Is Ozone therapy an adjunct treatment for SARS-CoV-2 / COVID-19 infection?

Arias-Vázquez, Pedro Iván; Arcila-Novelo, Russell; Ramírez-Wakamatzu, María Antonieta

doi:10.1590/s2175-97902022e20775

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Brazilian Journal of Pharmaceutical Sciences

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Article • Braz. J. Pharm. Sci. 58 • 2022 • https://doi.org/10.1590/s2175-97902022e20775 copy

Is Ozone therapy an adjunct treatment for SARS-CoV-2 / COVID-19 infection?

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Up to today, there is no specific treatment against SARS-CoV-2 / COVID-19 infection; there the necessity to search for alternatives that help patients with COVID-19. The objective of this study was to review the use of ozone therapy as adjunct treatment for SARS-CoV-2 / COVID-19 infection, highlighting the mechanisms of action, forms of application and current clinical evidence. A systematic review was conducted in electronic databases, searching the terminology Ozone “or” Ozone therapy “and” SARS-CoV-2 or COVID-19 or Coronavirus. Results: nineteen studies were included; ten were editorials, comments, brief reports or reviews, and nine clinical studies. We found that ozone therapy could be favorable for treating patients infected with SARS-CoV-2 / COVID-19, through a direct antiviral effect, regulation of oxidative stress, immunomodulation and improvement of oxygen metabolism. Patients who were treated with ozone therapy responded favorably; therefore, ozone therapy appears to be a promising treatment for patients infected with SARS-CoV-2 / COVID-19. Its mechanism of action justifies its use as an adjuvant therapy; however, scientific evidence is based on case series and clinical trials are necessary to corroborate its effectiveness and safety.

Keywords:
Ozone therapy; Infection; COVID-19

Author and year.	Design	Patients treated	Treatment characteristics	Results	Level of Evidence
*Wu et al., 2020*Wu J, Tan C, Yu H, Wang Y, Tian Y. Case Report: Recovery of One ICU-Acquired COVID-19 Patient Via Ozonated Autohemotherapy. SSRN. 2020. doi:10.2139/ssrn.3561379 https://doi.org/10.2139/ssrn.3561379... .	Case report study.	One patient (56 years) with severe pneumonia due to COVID-19, with hypoxemia and need of high-flow nasal cannula oxygen therapy.	Antiviral therapy, antibiotics, immunoglobulin, corticosteroid and high-flow nasal cannula oxygen therapy. Ozone Therapy: Major Autohemotherapy with 100 ml of venous blood ozonized at 40 μg/ml for 5 consecutive days.	Clinical improvement with decreased need of high-flow nasal cannula and decreased inflammatory markers.	IV
Zheng, Dong, Ku, 2020Zheng Z, Dong M, Ku H. A preliminary evaluation on the efficacy of ozone therapy in the treatment of COVID-19. J Med Virol. 2020;92(11):2348-2350. doi: 10.1002/jmv.26040 https://doi.org/10.1002/jmv.26040... .	Case report study	Two patients (53 and 66 years) with severe COVID-19, pneumonia with hypoxemia and need of supplemental oxygen.	Antiviral therapy, antibiotics, immunoglobulin, supplemental oxygen. Ozone Therapy: Major Autohemotherapy with 100 ml ozonized venous blood at 20 μg/ml for 7 consecutive days.	In both cases there was clinical improvement with a decrease in the need for supplemental oxygen and a decrease in inflammatory markers. After treatment, in both patients remitted symptoms and discharged testing negative for SARS-CoV-2.	IV
*Fernández-Cuadros et al., 2020b*Fernández-Cuadros MA, 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. 2020b;3:1-9..	Case report study.	Four patients (median 66.2 years) with severe bilateral pneumonia due to COVID-19, with hypoxemia and need of supplemental oxygen with nasal glasses or face mask in three of them.	Hydroxychloroquine, antiviral therapy, antibiotics, corticosteroids, monoclonal antibodies and high flow high-flow oxygen therapy. Ozone Therapy: Rectal insufflation of 100 ml of ozone at concentration of 35 μg/ml 5 consecutive days.	Clinical improvement with decreased need for supplemental oxygen, improved oxygen saturation and decreased inflammatory markers.	IV
*Hernández et al., 2020b*Hernández A, Viñals M, Isidoro T, Vilás F. Potential Role of Oxygen-Ozone Therapy in Treatment of COVID-19 Pneumonia. Am J Case Rep. 2020b;21:e925849..	Case report study.	Three patients (49, 61 and 64 years) with COVID-19 pneumonia, with hypoxemia and respiratory distress, with need of supplemental oxygen with face mask.	Unspecified drug treatment. Supplemental oxygen with face mask Ozone Therapy: Major Autohemotherapy with 200 ml ozonized venous blood at 40 μg/ml for 4 to 6 daily sessions.	Improvement of hypoxemia and decreases in inflammatory markers. No patient required invasive mechanical ventilation. All patients were discharged home on days 3-4 after ozone therapy.	IV
Peña-Lora, Albaladejo-Florín, Fernández-Cuadros, 2020Peña-Lora DY, Albaladejo-Florín MJ, Fernández-Cuadros ME. Usefulness of rectal ozonetherapy in a geriatric patient with severe COVID-19 pneumonia. Rev Esp Geriatr Gerontol. 2020. (in press). doi:10.1016/j.regg.2020.07.005 https://doi.org/10.1016/j.regg.2020.07.0... .	Case report study.	One patient (84 years) with COPD and pneumonia due to COVID-19, with hypoxemia and increase in the requirement of supplemental oxygen.	Antibiotics, corticosteroids and oxygen therapy. Ozone Therapy: Rectal insufflation of 100 ml of ozone at concentration of 35 μg/ml 5 consecutive days.	Decreases in inflammatory and thromboembolic markers, normalization of oxygen demand and radiological improvement. Medical discharge	IV
*Hernández et al., 2020c*Hernández A, Viñals M, Pablos A, Vilás F, Papadakos PJ, Wijeysundera D, et al. Ozone Therapy for Patients with SARS-COV-2 Pneumonia: A Single-Center Prospective Cohort Study. Insights Biomed. 2020c;5(4):13..	Prospective cohort study.	Eighteen patients with COVID-19 pneumonia with oxygen saturation <94%. Nine patients with standard treatment for pneumonia due to COVID - 19 (age 71 years± 18). Nine patients with additional ozone therapy (age 64 years± 11).	All patients received usual clinical care for COVID-19 pneumonia: hydroxychloroquine, antivirals, corticosteroids, and antibiotics. Supplemental oxygen therapy. Ozone Therapy: Major Autohemotherapy with 200 ml ozonized venous blood at 40 μg/ml twice daily for a median of 4 days.	The ozone therapy group showed a shorter time to achieve clinical improvement (-11.3 days 95% CI -22.25 to -0.42), as well as significantly shorter time to a 2-fold reduction in concentrations of C-protein reactive, ferritin, D -dimer and lactate dehydrogenase.	III
*Franzini et al., 2020*Franzini M, Valdenassi L, Ricevutic G, Chirumbolod S, Depfenharte M, Bertossif D, et al. Oxygen-ozone (O2- O3) immunoceutical therapy for patients with COVID-19. Preliminary evidence reported. Int Immunopharmacol. 2020;88:106879..	Case series study.	Fifty patients (mean age 75 years ± 11.4) with COVID-19 pneumonia, with acute respiratory disease syndrome undergoing non-invasive mechanical ventilation. 48 patients completed the study, 2 died.	Hydroxychloroquine, anticoagulants, corticosteroids, and antibiotics. Supplemental oxygen therapy. Ozone Therapy: 3 - 5 (median = 4) cycles of Major Autohemotherapy with 100-200 ml (median 125 ml) ozonized venous blood at 45 μg/ml with daily application.	A significant reduction of inflammatory and thromboembolic markers was observed. Furthermore, amelioration in respiratory and gas exchange markers were reported.	IV
Schwartz, Narro, 2020Schwartz A, Narros RM. COVID-19 Dermatological manifestations. Presentation of two cases. Ozone Ther Global J. 2020;10(1):27-38..	Case report study.	Two cases with skin lesions due to COVID-19: First case: (4-year-old girl) with itchy skin rashes. Second case: (70-year-old man) with erythematous prugiriform type rash.	First case: Acetaminophen Ozone Therapy: Rectal insufflation: 50 ml at 25 μg/ml 2 sessions. 50 ml at 30 μg/ml 2 sessions. 75 ml at 30 μg/ml 3 sessions. 100 ml at 30 μg/ml 3 sessions. Ozonated oil, dermal application twice a day. Antioxidants.	In both cases, the lesions disappeared at the end of the 10 treatment sessions.	IV
	Case report study.		Second case: Anticoagulant. Ozone Therapy: Ozonized Saline Solution at 5 μg/ml applied daily for 5 days, followed by 5 days at 3 μg/ml. Ozonized oil, dermal application twice a day. Antioxidants.		IV
*Schwartz et al., 2020*Schwartz A, Martínez-Sánchez G, Menassa de Lucía A, Mejía-Viana S, Alina-Mita C. Complementary Application of the Ozonized Saline Solution in Moderate and Severe Patients with Pneumonia Covid-19: Efficacy and Tolerability. Preprints 2020, 2020060233. doi:10.20944/preprints202006.0233.v1 https://doi.org/10.20944/preprints202006... .	Case series study.	Twenty-five patients (mean age 55 years) with mild to severe COVID-19 pneumonia, 14 of them needed supplemental oxygen. All patients completed the study.	Hydroxychloroquine, Tocilizumab, anticoagulants, corticosteroids, antibiotics. Ozone Therapy: 200 ml of Ozonized Saline Solution at 5 μg/ml applied daily for 5 days, followed by 5 days at 3 μg/ml.	Improvement in 76% of treated patients, with reduction of symptoms such as dyspnea, weakness and fever, as well as decreased inflammatory markers. None of the patients treated with ozone therapy died.	IV

Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
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[1] *Correspondence: P.I. Arias - Vazquez. Universidad Juárez Autónoma de Tabasco. División Académica Multidisciplinaria de Comalcalco. Ranchería Sur, Cuarta Sección, C.P. 86650. Comalcalco, Tabasco, México. Phone: +52 9331253495. E-mail: pivanav@gmail.com.