Ozone as an adjuvant therapy for COVID-19: A systematic review and meta-analysis

Objective: Ozone adjuvant in COVID-19 management showed conflicting results in prior studies. Here, we aimed to comprehensively evaluate benefits and side effects of ozone as adjuvant therapy in COVID-19 patients. Methods: Systematic searches were conducted in MEDLINE, ScienceDirect, Cochrane Library, Springer, medRxiv, and ProQuest for articles investigating ozone as adjuvant therapy in COVID-19. Clinical and laboratory outcomes, mortality, length of hospital stay, intensive care unit (ICU) admission, and adverse events were assessed. Results: Thirteen studies were included in this review. Case-control studies, but not randomized controlled trials (RCTs), showed a decrease in mortality following ozone therapy (OR = 0.24 (95% CI [0.07–0.76]), p = 0.02, I² = 0%, fixed-effect). However, ozone therapy did not improve the length of hospital stay (SMD = -0.99 (95 %CI −2.44 to 0.45), p = 0.18, I² = 84%, random-effects) and ICU admission (RR = 0.57 (95 %CI [0.05–6.71]), I² = 73%, p = 0.65, random-effects). Consecutive case control studies suggested that ozone therapy significantly improved levels of D-dimer (p = 0.0060), lactate dehydrogenase (LDH; p = 0.0209), C-reactive protein (CRP; p = 0.0040) and interleukin (IL)-6 (p = 0.0048) as compared to standard therapy alone. Conclusions: The beneficial effect of ozone in COVID-19 management seems to be limited to the improvements of laboratory parameters among severe patients, including the reduction of IL-6, LDH, CRP, and D-dimer levels. Meanwhile, other study endpoints, such as mortality, length of stay and ICU admission, were not improved following ozone therapy, although it may partly be due to a shorter duration of viral clearance. Furthermore, no serious adverse event was reported following ozone therapy, suggesting its high safety profile.