The maladaptive vascular response in COVID-19 acute respiratory distress syndrome and recovery

Price, D. R.; Benedetti, E.; Hoffman, K.; Gomez-Escobar, L.; Alvarez-Mulett, S.; Capili, A.; Sarwath, H.; Parkhurst, C. N.; LaFond, E.; Weidman, K.; Ravishankar, A.; Cheong, J. G.; Batra, R.; Buyukozkan, M.; Chetnik, K.; Easthausen, I.; Schenck, E. J.; Racanelli, A. C.; Outtz Reed, H.; Laurence, J. C.; Josefowicz, S. Z.; Lief, L.; Choi, M. E.; Rafii, S.; Schmidt, F.; Borczuk, A. C.; Krumsiek, J.; Choi, A. M. K.

Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development ("at risk", N=59), an intensive care unit cohort with ARDS ("ARDS", N=31), and a cohort recovering from ARDS ("recovery", N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.