Safety and Changes in Health-Related Quality of Life After Epidural Oxygen Injection for Long COVID/Post-COVID Syndrome: A Multicenter Retrospective Study.

Background/Objectives: Long COVID/post-COVID-19 syndrome is associated with persistent symptoms, including fatigue, headache, and autonomic dysfunction, leading to impaired health-related quality of life (HRQoL). Although epidural oxygen injections have been used in patients with chronic post-traumatic headache and mild traumatic brain injury, their safety and therapeutic effects have not been systematically evaluated. Methods: In this multicenter retrospective study, patients with Long COVID/post-COVID-19 syndrome who underwent their first epidural oxygen injection between April 2022 and December 2025 were included. Safety was assessed by reviewing adverse events. HRQoL was evaluated using the Japanese version of the 36-Item Short-Form Health Survey version 2 (SF-36v2®) before treatment and approximately one month afterward. Paired SF-36v2® scores were compared using the Wilcoxon signed-rank test with Bonferroni correction. Results: Forty-two patients were included (mean age, 31.9 ± 16.2 years; 21 males). The mean interval between COVID-19 infection and treatment was 16.7 ± 12.8 months. Adverse events occurred in eight patients (subcutaneous emphysema, n = 5; dyspnea, n = 2; back pain, n = 1); they all resolved spontaneously within one week, with no deaths, hospitalizations, or long-term sequelae. Paired SF-36v2® data were available for 35 patients. The median scores improved across all domains, with the greatest increase observed in vitality (+25.0 points). All improvements remained significant after Bonferroni correction. Conclusions: Epidural oxygen injection demonstrated a favorable short-term safety profile and was associated with improved HRQoL in patients with Long COVID/post-COVID-19 syndrome. Prospective controlled studies using objective outcome measures are needed to confirm efficacy and clarify the underlying mechanisms.