Bronchial Aspirate-Based Profiling Identifies MicroRNA Signatures Associated With COVID-19 and Fatal Disease in Critically Ill Patients

Marta Molinero; Iván D Benítez; Jessica González; Clara Gort-Paniello; Anna Moncusí-Moix; Fátima Rodríguez-Jara; María C García-Hidalgo; Gerard Torres; J J Vengoechea; Silvia Gómez; Ramón Cabo; Jesús Caballero; Jesús F Bermejo-Martin; Adrián Ceccato; Laia Fernández-Barat; Ricard Ferrer; Dario Garcia-Gasulla; Rosario Menéndez; Ana Motos; Oscar Peñuelas; Jordi Riera; Antoni Torres; Ferran Barbé; David de Gonzalo-Calvo

doi:10.3389/fmed.2021.756517

Bronchial Aspirate-Based Profiling Identifies MicroRNA Signatures Associated With COVID-19 and Fatal Disease in Critically Ill Patients

Front Med (Lausanne). 2022 Feb 3:8:756517. doi: 10.3389/fmed.2021.756517. eCollection 2021.

Authors

Marta Molinero¹, Iván D Benítez^{1

2}, Jessica González¹, Clara Gort-Paniello^{1

2}, Anna Moncusí-Moix^{1

2}, Fátima Rodríguez-Jara^{1

2}, María C García-Hidalgo¹, Gerard Torres^{1

2}, J J Vengoechea¹, Silvia Gómez^{1

2}, Ramón Cabo¹, Jesús Caballero³, Jesús F Bermejo-Martin^{2

4

5}, Adrián Ceccato², Laia Fernández-Barat^{2

6}, Ricard Ferrer^{2

7}, Dario Garcia-Gasulla⁸, Rosario Menéndez^{2

9}, Ana Motos^{2

6}, Oscar Peñuelas^{2

10}, Jordi Riera^{2

7}, Antoni Torres^{2

6}, Ferran Barbé^{1

2}, David de Gonzalo-Calvo^{1

2}

Affiliations

¹ Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain.
² CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain.
³ Intensive Care Department, University Hospital Arnau de Vilanova, IRBLleida, Lleida, Spain.
⁴ Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain.
⁵ Group for Biomedical Research in Sepsis (BioSepsis), Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
⁶ Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, IDIBAPS, Barcelona, Spain.
⁷ Intensive Care Department, Vall d'Hebron Hospital Universitari, SODIR Research Group, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain.
⁸ Barcelona Supercomputing Center (BSC), Barcelona, Spain.
⁹ Pulmonology Service, University and Polytechnic Hospital La Fe, Valencia, Spain.
¹⁰ Hospital Universitario de Getafe, Madrid, Spain.

Abstract

Background: The pathophysiology of COVID-19-related critical illness is not completely understood. Here, we analyzed the microRNA (miRNA) profile of bronchial aspirate (BAS) samples from COVID-19 and non-COVID-19 patients admitted to the ICU to identify prognostic biomarkers of fatal outcomes and to define molecular pathways involved in the disease and adverse events.

Methods: Two patient populations were included (n = 89): (i) a study population composed of critically ill COVID-19 and non-COVID-19 patients; (ii) a prospective study cohort composed of COVID-19 survivors and non-survivors among patients assisted by invasive mechanical ventilation (IMV). BAS samples were obtained by bronchoaspiration during the ICU stay. The miRNA profile was analyzed using RT-qPCR. Detailed biomarker and bioinformatics analyses were performed.

Results: The deregulation in five miRNA ratios (miR-122-5p/miR-199a-5p, miR-125a-5p/miR-133a-3p, miR-155-5p/miR-486-5p, miR-214-3p/miR-222-3p, and miR-221-3p/miR-27a-3p) was observed when COVID-19 and non-COVID-19 patients were compared. In addition, five miRNA ratios segregated between ICU survivors and nonsurvivors (miR-1-3p/miR-124-3p, miR-125b-5p/miR-34a-5p, miR-126-3p/miR-16-5p, miR-199a-5p/miR-9-5p, and miR-221-3p/miR-491-5p). Through multivariable analysis, we constructed a miRNA ratio-based prediction model for ICU mortality that optimized the best combination of miRNA ratios (miR-125b-5p/miR-34a-5p, miR-199a-5p/miR-9-5p, and miR-221-3p/miR-491-5p). The model (AUC 0.85) and the miR-199a-5p/miR-9-5p ratio (AUC 0.80) showed an optimal discrimination value and outperformed the best clinical predictor for ICU mortality (days from first symptoms to IMV initiation, AUC 0.73). The survival analysis confirmed the usefulness of the miRNA ratio model and the individual ratio to identify patients at high risk of fatal outcomes following IMV initiation. Functional enrichment analyses identified pathological mechanisms implicated in fibrosis, coagulation, viral infections, immune responses and inflammation.

Conclusions: COVID-19 induces a specific miRNA signature in BAS from critically ill patients. In addition, specific miRNA ratios in BAS samples hold individual and collective potential to improve risk-based patient stratification following IMV initiation in COVID-19-related critical illness. The biological role of the host miRNA profiles may allow a better understanding of the different pathological axes of the disease.

Keywords: COVID-19; SARS-CoV-2; acute respiratory distress syndrome; mechanical ventilation; microRNA.

Copyright © 2022 Molinero, Benítez, González, Gort-Paniello, Moncusí-Moix, Rodríguez-Jara, García-Hidalgo, Torres, Vengoechea, Gómez, Cabo, Caballero, Bermejo-Martin, Ceccato, Fernández-Barat, Ferrer, Garcia-Gasulla, Menéndez, Motos, Peñuelas, Riera, Torres, Barbé and de Gonzalo-Calvo.