Randomised clinical trials with hyperbaric oxygen in COVID-19 and Long COVID : transcriptomic insights into benefits and harms

The flow from transcription of genes through translation and processing of proteins is a common basis for all life. Redox homeostasis is crucial for the defence against oxidative stress. We adapt through hormesis; non-lethal stress regulates redox-sensitive systems to maintain homeostasis. If the stress is chronic or acutely overwhelming, the cells can either go into apoptosis or into senescence to maintain homeostasis. Similar effects have been seen with HBOT as with intermittent oxygen deprivation. Hyperbaric oxygen therapy (HBOT) is delivered in a pressure chamber by breathing 100% oxygen intermittently, several times a week, in an ambient pressure equivalent to 10-20 meters of seawater. The aim of this thesis was to evaluate potential harms of HBOT for novel indications and to explore biomarkers in experimental and clinical trials in order to enable future precision medicine. We used methods evaluated on healthy volunteers in randomised clinical trials (RCTs) conducted in compliance with good clinical practice (ICH-GCP).

In Paper I, we evaluated Electron paramagnetic resonance (EPR) spectroscopy for measuring reactive oxygen species (ROS) in blood and RNA sequencing (RNAseq) of monocytes in peripheral blood (PBMC), and compared HBOT and HIIT in ten healthy volunteers. We could measure ROS in blood in the same physiological range in both interventions. We also discovered pathways involved in adaption to hypoxia and inflammation that were similar in both interventions. In Papers II and III, we evaluated harms and explored RNAseq in PBMC in an open label RCT where 31 patients with severe COVID- 19 were randomised to HBOT or best practice. We observed similar frequencies of adverse events (AEs) in the two groups and could not see any negative effect on vital signs or oxygenation. We discovered a unique transcriptomic signature in the subjects that had received HBOT. The differentially expressed genes were associated with the unfolded protein response, apoptosis, and immune response. In Paper IV, we evaluated harms and described health related quality of life (HRQoL)in an interim analysis of the first 20 subjects froma placebo controlled RCT where 80 patients with Long COIVD were randomised to HBOT or sham treatment. We reported more AEs than expected and severe physical and mental disabilities with a very poor HRQoL. Most AEs were mild, and all were transient.

We have shown that HBOT shares similarities in immune response with HIIT in healthy volunteers. HBOT has a favourable profile of harms and has a potent immunomodulatory effect that is associated with fast recovery for critical COVID-19 patients. HBOT has a favourable profile of harms for patients with post COVID-19 condition. The results provide a base for future clinical trials with HBOT.

List of scientific papers

I. Comparing the blood response to hyperbaric oxygen with high intensity interval training - a cross-over study in healthy volunteers. Kjellberg A, Lindholm ME, Zheng X, Liwenborg L, Rodriguez-Wallberg KA, Catrina S-B, Lindholm P. Antioxidants. 2023;12:2043.
https://doi.org/10.3390/antiox12122043

II. COVID-19-Induced Acute Respiratory Distress Syndrome Treated with Hyperbaric Oxygen: Interim Safety Report from a Randomized Clinical Trial (COVID-19-HBO). Kjellberg A, Douglas J, Hassler A, Al-Ezerjawi S, Bostrom E, Abdel-Halim L, Liwenborg L, Hetting E, Jonasdottir Njastad AD, Kowalski J, Catrina SB, Rodriguez-Wallberg KA, Lindholm P. J Clin Med. 2023;12.
https://doi.org/10.3390/jcm12144850

III. 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. Kjellberg A, Zhao A, Lussier A, Hassler A, Al- Ezerjawi S, Boström E, Catrina S-B, Bergman P, Rodriguez-Wallberg KA, Lindholm P. Pre-print: doi.org/10.21203/rs.3.rs-3699049/v1 [Manuscript]

IV. Hyperbaric Oxygen Therapy for Long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial. Kjellberg A, Hassler A, Bostrom E, El Gharbi S, Al-Ezerjawi S, Kowalski J, Rodriguez Wallberg KA, Bruchfeld J, Stahlberg M, Nygren-Bonnier M, Runold M, Lindholm P. BMC Infect Dis. 2023;23:33.
https://doi.org/10.1186/s12879-023-08002-8