Biomedicine & Pharmacotherapy (Oct 2022)
Genome-wide transcriptional profiling of pulmonary functional sequelae in ARDS- secondary to SARS-CoV-2 infection
- María C. García-Hidalgo,
- Rafael Peláez,
- Jessica González,
- Sally Santisteve,
- Iván D. Benítez,
- Marta Molinero,
- Manel Perez-Pons,
- Thalía Belmonte,
- Gerard Torres,
- Anna Moncusí-Moix,
- Clara Gort-Paniello,
- Maria Aguilà,
- Faty Seck,
- Paola Carmona,
- Jesús Caballero,
- Carme 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,
- David de Gonzalo-Calvo,
- Ignacio M. Larráyoz
Affiliations
- María C. García-Hidalgo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Rafael Peláez
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, Logroño, Spain
- Jessica González
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Sally Santisteve
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- Iván D. Benítez
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Marta Molinero
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Manel Perez-Pons
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Thalía Belmonte
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Gerard Torres
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Anna Moncusí-Moix
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Clara Gort-Paniello
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Maria Aguilà
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- Faty Seck
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- Paola Carmona
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain
- Jesús Caballero
- Grup de Recerca Medicina Intensiva, Intensive Care Department Hospital Universitari Arnau de Vilanova, Lleida, Spain
- Carme Barberà
- Intensive Care Department, University Hospital Santa María, IRBLleida, Lleida, Spain
- Adrián Ceccato
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Hospital Universitari Sagrat Cor, Barcelona, Spain
- Laia Fernández-Barat
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Servei de Pneumologia, Hospital Clinic; Universitat de Barcelona; IDIBAPS, Barcelona, Spain
- Ricard Ferrer
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Intensive Care Department, Vall d’Hebron Hospital Universitari. SODIR Research Group, Vall d’Hebron Institut de Recerca (VHIR), Spain
- Dario Garcia-Gasulla
- Barcelona Supercomputing Center (BSC), Barcelona, Spain
- Jose Ángel Lorente-Balanza
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Hospital Universitario de Getafe, Madrid, Spain
- Rosario Menéndez
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Pulmonology Service, University and Polytechnic Hospital La Fe, Valencia, Spain
- Ana Motos
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Servei de Pneumologia, Hospital Clinic; Universitat de Barcelona; IDIBAPS, Barcelona, Spain
- Oscar Peñuelas
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Hospital Universitario de Getafe, Madrid, Spain
- Jordi Riera
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Intensive Care Department, Vall d’Hebron Hospital Universitari. SODIR Research Group, Vall d’Hebron Institut de Recerca (VHIR), Spain
- Jesús F. Bermejo-Martin
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Hospital Universitario Río Hortega de Valladolid, Valladolid, Spain; Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
- Antoni Torres
- CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Pneumology Department, Clinic Institute of Thorax (ICT), Hospital Clinic of Barcelona, Insitut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), ICREA, University of Barcelona (UB), Barcelona, Spain
- Ferran Barbé
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain
- David de Gonzalo-Calvo
- Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Lleida, Spain; CIBER of Respiratory Diseases (CIBERES), Institute of Health Carlos III, Madrid, Spain; Correspondence to: Translational Research in Respiratory Medicine, University Hospital Arnau de Vilanova and Santa Maria, IRBLleida, Avda. Alcalde Rovira Roure 80, Lleida 25198, Spain.
- Ignacio M. Larráyoz
- Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area Center for Biomedical Research of La Rioja, CIBIR, Logroño, Spain; GRUPAC, Department of Nursing, University of La Rioja, Logroño, Spain; Correspondence to: Biomarkers and Molecular Signaling Group, Neurodegenerative Diseases Area, Center for Biomedical Research of La Rioja, CIBIR. C. Piqueras, 98, Logroño 26006, Spain.
- Journal volume & issue
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Vol. 154
p. 113617
Abstract
Background: Up to 80% of patients surviving acute respiratory distress syndrome (ARDS) secondary to SARS-CoV-2 infection present persistent anomalies in pulmonary function after hospital discharge. There is a limited understanding of the mechanistic pathways linked to post-acute pulmonary sequelae. Aim: To identify the molecular underpinnings associated with severe lung diffusion involvement in survivors of SARS-CoV-2-induced ARDS. Methods: Survivors attended to a complete pulmonary evaluation 3 months after hospital discharge. RNA sequencing (RNA-seq) was performed using Illumina technology in whole-blood samples from 50 patients with moderate to severe diffusion impairment (DLCO<60%) and age- and sex-matched individuals with mild-normal lung function (DLCO≥60%). A transcriptomic signature for optimal classification was constructed using random forest. Transcriptomic data were analyzed for biological pathway enrichment, cellular deconvolution, cell/tissue-specific gene expression and candidate drugs. Results: RNA-seq identified 1357 differentially expressed transcripts. A model composed of 14 mRNAs allowed the optimal discrimination of survivors with severe diffusion impairment (AUC=0.979). Hallmarks of lung sequelae involved cell death signaling, cytoskeleton reorganization, cell growth and differentiation and the immune response. Resting natural killer (NK) cells were the most important immune cell subtype for the prediction of severe diffusion impairment. Components of the signature correlated with neutrophil, lymphocyte and monocyte counts. A variable expression profile of the transcripts was observed in lung cell subtypes and bodily tissues. One upregulated gene, TUBB4A, constitutes a target for FDA-approved drugs. Conclusions: This work defines the transcriptional programme associated with post-acute pulmonary sequelae and provides novel insights for targeted interventions and biomarker development.