A blood microRNA classifier for the prediction of ICU mortality in COVID-19 patients: a multicenter validation study
David De Gonzalo-Calvo, Marta Molinero, Iván D Benítez, Manel Perez-Pons, Nadia García-Mateo, Alicia Ortega, Tamara Postigo, María C García-Hidalgo, Thalia Belmonte, Carlos Rodríguez-Muñoz, Jessica González, Gerard Torres, Clara Gort-Paniello, Anna Moncusí-Moix, Ángel Estella, Luis Tamayo Lomas, Amalia Martínez De La Gándara, Lorenzo Socias, Yhivian Peñasco, Maria Del Carmen De La Torre, Elena Bustamante-Munguira, Elena Gallego Curto, Ignacio Martínez Varela, María Cruz Martin Delgado, Pablo Vidal-Cortés, Juan López Messa, Felipe Pérez-García, Jesús Caballero, José M Añón, Ana Loza-Vázquez, Nieves Carbonell, Judith Marin-Corral, Ruth Noemí Jorge García, Carmen Barberà, Adrián Ceccato, Laia Fernández-Barat, Ricard Ferrer, Dario Garcia-Gasulla, Jose Ángel Lorente-Balanza, Rosario Menéndez, Ana Motos, Oscar Peñuelas, Jordi Riera, Jesús F Bermejo-Martin, Antoni Torres, Ferran Barbé
Respiratory Research, doi:10.1186/s12931-023-02462-x
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
Abbreviations
Declarations Ethics approval and consent to participate The study protocol was approved by the respective ethics committee of each participating hospital. The study was designed and conducted in compliance with the Declaration of Helsinki and national and international law on data protection.
Consent for publication Not applicable.
Competing interests The authors declare no competing interests.
Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
Battaglini, Lopes-Pacheco, Castro-Faria-Neto, Pelosi, Rocco, Laboratory biomarkers for diagnosis and prognosis in COVID-19, Front Immunol
Blanco-Domínguez, Sánchez-Díaz, De La Fuente, Borreguero, Matesanz-Marín et al., A Novel circulating MicroRNA for the detection of Acute Myocarditis, N Engl J Med
Carbonell, Urgelés, Rodríguez, Bodí, Martín-Loeches et al., Mortality comparison between the first and second/third waves among 3,795 critical COVID-19 patients with pneumonia admitted to the ICU: a multicentre retrospective cohort study, Lancet Reg Health-Eur
De Bruin, Bos, Van Roon, Boer, Schuurman et al., Clinical features and prognostic factors in Covid-19: a prospective cohort study, EBioMedicine
De Gonzalo-Calvo, Benítez, Pinilla, Carratalá, Moncusí-Moix et al., Circulating microRNA profiles predict the severity of COVID-19 in hospitalized patients, Transl Res
Devaux, Pinet, De Gonzalo-Calvo, The non-coding transcriptome as a New Player in Intercellular Communication, Front Mol Biosci
Dongelmans, Termorshuizen, Brinkman, Bakhshi-Raiez, Arbous et al., Characteristics and outcome of COVID-19 patients admitted to the ICU: a nationwide cohort study on the comparison between the first and the consecutive upsurges of the second wave of the COVID-19 pandemic in the Netherlands, Ann Intensive Care
Evangelou, Veroutis, Paschalaki, Foukas, Lagopati et al., Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis, Eur Respir J
Fernández-Pato, Virseda-Berdices, Resino, Ryan, Martínez-González et al., Plasma miRNA profile at COVID-19 onset predicts severity status and mortality, Emerg Microbes Infect
Giuliani, Matacchione, Ramini, Di Rosa, Bonfigli et al., Circulating miR-320b and mir-483-5p levels are associated with COVID-19 in-hospital mortality, Mech Ageing Dev
Gorog, Storey, Gurbel, Tantry, Berger et al., Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 thrombosis biomarkers Colloquium, Nat Rev Cardiol
Gustafson, Ngai, Wu, Hou, Schoffel et al., Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies, EBioMedicine
Hermine, Porcher, Resche-Rigon, Tharaux, Ravaud, Effect of interleukin-6 receptor antagonists in critically ill adult patients with COVID-19 pneumonia: two randomised controlled trials of the CORI-MUNO-19 collaborative group, Eur Respir J
Hothorn, Lausen, On the exact distribution of maximally selected rank statistics, Comput Stat Data Anal
Kim, Park, Kang, Lee, Kim et al., Expression analyses of MicroRNAs in Hamster lung tissues infected by SARS-CoV-2, Mol Cells
Magen, Yacovzada, Yanowski, Coenen-Stass, Grosskreutz et al., Circulating miR-181 is a prognostic biomarker for amyotrophic lateral sclerosis, Nat Neurosci
Matarese, Gambardella, Sardu, Santulli, miR-98 regulates TMPRSS2 expression in human endothelial cells: key implications for COVID-19, Biomedicines
Mcdonald, Enguita, Taylor, Griffin, Priebe et al., Role of miR-2392 in driving SARS-CoV-2 infection, Cell Rep
Molinero, Benítez, González, Gort-Paniello, Moncusí-Moix et al., Bronchial aspirate-based profiling identifies MicroRNA Signatures Associated with COVID-19 and Fatal Disease in critically ill patients, Front Med (Lausanne)
Pinilla, Barbé, De, Calvo, MicroRNAs to guide medical decisionmaking in obstructive sleep apnea: a review, Sleep Med Rev
Poore, Ko, Valente, Henao, Sumner et al., A miRNA host response signature accurately discriminates Acute respiratory infection etiologies, Front Microbiol
Raut, Schöttker, Holleczek, Guo, Bhardwaj et al., A microRNA panel compared to environmental and polygenic scores for colorectal cancer risk prediction, Nat Commun
Recchiuti, Patruno, Mattoscio, Isopi, Pomilio et al., Resolvin D1 and D2 reduce SARS-CoV-2-induced inflammatory responses in cystic fibrosis macrophages, FASEB J
Ritchie, Phipson, Wu, Hu, Law et al., Limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res
Torres, Motos, Ceccato, Bermejo-Martin, De Gonzalo-Calvo et al., Methodology of a large Multicenter Observational Study of patients with COVID-19 in spanish intensive care units, Arch Bronconeumol
Torres, Motos, Riera, Fernández-Barat, Ceccato et al., The evolution of the ventilatory ratio is a prognostic factor in mechanically ventilated COVID-19 ARDS patients, Crit Care
Täubel, Hauke, Rump, Viereck, Batkai et al., Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human phase 1b randomized, double-blind, placebo-controlled study, Eur Heart J
Wilson, Kealy, James, Plowman, Newling et al., Integrated miRNA/cytokine/chemokine profiling reveals severity-associated step changes and principal correlates of fatality in COVID-19. iScience
Wynants, Van Calster, Collins, Riley, Heinze et al., Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal, BMJ
Yang, Zhao, Li, Liu, Zhu et al., Downregulated miR-451a as a feature of the plasma cfRNA landscape reveals regulatory networks of IL-6/ IL-6R-associated cytokine storms in COVID-19 patients, Cell Mol Immunol
