Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial

With more than 500 million confirmed cases of COVID-19 and 10% of infected individuals suffering persistent symptoms, patient-reported low health related quality of life has become a vast problem for individuals, health care systems and society for years to come [1].

Post COVID condition (PCC), also known as Long COVID is commonly defined as having a history of probable or confirmed SARS-CoV-2 infection, and persistent symptoms 3 months from the onset of COVID-19 [2]. Common symptoms are fatigue, shortness of breath and cognitive dysfunction [3]. Mechanisms are still an enigma but suggested mechanisms include auto-immune disease such as dysregulated T-cell activation, chronic oxidative stress, mitochondrial dysfunction, and endothelial dysfunction [4].

No effective evidence-based treatment options for the underlying condition have been widely adopted in clinical practice and many patients seek expensive “remedies” for self-management [5]. Hyperbaric oxygen (HBO₂) is a possibly effective drug but has not been evaluated for safety and efficacy in compliance with International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use-Good Clinical Practice (ICH-GCP) for PCC in clinical trials. It has been suggested to be effective in similar conditions such as Fibromyalgia and Chronic Fatigue syndrome [6, 7]. HBO₂ has become increasingly popular off-label, a couple of case reports/series are published and RCTs are on the way [8‐10]. Since the first submission of this manuscript one RCT including 73 subjects have shown an improvement of neurocognitive function and symptoms in PCC with 40 sessions of HBO₂ at 2 Bar for 90 min with five-minute air breaks every 20 min [11]. Our hypothesis for use of HBO₂ in PCC is based on the hyperoxic-hypoxic paradox with activation of Hypoxia Inducible Factor 1 and 2 (HIF-1 and HIF-2) and downstream regulation of hypoxia and inflammatory pathways [12, 13]. The rationale for using fewer and less frequent sessions is based on the above hypotheses, previous clinical experience and from experimental research including own unpublished data. The safety profile of HBO₂ is well known for accepted indications but has not been described in compliance with ICH-GCP and is not an accepted treatment for patients diagnosed with PCC [14]. The aim of the interim analysis was to evaluate safety of HBO₂ for our cohort by evaluating reported adverse events (AE) and serious adverse events (SAE) in compliance with ICH-GCP.

Twenty subjects had safety data available at 13 weeks. Demographic characteristics are presented in Table 1. Self-reported HRQoL in RAND-36 was very low in physical domains at baseline compared to Swedish norm data; PF 31.75(19.55) vs 83.5(23.9) (95% Confidence interval 22.60–40.90) p < 0.001, RP 0(0) vs 75.4(37.6) p < 0.001 and statistically significantly lower in all domains except Role emotional (RE) (Fig. 3). Self-reported HRQoL in EQ-5D was very low; index 0.36 (0.22) (95% CI 0.25–0.46) vs 0.87(95% CI 0.82–0.92) p < 0.001 and visual analogue scale (VAS) 39.1 (16.75)) (95% CI 31.26–46.94) vs 85.1 (1.05)) (95% CI 81–89) p < 0.001 compared to age and sex matched norm data (Fig. 4). Performance in physical tests were very low at baseline compared to international norm data; 6MWT 442 (180) (95% CI 357.7–525.8) vs 662 (18) meters and CST 13(5.1) (95% CI 10.51–15.29) vs 25 (1.23) (95% CI 22.95–27.60) stands in 30 s (Fig. 5). Baseline data of RHI in the 20 subjects in the interim analysis; 35% of the subjects have RHI < 1.67 i.e., endothelial dysfunction and 30% RHI 1.67–2.10 i.e., borderline ED at baseline. While numerically lower, this did not reach statistical significance compared to a ten-year older control group (Fig. 6).

Thirty-one AEs were recorded, at least one in 60% of subjects. No SAE was reported. Most AE were grade 1, 6 were grade 2. In 20 AEs, there was at least a possible relationship with the study drug. The most common AE was cough and chest pain/discomfort. All AE were transient. (Additional file 1, AE listings).

Our results show that the self-reported HRQoL is extremely low in our cohort compared to previously published data on Long COVID [21]. The reference data for RAND-36 and EQ-5D are based on Swedish populations matched for age and sex but not adjusted for level of education. Our cohort consists of highly educated subjects, therefore HRQoL is expected to be even higher but may also explain the very low result of Role Physical (expectations). Most of our subjects were infected during the first wave 2020 and were unvaccinated at the time. There may be a selection bias depending on this fact and there has also been a selection of patients referred to our PCC clinic; only the most serious cases were accepted. According to our protocol with “sham treatment” we are not able to adjust the dose with pressure, only time. For some subjects the time was reduced due to cough or chest discomfort during treatment and some subjects was not able to complete all ten treatments. A protocol that allows a lower pressure or individually adjusted may be beneficial for compliance. The previously published RCT reported no significant difference in side effects between the groups (35.1% and 38.9%, p = 0.739 in the HBO₂ and control groups respectively) and no discontinuation of the treatment due to side effects [11]. Given the frailty of this group it’s possible that AEs occurred in the placebo treatment group due to the effort of participation or by breathing non humidified air. Alternative explanations for the higher rate of adverse events are difference in disease severity or difference in treatment protocols. Very few in our cohort would be able to accept treatments on two consecutive days, due to severe fatigue.

HBO₂ appears to have a favorable safety profile for PCC considering the absence of SAE but an unexpected high frequency of AE was observed. Most of them were mild and all of them were transient. We speculate that frequency of AE could be reduced by individual dosing. This safety analysis enables further investigation of the efficacy of HBO₂ within the HOT-LoCO trial and may help other researchers in designing trials.