Fast recovery of COVID-19-induced acute respiratory distress syndrome after hyperbaric oxygen treatment and changes in endoplasmic reticulum (ER) stress response in peripheral monocytes – A randomized-controlled trial

Background: Many questions remain unanswered regarding the scientific understanding of SARS-CoV-2 and host interaction. There is an established need to develop anti-inflammatory agents with the potential to prevent or mitigate the development of severe COVID-19, targeting viral replication and/or the immune response. To address these unmet needs, we investigated the effects of oxygen treatment (HBOT) on clinical inflammatory markers, peripheral blood cells and transcriptional changes in patients with severe COVID-19. Methods: : In this pre-defined sub-study of a randomized controlled clinical trial, critical COVID-19 patients with moderate acute respiratory distress syndrome (ARDS) at one Swedish university hospital were enrolled and randomly assigned (1:1) to HBOT plus best practice or best practice (Control) and followed up on nine visits for 30 days. HBOT was administered with five treatments at 2.4 atmospheres absolute (ATA) for 80 min each, the first seven days. Clinical inflammatory markers, lymphocyte phenotyping with flow cytometry, and bulk RNA sequencing (RNAseq) were analyzed on peripheral blood monocytes (PBMCs). Results: : Between December 3 rd 2020, and May 17 th 2021, 23 patients were randomized, and 17 were analyzed. RNAseq revealed 791 differentially expressed genes in the HBOT group compared to 46 in the control group at Day 7 vs. baseline. Gene set enrichment analysis revealed unique decreases of the unfolded protein response (UPR) and inflammatory response in the HBOT group. The HBOT group recovered faster. National early warning score (NEWS) was lower in the HBOT group (ANOVA, F(8, 120) = 3.817, p < 0.001) and PaO2/FiO2 was higher in the HBOT group (Mixed effects model, F(8, 94) = 2.900, p < 0.01). The HBOT group had a shorter mean hospital length of stay (HLoS), 16 vs. 26 days (95.99% CI -16-0), p=0.045, saving ~300.000 USD. Conclusions: : Pathways related to viral-induced ER stress with downregulation of the UPR and inflammatory response in critical COVID-19 patients treated with HBOT was significantly different compared to controls and associated with faster recovery and reduced HLoS. Trial registration: NCT04327505 (March 31, 2020) and EudraCT 2020-001349-37 (April 24, 2020)