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COVID-19 is a pandemic related with reduced immunity, high inflammatory activity and high oxidative stress activity. With its anti-microbial, immunity promoting, and oxidative balance modulating efficacy ozone seems to have a promising role in the management of COVID-19. This systematic review of experimental and clinical studies was done to assess the role of ozone in the treatment of COVID-19 patients and to bring out gaps in research design, methodology and patient selection in order to provide basis for further research using more standardized methodologies to build homogeneous evidence. We carried out adatabase search of PubMed using “Ozone therapy in Covid-19”, “ozone in covid-19 case control”, “Treatment of COVID-19 using ozone” as the search words. PRISMA guidelines for systematic review were followed. A total of 14 relevant articles were selected. The studies were grouped according to the type of study. Pooled rates for different outcomes were noted using a Meta-analytical approach using Microsoft Excel software. Odds ratios for pooled data were calculated. The experimental studies showed the feasibility of ozone in COVID-19 disinfection/viral load reduction. The case studies together included a total of 9 cases. All the cases showed symptomatic improvement and there was no mortality. In a prospective interventional study, the major promising outcome was ~10% increase in SpO2 level. In six randomized controlled trials that included 134 cases (where ozone was used as part of treatment) and 115 controls (where ozone was not used as part of the treatment), the pooled mortality rate was significantly lower in cases (3.7%) as compared to that in controls (10.4%) (OR=0.33; 95% CI=0.11-0.97; p=0.045). A promising role of ozonation was also seen for Intensive Care/Orotracheal intubation. The findings of study suggest that ozone therapy seems to have a promising impact on COVID-19 treatment.
Accessed 25th May, 2021.
Kashyap S, Gombar S, Yadlowsky S, Callahan A, Fries J, Pinsky BA, Shah NS. Measure what matters: Counts of hospitalized patients are a better metric for health system capacity planning for a reopening. J Am Med Inform Assoc. 2020;27(7):1026–1131.
Ciaccio M, Agnello L. Biochemical biomarkers alterations in Corona virus Disease 2019 (COVID-19). Diagnosis (Berl). 2020;7(4):365-372.
Mardani R, Ahmadi Vasmehjani A, Zali F, et al. Laboratory Parameters in Detection of COVID-19 Patients with Positive RT-PCR; A Diagnostic Accuracy Study. Arch AcadEmerg Med. 2020;8(1):e43.
Mimohammadi S, Kianmehr A, Arefi M, Mahrooz A. Biochemical parameters and pathogenesis of SARS-CoV-2 infection in vital organs: COVID-19 outbreak in Iran.
Aguilar RB, Hardigan P, Mayi B, Sider D, Piotrkowski J, Mehta JP, Dev J, Seijo Y, Camargo AL, Andux L, Hagen K, Hernandez MB. Current Understanding of COVID-19 Clinical Course and Investigational Treatments. Front Med (Lausanne). 2020;7:555301.
Kantri A, Ziati J, Khalis M, Haoudar A, El Aidaoui K, Daoudi Y, et al. Hematological and biochemical abnormalities associated with severe forms of COVID-19: A retrospective single-center study from Morocco. PLoS ONE. 2021;16(2):e0246295.
Zhang W, Zhao Y, Zhang F, et al. The use of anti-inflammatory drugs in the treatment of people with severe corona virus disease 2019 (COVID-19): The Perspectives of clinical immunologists from China. ClinImmunol. 2020;214:108393.
Bocci VA. Scientific and medical aspects of ozone therapy. State Art Arch Med Res. 2006; 37:425–35.
Gavazza A, Marchegiani A, Rossi G, Franzini M, Spaterna A, Mangiaterra S, Cerquetella M. Ozone Therapy as a Possible Option in COVID-19 Management.Front Public Health. 2020;8:417.
Thiele JJ, Traber MG, Polefka TG, Cross CE, Packer L. Ozone-exposure depletes vitamin E and induces lipid peroxidation in murine stratum corneum. J Invest Dermatol. 1997; 108(5):753-7.
Chen C, Arjomandi M, Balmes J, Tager I, Holland N. Effects of chronic and acute ozone exposure on lipid peroxidation and antioxidant capacity in healthy young adults. Environ Health Perspect. 2007;115(12): 1732-1737.
Togi S, TogiM, Nagashima S, Kitai Y, Muromoto R, Kashiwakura J-I, et al.Implication of NF-κB Activation on Ozone-Induced HO-1 Activation. BPB Reports. 2021; 4(2):59-63.
Yano H, Nakano R, Suzuki Y, Nakano A, Kasahara K, Hosoi H. Inactivation of severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) by gaseous ozone treatment. J Hosp Infect. 2020;106(4):837-838.
Criscuolo E, Diotti RA, Ferrarese R, Alippi C, Viscardi G, Signorelli C, Mancini N, Clementi M, Clementi N. Fast inactivation of SARS-CoV-2 by UV-C and ozone exposure on different materials. Emerg Microbes Infect. 2021;10(1):206-210.
Zheng Z, Dong M, Hu K. A preliminary evaluation on the efficacy of ozone therapy in the treatment of COVID-19. J Med Virol. 2020;92(11):2348-2350.
Wu J, Tan CS, Yu H, et al. Recovery of Four COVID-19 Patients via Ozonated Autohemotherapy. Innovation (NY). 2020; 1(3):100060.
Peña-Lora DY, Albaladejo-Florín MJ, Fernández-Cuadros ME. Uso de ozonoterapia rectal en pacienteanciana con neumonía grave por COVID-19 [Usefulness of rectal ozonetherapy in a geriatric patient with severe COVID-19 pneumonia]. Rev Esp Geriat rGerontol. 2020;55(6):362-364.
Hendawy HA, Mosallam W, Abuelnaga ME, Sabry AM. Old Treatment for a New Disease: Can Rectal Ozone Insufflation Be Used for COVID-19 Management? A Case Report. SN ComprClin Med. 2021;1-4.
Franzini M, Valdenassi L, Ricevuti G, Chirumbolo S, Depfenhart M, Bertossi D, Tirelli U. Oxygen-ozone (O2-O3) immunoceutical therapy for patients with COVID-19. Preliminary evidence reported. IntImmunopharmacol. 2020;88:106879.
Fernández-Cuadros ME, Albaladejo-Florín MJ, Álava-Rabasa S, Usandizaga-Elio I, Martinez-Quintanilla Jimenez D, Peña-Lora D, et al. Effect of Rectal Ozone (O3) in Severe COVID-19 Pneumonia: Preliminary Results. SN Compr Clin Med. 2020;1-9. Epub ahead of print.
Araimo F, Imperiale C, Tordiglione P, Ceccarelli G, Borrazzo C, AlessandrFernández-Cuadros ME, Albaladejo-Florín MJ, Álava-RabasaS,Gallego-Galiana J, Perez-Cruz GF, Usandizaga-Elio I, et al. Compassionate Use of Rectal Ozone (O3) in Severe COVID-19 Pneumonia: A Case-Control Study [published online ahead of print, 2021 Mar 22]. SN Compr Clin Med. 2021;1-15.
Linki F, Santinelli L, Innocenti GP, Pinacchio C, Mauro V, Recchia GE, et al. Ozone as adjuvant support in the treatment of COVID-19: A preliminary report of probiozovid trial. J Med Virol. 2021;93(4):2210-2220.
Hernández A, Viñals M, Pablos A, Vilás A, Papadakos PJ, Wijeysundera DN, et al. Ozone therapy for patients with COVID-19 pneumonia: Preliminary report of a prospective case-control study. Int Immunopharmacol. 2021;90:107261.
Tascini C, Sermann G, Pagotto A, Sozio E, De Carlo C, Giacinta A, et al. Blood ozonization in patients with mild to moderate COVID-19 pneumonia: a single centre experience. Intern Emerg Med. 2021;16(3):669-675.
Fernández-Cuadros ME, Albaladejo-Florín MJ, Álava-RabasaS,Gallego-Galiana J, Perez-Cruz GF, Usandizaga-Elio I, et al. Compassionate Use of Rectal Ozone (O3) in Severe COVID-19 Pneumonia: A Case-Control Study [published online ahead of print, 2021 Mar 22]. SN ComprClin Med. 2021;1-15.
Shah M, Captain J, Vaidya V, et al. Safety and efficacy of ozone therapy in mild to moderate COVID-19 patients: A phase 1/11 randomized control trial (SEOT study). Int Immunopharmacol. 2021;91:107301.
Çolak Ş, GençYavuz B, Yavuz M, Özçelik B, Öner M, Özgültekin A, Şenbayrak S. Effectiveness of ozone therapy in addition to conventional treatment on mortality in patients with COVID-19. Int J ClinPract. 2021;e14321.
Azuma K, Mori T, Kawamoto K, Kuroda K, Tsuka T, Imagawa T, et al. Anti-inflammatory effects of ozonated water in an experimental mouse model. Biomed Rep. 2014;2(5):671-674.
Wei A, Feng H, Jia XM, Tang H, Liao YY, Li BR. Ozone therapy ameliorates inflammation and endometrial injury in rats with pelvic inflammatory disease. Biomed Pharmacother. 2018;107:1418-1425.
Wang X, Wang G, Liu C, Cai D. Effectiveness of intra-articular ozone injections on outcomes of post-arthroscopic surgery for knee osteoarthritis. Exp Ther Med. 2018;15(6):5323-5329.
Zeng J, Lei L, Zeng Q, Yao Y, Wu Y, Li Q, et al. Ozone Therapy Attenuates NF-κB-Mediated Local Inflammatory Response and Activation of Th17 Cells in Treatment for Psoriasis. Int J Biol Sci. 2020;16(11):1833-1845.
Fitzpatrick E, Holland OJ, Vanderlelie JJ. Ozone therapy for the treatment of chronic wounds: A systematic review. Int Wound J. 2018;15(4):633-644.
Mawsouf MN, Tanbouli TT, Viebahn-Hansler R. Ozone Therapy in Patients with Viral Hepatitis C: Ten Years' Experience. Ozone: Science and Engineering. 2012;34(6):451-458.
Blanco A, Ojembarrena FB, Clavo B, Negro C. Ozone potential to fight against SAR-COV-2 pandemic: facts and research needs. Environ SciPollut Res Int. 2021;28(13):16517-16531.
Fernández-Cuadros ME, Albaladejo-Florín MJ, Peña-Lora D, Álava-Rabasa S, Pérez-Moro OS. Ozone (O3) and SARS-CoV-2: Physiological Bases and Their Therapeutic Possibilities According to COVID-19 Evolutionary Stage [published online ahead of print, 2020 Jul 7]. SN Compr Clin Med. 2020;1-9.
Cattel F, Giordano S, Bertiond C, Lupia T, Corcione S, Scaldaferri M, et al. Ozone therapy in COVID-19: A narrative review. Virus Res. 2021;291:198207.
Izadi M, Cegolon L, Javanbakht M, Sarafzadeh A, Abolghasemi H, Alishiri G, et al. Ozone therapy for the treatment of COVID-19 pneumonia: A scoping review. Int Immunopharmacol. 2021;92:107307.
Gavazza A, Marchegiani A, Rossi G, Franzini M, Spaterna A, Magiaterra S, Cerquetella M. Ozone Therapy as a Possible Option in COVID-19 Management. Front Public Health. 2020;8:417.
Smith NL, Wilson AL, Gandhi J, Vatsia S, Khan SA. Ozone therapy: An overview of pharmacodynamics, current research, and clinical utility. Med Gas Res 2017;7:212-219.
Kesic MJ, Meyer M, Bauer R, Jaspers I. Exposure to ozone modulates human airway protease/antiprotease balance contributing to increased influenza A infection. PLoS One. 2012;7(4):e35108.