Frontiers in Immunology (Jul 2022)

Multiplex protein profiling of bronchial aspirates reveals disease-, mortality- and respiratory sequelae-associated signatures in critically ill patients with ARDS secondary to SARS-CoV-2 infection

  • Marta Molinero,
  • Marta Molinero,
  • Silvia Gómez,
  • Silvia Gómez,
  • Iván D. Benítez,
  • Iván D. Benítez,
  • J. J. Vengoechea,
  • J. J. Vengoechea,
  • Jessica González,
  • Jessica González,
  • Dinora Polanco,
  • Clara Gort-Paniello,
  • Clara Gort-Paniello,
  • Anna Moncusí-Moix,
  • Anna Moncusí-Moix,
  • María C. García-Hidalgo,
  • María C. García-Hidalgo,
  • Manel Perez-Pons,
  • Manel Perez-Pons,
  • Thalía Belmonte,
  • Thalía Belmonte,
  • Gerard Torres,
  • Gerard Torres,
  • Jesús Caballero,
  • Carme Barberà,
  • Jose Ignacio Ayestarán Rota,
  • Lorenzo Socías Crespí,
  • Adrián Ceccato,
  • Laia Fernández-Barat,
  • Laia Fernández-Barat,
  • Ricard Ferrer,
  • Ricard Ferrer,
  • Dario Garcia-Gasulla,
  • Jose Ángel Lorente-Balanza,
  • Jose Ángel Lorente-Balanza,
  • 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/fimmu.2022.942443
Journal volume & issue
Vol. 13

Abstract

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IntroductionBronchial aspirates (BAS) obtained during invasive mechanical ventilation (IMV) constitutes a useful tool for molecular phenotyping and decision making.AimTo identify the proteomic determinants associated with disease pathogenesis, all-cause mortality and respiratory sequelae in BAS samples from critically ill patients with SARS-CoV-2-induced ARDSMethodsMulticenter study including 74 critically ill patients with COVID-19 and non-COVID-19 ARDS. BAS were obtained by bronchoaspiration after IMV initiation. Three hundred sixty-four proteins were quantified using proximity extension assay (PEA) technology. Random forest models were used to assess predictor importance.ResultsAfter adjusting for confounding factors, CST5, NADK, SRPK2 and TGF-α were differentially detected in COVID-19 and non-COVID-19 patients. In random forest models for COVID-19, CST5, DPP7, NADK, KYAT1 and TYMP showed the highest variable importance. In COVID-19 patients, reduced levels of ENTPD2 and PTN were observed in nonsurvivors of ICU stay, even after adjustment. AGR2, NQO2, IL-1α, OSM and TRAIL showed the strongest associations with in-ICU mortality and were used to construct a protein-based prediction model. Kaplan-Meier curves revealed a clear separation in mortality risk between subgroups of PTN, ENTPD2 and the prediction model. Cox regression models supported these findings. In survivors, the levels of FCRL1, NTF4 and THOP1 in BAS samples obtained during the ICU stay correlated with lung function (i.e., DLCO levels) 3 months after hospital discharge. Similarly, Flt3L and THOP1 levels were correlated with radiological features (i.e., TSS). These proteins are expressed in immune and nonimmune lung cells. Poor host response to viral infectivity and an inappropriate reparative mechanism seem to be linked with the pathogenesis of the disease and fatal outcomes, respectively.ConclusionBAS proteomics identified novel factors associated with the pathology of SARS-CoV-2-induced ARDS and its adverse outcomes. BAS-based protein testing emerges as a novel tool for risk assessment in the ICU.

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