Clinical effectiveness of medical ozone therapy in COVID-19: the evidence and gaps map.

Ozone therapy (OT), a medical procedure, has been showing good results during the coronavirus disease (COVID-19). We aimed to build an evidence and gaps map (EGM) of OT in the COVID-19 ranking the articles found according to levels of evidence and outcomes. The EGM brings bubbles of different sizes and different colors according to the articles. The OT intervention used was major or minor autohemotherapy, rectal insufflation and ozonized saline solution. EGM was based on 13 clinical studies using OT for COVID-19 involving a total of 271 patients. We found 30 outcomes related to OT in COVID-19. Our EGM divided the outcomes into six groups: 1-clinical improvement; 2-hospitalization; 3-inflammatory, thromboembolic, infectious, or metabolic markers; 4-radiological aspects, 5-viral infection and 6-adverse events. Major autohemotherapy was present in 19 outcomes, followed by rectal insufflation. Improvement in clinical symptoms of COVID-19, improvement of respiratory function, improvement of oxygen saturation, reduction in hospital internment, decrease in C-reactive protein, decrease in ferritin, decrease in lactate dehydrogenase, decrease in interleukin 6, decrease in D-dimer, radiological improvement of lung lesions and absence of reported adverse events were related in the papers. The most commonly used concentrations of OT in major autohemotherapy and in rectal insufflation were 40 µg/mL and 35 µg/mL, respectively. Here, we bring the first EGM showing the efficacy and safety of OT in the treatment of COVID-19. OT can be used as integrative medical therapy in COVID-19 at a low cost and improve the health conditions of the patients.

The role of ozone therapy in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19): a review.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has rapidly swept across the world. As new knowledge regarding treatment options for COVID-19 has emerged, the use of ozone therapy in the context of SARS-CoV-2 infection as an integrative therapeutic option supplementary to standard treatment regimen has been assessed in the present literature. We reviewed, critically analyzed, and summarized all present published literature on ozone therapy in association with COVID-19 via the PubMed database. Various reports and studies on the use of ozone (major autohemotherapy, rectal ozone insufflation, ozone inhalation) in patients affected by COVID-19 indicate that ozone therapy may reduce morbidity and accelerate recovery, while exhibiting a high safety profile with no relevant adverse effects. Current literature suggests that integrating ozone therapy into the existing standard of care and best available therapy for the treatment of COVID-19 patients offers major advantages in terms of superior clinical outcome parameters and amelioration of laboratory results. Further prospective studies are warranted to guide the next steps in the clinical application of ozone therapy and examine its impact on the course of COVID-19.

Benefits of ozone on mortality in patients with COVID-19: A systematic review and meta-analysis.

BACKGROUND: The Coronavirus disease-2019 (COVID-19) pandemic continues, and the death toll continues to surge. Ozone therapy has long been used in the treatment of a variety of infectious diseases, probably through its antioxidant properties and the supply of oxygen to hypoxic tissues. This systematic review and meta-analysis aimed to determine the efficacy of ozone on mortality in patients with COVID-19. METHODS: A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Prospective controlled trials on treatment of COVID-19 with ozone, compared with placebo or blank, were reviewed. Studies were pooled to risk ratios (RRs) and weighted mean differences (WMDs), with 95% confidence intervals (CIs). RESULTS: Eight trials (enrolling 371 participants) met the inclusion criteria. Ozone therapy showed significant effects on mortality (RR 0.38, 95% CI 0.17-0.85; P = 0.02), length of hospital stay (WMD -1.63 days, 95% CI -3.05 to -0.22 days; P = 0.02), and polymerase chain reaction (PCR) positivity (RR 0.07, 95% CI 0.01-0.34; P = 0.001). CONCLUSIONS: Ozone therapy significantly reduced mortality, PCR positivity, and length of stay in hospitalized patients with COVID-19. Ozone therapy should be considered for COVID-19 patients.

[The role of systemic ozone therapy in the rehabilitation of patients after COVID-19]. / Rol' sistemnoi ozonoterapii v reabilitatsii patsientov, perenesshikh COVID-19.

OBJECTIVE: To evaluate the effectiveness and safety of ozone therapy in rehabilitation of patients with previous COVID-19. MATERIAL AND METHODS: A randomized controlled clinical trial included 51 patients aged 29 - 78 years with SARS-CoV-2 pneumonia (J12.8). Patients were divided into 3 comparable groups depending on the complex of rehabilitation. In the first (control) group (n=17), a 10-day course included daily breathing exercises and physiotherapy for the lungs (drug electrophoresis and low-frequency magnetotherapy). In the second (main) group (n=18), rehabilitation was combined with daily intravenous infusions of ozonized saline with ozone concentration of 2.0 mg/l within 5 days with subsequent standard rehabilitation. In the third group (n=16), patients received 5 ozone therapy procedures every other day. To determine the effectiveness and safety of systemic ozone therapy in rehabilitation of patients with previous COVID-19, we analyzed oxygen saturation, laboratory data (D-dimer and C-reactive protein), need for oxygen support before and after rehabilitation course. Complaints and quality of life throughout the rehabilitation program were assessed using the EQ-5D questionnaire. RESULTS: All patients had positive changes of all parameters. There were no adverse reactions throughout the rehabilitation program and 2 months later. We observed higher effectiveness of rehabilitation with systemic ozone therapy. Moreover, daily ozone therapy had a better effect on laboratory parameters compared to ozone therapy every other day. CONCLUSION: Ozone therapy is safe and effective in complex rehabilitation of patients with previous COVID-19. Further studies of large samples are needed to determine indications and appropriate criteria for this rehabilitation program.

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. (PROSPERO ID: CRD42021278018).

COVID-19 and low back pain: previous infections lengthen recovery time after intradiscal ozone therapy in patients with herniated lumbar disc.

PURPOSE: To assess and compare the clinical effectiveness of percutaneous intradiscal ozone therapy in patients affected by lumbar disc herniation, with and without history of COVID-19 infection. MATERIALS AND METHODS: After the rising of COVID-19 pandemics in Italy, 47 consecutive percutaneous intradiscal ozone therapies were performed on patients with low back pain and/or sciatic pain due to lumbar disc herniation. Among these, 19 had suffered from COVID-19 and successively recovered with no residual symptoms, while the remaining 28 had not previously been affected by COVID-19 and were not convalescent. Oswestry Disability Index (ODI) was administered before the treatment and at 1-month and 3-month follow-up in order to assess the clinical outcome. RESULTS: The two groups were similar in terms of patient age (p-value 0.54), treated levels (p-value 0.26) and pre-procedure ODI (p-value 0.33). Technical success was achieved in all cases. In patients previously affected by COVID-19, mean ODI decrease was 11.58 ± 9.51 (35.72%) at 1-month follow-up and 20.63 ± 9.87 (63.63%) at 3-month follow-up. In patients never affected by COVID-19, mean ODI decrease was 20.93 ± 10.53 (58.73%) at 1-month follow-up and 22.07 ± 11.36 (61.92%) at 3-month follow-up. Eventually, clinical success was registered in 84.21% (16/19) of patients with history of COVID-19 infection and in 85.71% (24/28) of patients with no history of COVID-19 infection. No major complication was registered. CONCLUSIONS: In case of lumbar disc herniation treated with percutaneous intradiscal ozone therapy, patients previously affected by COVID-19 showed a significantly longer recovery time.

Nrf2/Keap1/ARE signaling: Towards specific regulation.

The Nrf2 transcription factor governs the expression of hundreds genes involved in cell defense against oxidative stress, the hallmark of numerous diseases such as neurodegenerative, cardiovascular, some viral pathologies, diabetes and others. The main route for Nrf2 activity regulation is via interactions with the Keap1 protein. Under the normoxia the Keap1 binds the Nrf2 and targets it to the proteasomal degradation, while the Keap1 is regenerated. Upon oxidative stress the interactions between Nrf2 and Keap1 are interrupted and the Nrf2 activates the transcription of the protective genes. Currently, the Nrf2 system activation is considered as a powerful cytoprotective strategy for treatment of different pathologies, which pathogenesis relies on oxidative stress including viral diseases of pivotal importance such as COVID-19. The implementation of this strategy is accomplished mainly through the inactivation of the Keap1 "guardian" function. Two approaches are now developing: the Keap1 modification via electrophilic agents, which leads to the Nrf2 release, and direct interruption of the Nrf2:Keap1 protein-protein interactions (PPI). Because of theirs chemical structure, the Nrf2 electrophilic inducers could non-specifically interact with others cellular proteins leading to undesired effects. Whereas the non-electrophilic inhibitors of the Nrf2:Keap1 PPI could be more specific, thereby widening the therapeutic window.

Potential therapeutic effect of oxygen-ozone in controlling of COVID-19 disease.

Atmospheric ozone is produced when nitrogen oxides react with volatile organic compounds. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains a unique N-terminal fragment in the Spike protein, which allows it to bind to air pollutants in the environment. 'Our approach in this review is to study ozone and its effect on the SARS-CoV-2 virus and patients with coronavirus disease 2019 (COVID-19). Article data were collected from PubMed, Scopus, and Google Scholar databases. Ozone therapy has antiviral properties, improves blood flow, facilitates the transfer of oxygen in hypoxemic tissues, and reduces blood coagulation phenomena in COVID-19 patients. Ozone has immunomodulatory effects by modulating cytokines (reduction of interleukin-1, interleukin-6, tumor necrosis factor-α, and interleukin-10), induction of interferon-γ, anti-inflammatory properties by modulating NOD-, LRR- and pyrin domain-containing protein 3, inhibition of cytokine storm (blocking nuclear factor-κB and stimulating nuclear factor erythroid 2-related factor 2 pathway), stimulates cellular/humoral immunity/phagocytic function and blocks angiotensin-converting enzyme 2. In direct oxygen-ozone injection, oxygen reacts with several biological molecules such as thiol groups in albumin to form ozonoids. Intravenous injection of ozonated saline significantly increases the length of time a person can remain hypoxic. The rectal ozone protocol is rectal ozone insufflation, resulting in clinical improvement in oxygen saturation and biochemical improvement (fibrinogen, D-dimer, urea, ferritin, LDH, interleukin-6, and C-reactive protein). In general, many studies have shown the positive effect of ozone therapy as a complementary therapy in the recovery of COVID-19 patients. All the findings indicate that systemic ozone therapy is nontoxic and has no side effects in these patients.

Using Ozone Therapy as an Option for Treatment of COVID-19 Patients: A Scoping Review.

Recent investigations are seeking a novel treatment to control the new pandemic of coronavirus 19 (COVID-19). The aim of this systematic review was to study the effect of ozone therapy on COVID-19 patients and the available supporting evidence. Electronic databases including MEDLINE (via PubMed), EMBASE, Cochrane Library (CENTRAL), and TRIP, clinical trial registries, and preprint sources were searched for published evidence-based articles. In addition, manual searching was conducted for articles published up to April 6, 2020, using MeSH and free text keywords with no language limitation. Articles were screened, categorized, and extracted for relative data. Data were reported in a descriptive manner. Among 234 articles, 9 were selected for review of the inclusion criteria. No published original articles were found regarding the efficacy of ozone therapy on COVID-19. Five review studies were found in which the potential role of systemic ozone therapy was concluded to be effective in controlling COVID-19 because of its antiviral, oxygenation, anti-inflammatory, oxidation balancing, and immunomodulation effects. Three ongoing clinical trials were registered in China. A preliminary report of an ongoing study in Italy on 46 patients (11 intubated and 35 non-intubated) showed that in 39 (84%) of the patients, an improvement was seen. In spite of the promising background data, as well as the expert opinions and a preliminary report indicating the effectiveness of ozone, there is still not enough evidence to confirm this as a viable treatment option for COVID-19.

A pilot study for treatment of COVID-19 patients in moderate stage using intravenous administration of ozonized saline as an adjuvant treatment-registered clinical trial.

OBJECTIVE: Ozone therapy has tremendous therapeutic potential owing to its antiviral, anti-inflammatory and antioxidant properties, and potential to improve oxygenation. A pilot clinical trial was conducted to evaluate the safety and efficacy ofintravenous ozonised saline treatment in patients with moderate COVID-19 pneumonia. PATIENTS AND METHODS: 10 patients were administered 200 ml freshly prepared ozonised saline intravenously over 1 h once a day for 8 days along with standard medical treatment. Clinical symptoms were monitored everyday and laboratory biomarkers, radiological findings at 1,3,6,10 days. Telephonic follow up was done for all after discharge till Day 14. 7 out of 10 patients required oxygen supplementation at recruitment. RESULTS: There was severe adverse event recorded in the study group.All patients improved from moderate to mild category in average 8 days and were discharged in average 9.7 days. None deteriorated to severe stage. All clinical symptoms resolved within 6 days and oxygen supplementation requirement reduced to none within 4.1 days. There wasstatistically significant reduction inCRP (p = 0.003), D-Dimer (p = 0.049), IL6 (p = 0.002)and statistically significant improvement (p = 0.001) in SpO2/FiO2 ratio. Change in LDH was borderline statistically not significant (p = 0.058).All patients showed significant resolution of bilateral interstitial infiltrates at the end of 10 days. CONCLUSION: Resolved clinical symptoms, improved oxygenation, clearance of infiltrates on Chest X-ray and improvement in biomarkers in a short period with non-progression of the disease showed that IV ozonised saline therapy was safe and effective to prevent disease progression in COVID-19, making it an effective novel therapeutic tool.

Ozone therapy for the treatment of COVID-19 pneumonia: A scoping review.

Severe forms of COVID-19 can evolve into pneumonia, featured by acute respiratory failure due to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In viral diseases, the replication of viruses is seemingly stimulated by an imbalance between pro-oxidant and antioxidant activity as well as by the deprivation of antioxidant mechanisms. In COVID-19 pneumonia, oxidative stress also appears to be highly detrimental to lung tissues. Although inhaling ozone (O3) gas has been shown to be toxic to the lungs, recent evidence suggests that its administration via appropriate routes and at small doses can paradoxically induce an adaptive reaction capable of decreasing the endogenous oxidative stress. Ozone therapy is recommended to counter the disruptive effects of severe COVID-19 on lung tissues, especially if administered in early stages of the disease, thereby preventing the progression to ARDS.

Safety and efficacy of ozone therapy in mild to moderate COVID-19 patients: A phase 1/11 randomized control trial (SEOT study).

INTRODUCTION: The Corona virus disease 19 (COVID-19) has accounted for multiple deaths and economic woes.While the entire medical fraternity and scientists are putting their best feet forward to find a solution to contain this deadly pandemic, there is a growing interest in integrating other known alternative therapies in to standard care. This study is aimed at evaluating the safety and efficacy of ozone therapy (OT), as an adjuvant to the standard of care (SOC). METHODS: In the current randomized control trial, 60 patients with mild to moderate score NEWS score were included in two parallel groups (n = 30/group). The interventional group (OZ) received ozonized rectal insufflation and minor auto haemotherapy, daily along with SOC, while the control group (ST) received SOC alone. The main outcome measures included changes in clinical features, oxygenation index (SpO2), NEWS score, Reverse transcription polymerase chain reaction(RT-PCR), inflammatory markers, requirement of advanced care, and metabolic profiles. RESULTS: The OZ group has shown clinically significant improvement in the mean values of all the parameters tested compared to ST Group. However, statistical significance were only observed in RT-PCR negative reaction (P = 0.01), changes in clinical symptoms (P < 0.05) and requirement for Intensive care (P < 0.05). No adverse events were reported in OZ group, as against 2 deaths reported in ST group. CONCLUSION: OT when integrated with SOC can improve the clinical status and rapidly reduce the viral load compared to SOC alone, which facilitate early recovery and check the need for advanced care and mortality as demonstrated in this study.

Ozone therapy for patients with COVID-19 pneumonia: Preliminary report of a prospective case-control study.

BACKGROUND: There is still no specific treatment strategies for COVID-19 other than supportive management. DESIGN: A prospective case-control study determined by admittance to the hospital based on bed availability. PARTICIPANTS: Eighteen patients with COVID-19 infection (laboratory confirmed) severe pneumonia admitted to hospital between 20th March and 19th April 2020. Patients admitted to the hospital during the study period were assigned to different beds based on bed availability. Depending on the bed the patient was admitted, the treatment was ozone autohemotherapy or standard treatment. Patients in the case group received ozonated blood twice daily starting on the day of admission for a median of four days. Each treatment involved administration of 200 mL autologous whole blood enriched with 200 mL of oxygen-ozone mixture with a 40 µg/mL ozone concentration. MAIN OUTCOMES: The primary outcome was time from hospital admission to clinical improvement. RESULTS: Nine patients (50%) received ozonated autohemotherapy beginning on the day of admission. Ozonated autohemotherapy was associated with shorter time to clinical improvement (median [IQR]), 7 days [6-10] vs 28 days [8-31], p = 0.04) and better outcomes at 14-days (88.8% vs 33.3%, p = 0.01). In risk-adjusted analyses, ozonated autohemotherapy was associated with a shorter mean time to clinical improvement (-11.3 days, p = 0.04, 95% CI -22.25 to -0.42). CONCLUSION: Ozonated autohemotherapy was associated with a significantly shorter time to clinical improvement in this prospective case-control study. Given the small sample size and study design, these results require evaluation in larger randomized controlled trials. CLINICAL TRIAL REGISTRATION NUMBER: NCT04444531.

Safety, pitfalls, and misunderstandings about the use of ozone therapy as a regenerative medicine tool. A narrative review.

Despite various opinions and healthy controversy on Ozone Therapy (OT), the practices of this therapy have increased worldwide. Main areas of study with consistent scientific outcomes are the topical treatment of both disk herniation and periodontal disease. On the other hand, there is a net dissociation of the scientific resonance concerning systemic oxygen/ozone treatments. It is our intention to discuss in logical terms the numerous papers that commendably reported adverse reactions attributable to OT, focusing our attention mainly to the techniques of administration and not to the simple contact of ozone with biological material. The case reports on OT treatments safety concerns discussed on international journals, make it possible to state that most safety issues are secondary to infections or traumatic reactions due to malpractice. Commonly, the molecule of ozone itself is not responsible of severe reactions at the therapeutic modalities. The millions of patients treated so far from the thousands of physicians correctly practicing OT world widely in the last 40 years demonstrate the safety of this simple and cost-effective regenerative medicine tool. The promising therapeutic implications also for the current COVID-19 emergency are a further stimulus to the standardization of this therapeutic resource with multiple application specificities.

Oxygen-ozone (O2-O3) immunoceutical therapy for patients with COVID-19. Preliminary evidence reported.

OBJECTIVE: This study evaluated the potential efficacy of a novel approach to treat COVID-19 patients, using an oxygen-ozone (O2-O3) mixture, via a process called Oxygen-Ozone- Immunoceutical Therapy. The methodology met the criteria of a novel, promising approach to treat successfully elderly COVID-19 patients, particularly when hospitalized in intensive care units (ICUs) Experimental design: We investigated the therapeutic effect of 4 cycles of O2-O3 in 50 hospitalized COVID-19 subjects suffering from acute respiratory disease syndrome (ARDS), aged more than 60 years, all males and undergoing non invasive mechanical ventilation in ICUs. RESULTS: Following O2-O3 treatment a significant improvement in inflammation and oxygenation indexes occurred rapidly and within the first 9 days after the treatment, despite the expected 14-20 days. A significant reduction of inflammatory and thromboembolic markers (CRP, IL-6, D-dimer) was observed. Furthermore, amelioration in the major respiratory indexes, such as respiratory and gas exchange markers (SatO2%, PaO2/FiO2 ratio), was reported. CONCLUSION: Our results show that O2-O3 treatment would be a promising therapy for COVID-19 patients. It leads patients to a fast recovery from ARDS via the improvement of major respiratory indexes and blood gas parameters, following a relatively short time of dispensed forced ventilation (about one to two weeks). This study may encourage the scientific community to further investigate and evaluate the proposed method for the treatment of COVID-19 patients.

Blood ozonization in patients with mild to moderate COVID-19 pneumonia: a single centre experience.

The emerging outbreak of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread worldwide. We prescribed some promising medication to our patients with mild to moderate pneumonia due to SARS-CoV-2, however such drugs as chloroquine, hydrossichloroquine, azithromycin, antivirals (lopinavir/ritonavir, darunavir/cobicistat) and immunomodulating agents (steroids, tocilizumab) were not confirmed as effective against SARS-CoV2. We, therefore, started to use auto-hemotherapy treated with an oxygen/ozone (O2/O3) gaseous mixture as adjuvant therapy. In Udine University Hospital (Italy) we performed a case-control study involving hospitalized adult patients with confirmed COVID-19 with mild to moderate pneumonia. Clinical presentations are based upon clinical phenotypes identified by the Italian Society of Emergency and Urgency Medicine (SIMEU-Società Italiana di Medicina di Emergenza-Urgenza) and patients that met criteria of phenotypes 2 to 4 were treated with best available therapy (BAT), with or without O3-autohemotherapy. 60 patients were enrolled in the study: 30 patients treated with BAT and O2/O3 mixture, as adjuvant therapy and 30 controls treated with BAT only. In the group treated with O3-autohemotherapy plus BAT, patients were younger but with more severe clinical phenotypes. A decrease of SIMEU clinical phenotypes was observed (2.70 ± 0.67 vs. 2.35 ± 0.88, p = 0.002) in all patients during hospitalization but this clinical improvement was statistically significant only in O3-treated patients (2.87 ± 0.78 vs. 2.27 ± 0.83, p < 0.001), differently to the control group (2.53 ± 0.51 vs. 2.43 ± 0.93, p = 0.522). No adverse events were observed associated with the application of O2/O3 gaseous mixture. O2/O3 therapy as adjuvant therapy could be useful in mild to moderate pneumonia due to SARS-CoV-2. Randomized prospective study is ongoing [Clinical Trials.gov ID: Z7C2CA5837].

Ozone therapy in COVID-19: A narrative review.

The main objective of this narrative review is to describe the available evidence on the possible antiviral activity of ozone in patients with COVID-19 and its therapeutic applicability through hospital protocols. Amongst different possible therapies for SARS-CoV-2 pneumonia, ozone therapy seems to have an immunological role because of the modulation of cytokines and interferons, including the induction of gamma interferon. Some data suggest the possible role of ozone therapy in SARS, either as a monotherapy or, more realistically, as an adjunct to standard treatment regimens; therefore, there is increasing interest in the role of ozone therapy in COVID-19 treatment The PubMed and Scopus databases and the Italian Scientific Society of Oxygen Ozone Therapy website were used to identify articles focused on ozone therapy. The search was limited to articles published from January 2011 to July 2020. Of 280 articles found on ozone therapy, 13 were selected and narratively reviewed. Ozone exerts antiviral activity through the inhibition of viral replication and direct inactivation of viruses. Ozone is an antiviral drug enhancer and is not an alternative to antiviral drugs. Combined treatment with involving ozone and antivirals demonstrated a reduction in inflammation and lung damage. The routes of ozone administration are direct intravenous, major autohaemotherapy and extravascular blood oxygenation-ozonation. Systemic ozone therapy seems useful in controlling inflammation, stimulating immunity and as antiviral activity and providing protection from acute coronary syndromes and ischaemia reperfusion damage, thus suggesting a new methodology of immune therapy. Systemic ozone therapy in combination with antivirals in COVID-19-positive patients may be justified, helpful and synergic.