Frontiers in Medicine (Feb 2022)

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

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

DOI
https://doi.org/10.3389/fmed.2021.756517
Journal volume & issue
Vol. 8

Abstract

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BackgroundThe 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.MethodsTwo 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.ResultsThe 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.ConclusionsCOVID-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.

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