, Spain; (14) Intensive Care Clinical Unit, Hospital Universitario Virgen de Rocío, 41013 Sevilla, Spain; (15) Hospital Santa Maria, IRBLleida, 25198 Lleida, Spain; (16) Critical Care Department, Hospital Universitario HM Montepríncipe, Universidad San Pablo-CEU, 28660 Madrid, Spain; (17) Servicio de Medicina Intensiva, Hospital Universitario Ramón y Cajal, 28034 Madrid, Spain; (18) Department of Intensive Care Medicine, Hospital Clínico Universitario Valladolid, 47003 Valladolid, Spain; (19) Critical Care Department, Hospital Universitari Arnau de Vilanova, IRBLleida, 25198 Lleida, Spain; (20) Hospital Álvaro Cunqueiro, 36213 Vigo, Spain; (21) Intensive Care Unit, Hospital Clínico y Universitario de Valencia, 46010 Valencia, Spain; (22) Department of Intensive Care Medicine, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain, (23) Department of Medicine, CHUS, Complejo Hospitalario Universitario de Santiago, 15076 Santiago de Compostela, Spain; (24) Department of Intensive Care, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, 08907 Barcelona, Spain; (25) Hospital de Mataró de Barcelona, 08301 Mataró, Spain; (26) Department of Medicine, Universitat Autònoma de Barcelona (UAB), Critical Care Department, Corpo-Ració Sanitària Parc Taulí, Sabadell, 08208 Barcelona, Spain; (27) Unidad de Cuidados Intensivos, Hospital San Pedro de Alcántara, 10003 Cáceres, Spain; (28) Intensive Care Unit, Hospital San Juan de Dios del Aljarafe, 41930 Sevilla, Spain; (29) Intensive Care Clinical Unit, Hospital Universitario Virgen Macarena, 41009 Seville, Spain; (30) Hospital General Universitario Gregorio Marañón, 28009 Madrid, Spain; (31) Intensive Care Department, Hospital Nuestra Señora de Gracia, 50009 Zaragoza, Spain; (32) Unidad de Medicina Intensiva, Hospital Universitario Virgen de Valme, 41014 Sevilla, Spain; (33) Critical Care Department, Hospital del Mar-IMIM, 08003 Barcelona, Spain; (34) Department of Intensive Medicine, Hospital Universitario Infanta Leonor, 28031 Madrid, Spain; (35) Critical Care Department, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain; (36) Critical Care Department, Complejo Asistencial Universitario de Palencia, 34005 Palencia, Spain; (37) Departamento de Biología Funcional, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, 33011 Oviedo, Spain; (38) Instituto de Investigación Sanitaria del Principado de Asturias, Hospital Central de Asturias, 33011 Oviedo, Spain; (39) Servei de Medicina Intensiva, Hospital Universitari Son Espases, Palma de Mallorca, 07120 Illes Balears, Spain; (40) Servicio de Medicina Intensiva, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain; (41) Servei de Medicina Intensiva, Hospital Universitari Germans Trias, 08916 Badalona, Spain; (42) Hospital Verge de la Cinta, 08916 Tortosa, Spain; (43) Hospital de Sant Joan d’Alacant, 03550 Alacant, Spain; (44) Servicio de Medicina Intensiva, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain; (45) Intensive Care Unit, Hospital Son Llàtzer, Palma de Mallorca, 07198 Illes Balears, Spain; (46) Critical Care Department, Hospital Dr. Negrín., 35019 Las Palmas de GC, Spain; (47) Critical Care Department, Hospital Universitario Río Hortega de Valladolid, 47102 Valladolid, Spain; (48) Intensive Care Unit, Complexo Hospitalario Universitario de Ourense, 32005 Ourense, Spain.Postprint (published version

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

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

Pulmonary function and radiologic features in survivors of critical COVID-19: a 3-month prospective cohort

© 2021 Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/BACKGROUND: More than 20% of hospitalized patients with COVID-19 demonstrate ARDS requiring ICU admission. The long-term respiratory sequelae in such patients remain unclear. RESEARCH QUESTION: What are the major long-term pulmonary sequelae in critical patients who survive COVID-19? STUDY DESIGN AND METHODS: Consecutive patients with COVID-19 requiring ICU admission were recruited and evaluated 3 months after hospitalization discharge. The follow-up comprised symptom and quality of life, anxiety and depression questionnaires, pulmonary function tests, exercise test (6-min walking test [6MWT]), and chest CT imaging. RESULTS: One hundred twenty-five patients admitted to the ICU with ARDS secondary to COVID- 19 were recruited between March and June 2020. At the 3-month follow-up, 62 patients were available for pulmonary evaluation. The most frequent symptoms were dyspnea (46.7%) and cough (34.4%). Eighty-two percent of patients showed a lung diffusing capacity of less than 80%. The median distance in the 6MWT was 400 m (interquartile range, 362-440 m). CT scans showed abnormal results in 70.2% of patients, demonstrating reticular lesions in 49.1% and fibrotic patterns in 21.1%. Patients with more severe alterations on chest CT scan showed worse pulmonary function and presented more degrees of desaturation in the 6MWT. Factors associated with the severity of lung damage on chest CT scan were age and length of invasive mechanical ventilation during the ICU stay. INTERPRETATION: Three months after hospital discharge, pulmonary structural abnormalities and functional impairment are highly prevalent in patients with ARDS secondary to COVID- 19 who required an ICU stay. Pulmonary evaluation should be considered for all critical COVID-19 survivors 3 months after discharge.This study was supported in part by the Instituto de Salud Carlos III [Grant CIBERESUCICOVID, COV20/00110] and was cofunded by European Regional Development Funds, “Una manera de hacer Europa.” D. d. G.-C. has received financial support from the Instituto de Salud Carlos III [Grant Miguel Servet 2020: CP20/00041], co-funded by the European Social Fund “Investing in Your Future.” L. P. acknowledges receiving financial support from the Ministry of Science, Innovation and Universities for the Training of University Lecturers (FPU19 / 03526).Peer ReviewedPostprint (author's final draft

Novel Antimicrobial Agents and Therapeutic Approaches for Nosocomial pneumonia Caused by Pseudomonas aeruginosa

[eng] INTRODUCTION: Nosocomial pneumonia caused by Pseudomonas aeruginosa is associated with high mortality and morbidity. Furthermore, the high incidence of multi-resistance to antimicrobials makes both empirical and targeted treatment a complex decision for clinicians. Various strategies have been proposed, including optimization of the concentration of antimicrobials via nebulization or through a better study of penetration at the lung level; as well as the use of new antimicrobial combinations such as ceftolozane-tazobactam, meropenem-nacubactam. OBJECTIVES: The key objectives were to: (i) clarify whether pharmacokinetic models constructed with locally comprehensive profiles (ELF) can lead to more precise estimates; (ii) elucidate the benefits of appropriate empiric antimicrobial treatment with ceftolozane- tazobactam compared to inappropriate empiric treatment; (iii) evaluate the efficacy of the antimicrobial combination of meropenem-nacubactam in P. aeruginosa strains that express KPC and overproduce AmpC; (iv) analyze the role of nebulized amikacin/fosfomycin as adjuvant therapy, compared to intravenous administration of meropenem in nosocomial pneumonia caused by P. aeruginosa. MATERIALS AND METHODS: The studies included in this doctoral thesis were primarily based on a porcine model of severe pneumonia and a lung infection model in neutropenic mice. The animals were inoculated with different strains of P. aeruginosa, to subsequently be randomized and treated depending on the design of each study. Microbiological, histological, inflammatory results and clinical parameters were analyzed. In addition, pharmacokinetic and pharmacodynamic analyzes were performed. MAIN RESULTS AND CONCLUSIONS: The main findings were that: (i) ELF models built with concentrations at dispersed points result in estimates similar to those built from concentrated profiles; (ii) appropriate initial treatment with ceftolozane- tazobactam decreased the bacterial load in respiratory secretions, prevented the development of resistance and achieved the therapeutic objective at the pharmacodynamic level; (iii) the addition of nacubactam to meropenem resulted in a substantial bacterial reduction in P. aeruginosa counts; (iv) and it was confirmed that nebulized amikacin/fosfomycin reduces the presence of P. aeruginosa in tracheal secretions and limits the development of resistance, but has negligible efficacy in lung tissue.[spa] INTRODUCCIÓN: La neumonía nosocomial causada por Pseudomonas aeruginosa está asociada a una alta mortalidad morbilidad. Además, la elevada incidencia de multirresistencias a los antimicrobianos, hacen que el tratamiento tanto empírico como dirigido sea una decisión compleja para los clínicos. Diversas estrategias se han planteado entre las que figuran la optimización de la concentración de los antimicrobianos vía la nebulización o través de un mejor estudio de la penetración a nivel pulmonar; así como el uso de nuevas combinaciones antimicrobianas como son ceftolozane-tazobactam, meropenem- nacubactam. OBJETIVOS: Los objetivos fundamentales fueron: (i) esclarecer si los modelos farmacocinéticos construidos con perfiles completos a nivel local (ELF, por sus siglas en inglés) pueden conducir a estimaciones más precisas; (ii) elucidar los beneficios del tratamiento antimicrobiano empírico apropiado con ceftolozane- tazobactam en comparación con el tratamiento empírico inapropiado; (iii) evaluar la eficacia de la combinación antimicrobiana de meropenem-nacubactam en cepas de P. aeruginosa que expresan KPC y sobreproducen AmpC; (iv) analizar el papel de la amikacina/fosfomicina nebulizada como terapia adyuvante, en comparación con la administración de intravenosa de meropenem en la neumonía nosocomial causada por P. aeruginosa. MATERIALES Y MÉTODOS: Los estudios incluidos en esta tesis doctoral se basaron fundamentalmente en un modelo porcino de neumonía grave y en un modelo de infección pulmonar en ratones neutropénicos. Los animales se inocularon con diferentes cepas de P. aeruginosa, para posteriormente ser randomizados y tratados en función del diseño de cada estudio. Se analizaron los resultados microbiológicos, histológicos, inflamatorios y parámetros clínicos. Además, se realizaron análisis farmacocinéticos y farmacodinámicos. PRINCIPALES RESULTADOS Y CONCLUSIONES: Los principales hallazgos fueron que: (i) los modelos ELF construidos con concentraciones en puntos dispersos dan como resultado estimaciones similares a los construidos a partir de perfiles concentrados; (ii) el tratamiento inicial apropiado con ceftolozane- tazobactam disminuyó la carga bacteriana en las secreciones respiratorias, evitó el desarrollo de resistencias y logró el objetivo terapéutico a nivel farmacodinámico; (iii) la adición de nacubactam a meropenem resultó en una reducción bacteriana sustancial en los recuentos de P. aeruginosa; (iv) y se corroboró que la amikacina/fosfomicina nebulizadas reduce la presencia de P. aeruginosa en las secreciones traqueales y limita el desarrollo de resistencias, pero tiene una eficacia insignificante en el tejido pulmonar

Novel Antimicrobial Agents and Therapeutic Approaches for Nosocomial pneumonia Caused by Pseudomonas aeruginosa

Programa de Doctorat en Medicina i Recerca Translacional[eng] INTRODUCTION: Nosocomial pneumonia caused by Pseudomonas aeruginosa is associated with high mortality and morbidity. Furthermore, the high incidence of multi-resistance to antimicrobials makes both empirical and targeted treatment a complex decision for clinicians. Various strategies have been proposed, including optimization of the concentration of antimicrobials via nebulization or through a better study of penetration at the lung level; as well as the use of new antimicrobial combinations such as ceftolozane-tazobactam, meropenem-nacubactam. OBJECTIVES: The key objectives were to: (i) clarify whether pharmacokinetic models constructed with locally comprehensive profiles (ELF) can lead to more precise estimates; (ii) elucidate the benefits of appropriate empiric antimicrobial treatment with ceftolozane- tazobactam compared to inappropriate empiric treatment; (iii) evaluate the efficacy of the antimicrobial combination of meropenem-nacubactam in P. aeruginosa strains that express KPC and overproduce AmpC; (iv) analyze the role of nebulized amikacin/fosfomycin as adjuvant therapy, compared to intravenous administration of meropenem in nosocomial pneumonia caused by P. aeruginosa. MATERIALS AND METHODS: The studies included in this doctoral thesis were primarily based on a porcine model of severe pneumonia and a lung infection model in neutropenic mice. The animals were inoculated with different strains of P. aeruginosa, to subsequently be randomized and treated depending on the design of each study. Microbiological, histological, inflammatory results and clinical parameters were analyzed. In addition, pharmacokinetic and pharmacodynamic analyzes were performed. MAIN RESULTS AND CONCLUSIONS: The main findings were that: (i) ELF models built with concentrations at dispersed points result in estimates similar to those built from concentrated profiles; (ii) appropriate initial treatment with ceftolozane- tazobactam decreased the bacterial load in respiratory secretions, prevented the development of resistance and achieved the therapeutic objective at the pharmacodynamic level; (iii) the addition of nacubactam to meropenem resulted in a substantial bacterial reduction in P. aeruginosa counts; (iv) and it was confirmed that nebulized amikacin/fosfomycin reduces the presence of P. aeruginosa in tracheal secretions and limits the development of resistance, but has negligible efficacy in lung tissue.[spa] INTRODUCCIÓN: La neumonía nosocomial causada por Pseudomonas aeruginosa está asociada a una alta mortalidad morbilidad. Además, la elevada incidencia de multirresistencias a los antimicrobianos, hacen que el tratamiento tanto empírico como dirigido sea una decisión compleja para los clínicos. Diversas estrategias se han planteado entre las que figuran la optimización de la concentración de los antimicrobianos vía la nebulización o través de un mejor estudio de la penetración a nivel pulmonar; así como el uso de nuevas combinaciones antimicrobianas como son ceftolozane-tazobactam, meropenem- nacubactam. OBJETIVOS: Los objetivos fundamentales fueron: (i) esclarecer si los modelos farmacocinéticos construidos con perfiles completos a nivel local (ELF, por sus siglas en inglés) pueden conducir a estimaciones más precisas; (ii) elucidar los beneficios del tratamiento antimicrobiano empírico apropiado con ceftolozane- tazobactam en comparación con el tratamiento empírico inapropiado; (iii) evaluar la eficacia de la combinación antimicrobiana de meropenem-nacubactam en cepas de P. aeruginosa que expresan KPC y sobreproducen AmpC; (iv) analizar el papel de la amikacina/fosfomicina nebulizada como terapia adyuvante, en comparación con la administración de intravenosa de meropenem en la neumonía nosocomial causada por P. aeruginosa. MATERIALES Y MÉTODOS: Los estudios incluidos en esta tesis doctoral se basaron fundamentalmente en un modelo porcino de neumonía grave y en un modelo de infección pulmonar en ratones neutropénicos. Los animales se inocularon con diferentes cepas de P. aeruginosa, para posteriormente ser randomizados y tratados en función del diseño de cada estudio. Se analizaron los resultados microbiológicos, histológicos, inflamatorios y parámetros clínicos. Además, se realizaron análisis farmacocinéticos y farmacodinámicos. PRINCIPALES RESULTADOS Y CONCLUSIONES: Los principales hallazgos fueron que: (i) los modelos ELF construidos con concentraciones en puntos dispersos dan como resultado estimaciones similares a los construidos a partir de perfiles concentrados; (ii) el tratamiento inicial apropiado con ceftolozane- tazobactam disminuyó la carga bacteriana en las secreciones respiratorias, evitó el desarrollo de resistencias y logró el objetivo terapéutico a nivel farmacodinámico; (iii) la adición de nacubactam a meropenem resultó en una reducción bacteriana sustancial en los recuentos de P. aeruginosa; (iv) y se corroboró que la amikacina/fosfomicina nebulizadas reduce la presencia de P. aeruginosa en las secreciones traqueales y limita el desarrollo de resistencias, pero tiene una eficacia insignificante en el tejido pulmonar