Ozone is a naturally energy-rich molecule that incorporates unique physicochemical and biological properties that suggest a possible role in SARS therapy, either as a monotherapy or, more realistically, as an addition to standard treatment regimens.
Due to the excess energy contained in the O 3 molecule , it is theoretically likely that O3 , unlike the organism-specific antiviral options available today, will show efficacy across the entire genotype and subtype spectrum of SARS. [Gérard V, Sunnen MD. SARS and ozone therapy: theoretical considerations. [cited in 2003].
Available from: http://www.triroc.com/sunnen/topics/sars.html ]
Ozone (O3 ) , a gas discovered in the mid-19th century, is a molecule composed of three oxygen atoms in a dynamically unstable structure due to the presence of mesomeric states.
The gas is colorless, with acrid and explosive odor in liquid or solid form.
It has a half-life of 40 min at 20 ° C and about 140 min at 0 ° C. Its fundamental function is to protect humans from the harmful effects of UV rays. Ozone is found less than 20 μg / m 3 from the earth’s surface at concentrations perfectly compatible with life.
Although O3 has dangerous effects, however, researchers have found that it has a multitude of therapeutic effects. [ Di Paolo N, Bocci V, Gaggioti E. Ozone therapy editorial review. Artificial organs Int J. 2004; 27: 168–75. – * – Bocci V. Does ozone therapy normalize cellular redox balance? Implications for the treatment of human immunodeficiency virus infection and many other diseases. Hypothesis Med. 1996; 46: 150–4 ]
Ozone has the ability to oxidize organic compounds, [Razumovskii, Zaikov. New York: Elsevier; 1984. Ozone and its reactions with organic compounds. Available from: http://ozonicsint.com/articles_vivo.html ] and has well known toxic effects on the respiratory tract when present in smog. [ Effects on health and the environment of tropospheric ozone. US EPA. 1997. Jul, available at: http://www.practicalasthma.net/pages/topics/aaozone.htm .- * – Folinsbee LJ. Effects of ozone exposure on lung function in humans. Rev Environ Health. 1981; 3: 211–40. ]
In medical use, the gas produced by oxygen for medical use is administered in precise therapeutic doses and never by inhalation, has excellent health benefits in dental caries, decreases in blood cholesterol and stimulates antioxidant responses, modifies oxygenation of the muscle at rest and is used in the complementary treatment of hypoxic and ischemic syndromes. [ Bocci V. Is it true that ozone is always toxic? The end of a dogma. Toxicol Appl Pharmacol. 2006; 16: 493-504. – * – Clavo B, Pérez JL, López L, Suárez G, Lloret M, Rodríguez V, et al. Effect of ozone therapy on muscle oxygenation. J Altern Complement Med. 2003; 9: 251–6. ]
Ozone therapy has been used and extensively studied for many decades altogether.
Its effects are proven, consistent and with minimal side effects. The O3 medical used to disinfect and treat disease has existed for over 150 years.
Used to treat infections, wounds and multiple diseases, the effectiveness of O3 has been well documented. It was used to disinfect drinking water before the turn of the last century. Ozone was known to treat up to 114 diseases. [ Shoemaker JM. Ozone therapy: history, physiology, indications, results. [cited in 2010] http://www.fullcircleequine.com/oz_therapy.pdf ]
Ozone therapy has been used since the 1800s and in 1896 the genius Nikola Tesla patented the first O3 generator in the United States, later forming the “Tesla Ozone Company”. [McLean L. The miracle of ozone therapy. [quoted in June 2009]. Available from: http://www.zeusinfoservice.com/Articles/TheMiracleofOzoneTherapy.pdf ].
During the First World War (1914-18) doctors who were familiar with O3 .
Its antibacterial properties, and with few other medical resources at their disposal, they applied it locally to infected wounds and found that O3 not only remedied infections but also had hemodynamic and anti-inflammatory properties. [ Stoker G. Ozone in chronic middle ear deafness. Hand. 1902; 160: 1187–8 .]
By the late 1980s, reports had emerged that German doctors were successfully treating HIV-infected patients with 03-AHT (autohemotherapy).
There was therefore no pharmaceutical treatment for HIV and a pandemic was feared, so Canadian authorities authorized the study to test the safety and efficacy of 03-AHT in AIDS patients.
Ohmine in 2005 highlighted how ozone can inactivate both enveloped viral strains [McIntyre type 1 herpes simplex (HSV-1), Elstree vaccine strain (VAC), Indian vesicular stomatitis virus (VSV), influenza A (H1N1) A / WS / 33], than other non-enveloped viruses [human adenovirus type 2 (Ad2)].
After ozonation, the viral load was greatly reduced in a short time, from 15 to 60 minutes depending on the viral strain. Transmission electron microscope images of Ad2, HSV-1, VAC, and VSV confirmed the drastic morphological changes resulting after ozone treatment.
Ozone (O3 is an allotropic form of the element oxygen, containing one more atom than atmospheric oxygen.
It is particularly unstable and spontaneously decomposes into diatomic oxygen, which, in practice, makes it very difficult to transport and store.
Ozone therapy has been used for therapeutic purposes since the beginning of the last century and its use is increasingly in demand nowadays.
It is characterized by the simplicity of its application, its great effectiveness and with a good tolerance. International reports of adverse reactions to the application of ozone therapy place it among the lowest incidences with 0.0007% [8,9].
The preconditioning effect of ozone is able to rebalance the disturbed redox state in the organism .
Biochemically, when the blood is exposed to ozone for several minutes, it immediately reacts with different molecules present in biological fluids, i.e. antioxidants, proteins, carbohydrates and, preferably, polyunsaturated fatty acids (Criegee reaction), leading to the formation of alpha-hydroxy – hydroperoxides, hydrogen peroxide, ozonides and aldehydes such as 4-hydroxinonenal.
These are important signaling molecules, with crucial roles modulating inflammation, cell proliferation, cell growth and cell death .
These alkenals can activate a nuclear transcription factor, called erythroid-related factor 2 (Nrf2) present in the cell cytoplasm bound to the Keap-1 protein.
This protein has -NH2 and, mainly, -SH groups (Cys273 and Cys288) which, by binding alkenals [for example 4-hydroxynonenal (4-HNE)] at picomolar levels, causes a conformational change favoring the dissociation of Nrf2.
This is then imported into the nucleus where, after forming a heterodimer with the Maf protein (musculoaponeurotic fibrosarcoma), it interacts with the Antioxidant Response Element (ARE) on DNA.
As a result, the synthesis of several antioxidant enzymes (superoxide dismutase, catalase, glutathione reductase, glutathione S-transferase, NADPH-quinone oxidoreductase, heat shock protein 70, phase II enzymes and heme-oxygenase-1) is upregulated in various organs. .
Furthermore, it reduces iron overload and the consequent oxidative stress induced by elevated ferritin .
Increasing the antioxidant capacity is the fundamental step to counteract the chronic inflammation typical of diseases aggravated by chronic oxidative stress.
Improved antioxidant response has been reported in patients with asthma and chronic obstructive pulmonary disease (COPD), such as emphysema, treated with ozone therapy [14-16].
Specifically, improvements in IgE levels, inflammatory response, respiratory clinical status were observed. Furthermore, in patients with rheumatoid arthritis, ozone has exerted beneficial effects [17,18].
This efficacy of ozone can not only be explained through its actions on cytokine control (IL-1, decreased IL-6 and tumor necrosis factor α-TNFα) but can also restore cellular redox balance.
It is known that reactive oxygen species can function as a second messenger to activate the nuclear transcription factor NF-κB, which orchestrates the expression of a spectrum of genes involved in the inflammatory response.
Nrf2 is able to modulate inflammation through multiple mechanisms, such as the regulation of redox homeostasis and the suppression of pro-inflammatory genes, both directly and through interaction with NF-κB .
Nrf2-mediated ROS homeostatic control can break this vicious circle. Nrf2 reduces inflammation by preventing the recruitment of RNA polymerase II to initiate gene transcription of the pro-inflammatory cytokines IL-6 and IL-1β .
Nrf2’s ability to maintain redox homeostasis prevents DNA damage, preserves proteostasis, and improves mitochondrial function while suppressing acute and chronic inflammation .
The antioxidant and anti-inflammatory effects of ozone result in the activation of Nrf2, which is therefore considered a key factor in the effectiveness of ozone treatments.
A previous study reported that ozone preconditioning significantly reduced NF-κB expression and inhibited inflammatory responses in hepatic ischemic / reperfusion injury .
Ozone can achieve a balance between Nrf2 and NF-κB, modulating the expression of pro-inflammatory cytokines with an important effect in cytoprotection (Figure 1) .
Furthermore, the Nrf2 activator can attenuate aberrant inflammation mediated by the Toll-Like Receptor (TLR) by activating intrinsic cytoprotective proteins and suppressing pro-inflammatory mediators.
Thus, these two main signaling pathways can interact differentially and their cross-talk can be manipulated to regulate inflammation .
Activation of TLRs is essential for the initiation of an inflammatory response against pathogens, triggering the production of inflammatory cytokines, improving adaptive immunity .
At the same time, there is also a negative feedback mechanism that could prevent the over-activation of TLR signaling that could otherwise result in chronic inflammation or autoimmunity.
Activation of Nrf2 interferes with the expression of pro-inflammatory proteins and suppresses inflammation.
The interaction of TLR and Nrf2 helps in the regulation of the inflammatory process. The link between TLR signaling and the Nrf2-Keap1 pathway can act as a bridge between immune regulation and oxidative stress responses through the regulation of inflammation .
Ozone preconditioning was shown to improve inflammation and renal damage by blocking activation of the TLR4-NF-κB pathway in renal ischemia / reperfusion injury.
Furthermore, ozone significantly reduced the mRNA level of TNF-α, IL-1β, IL-6, ICAM-1 (Intercellular Adhesion Molecule 1) and MCP-1 (monocyte chemotactant protein 1) . On the other hand, in vitro medical ozone has proven effective against viruses, bacteria, fungi and spores, destroying the cell membrane and the envelope of viruses .
Figure 1: ozone and its relationship with Nrf2 and NF-κB.
Ozone, at therapeutic doses, is capable of producing a small transient and controlled oxidative stress. The nuclear transcription factor Nrf2 is usually present in the cytosol as a complex with the Keap-1 protein. 4-HNE (active ozone metabolite) binds to Keap1 Cys 151 and suppresses the constitutive inhibition of Nrf2, which then translocates to the nucleus. After binding to Maf, Nrf2 binds to ARE and activates the synthesis of highly cytoprotective enzymes (SOD, catalase, GSH, heme-oxygenase-1, HSP, etc.) while maintaining a redox balance. NF-ÎºB is also a regulated redox transcription factor, involved in inflammation, immune function, cell growth, and apoptosis. At rest, it exists in an inactive form complexed with the IκB inhibitor. In the presence of oxidative stress, H2O2 (active ozone metabolite) activates a tyrosine kinase which phosphorylates IκB and causes it to detach from the inactive complex. The heterodimer readily moves from the cytosol to the nucleus, where it regulates gene expression by forming new proteins such as cytokines (IL-1, IL-2, IL-6, IL-10, TNF-α), COX-2 , iNOS, adhesion molecules (ICAM), tissue factor, immunoregulatory molecules. At the same time, these two pathways inhibit each other at their transcription level via protein-protein interactions or through secondary messenger effects . Nrf2 opposes the transcriptional upregulation of proinflammatory cytokine genes. Nrf2 binds to the proximity of inflammatory cytokine genes, including IL-6 and IL-1β, and inhibits their transcription. The Nrf2 pathway also inhibits NF-ÎºB-mediated transcription by preventing IÎºB-Î ± degradation. At the same time, Nrf2 upregulates the expression of genes that encode antioxidant proteins. Similarly, NF-ÎºB-mediated transcription reduces Nrf2 activation by reducing ARE gene transcription, among other factors. Therefore, it can be considered that ozone is involved in the balance between these two transcription factors.
Nrf2, factor 2 related to nuclear erythroid factor 2; Keap1, a protein derived from Kelch-like erythroid cells; Maf, musculoaponeurotic fibrosarcoma; ARE, antioxidant response element; HO-1, heme oxygenase-1; 4-HNE, 4-hydroxynonenal; HSP, heat shock proteins; SOD, superoxide dismutase; GSH, reduced glutathione; H2O2, hydrogen peroxide; TNF, tumor necrosis factor; COX-2, cyclooxygenase-2; ICAM, intercellular adhesion molecule; iNOS, inducible nitric oxide synthase.
According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious public health problem.
An epidemic that causes lower respiratory tract infection. and completely inexplicable, it was first reported to the WHO National Office in China on December 31, 2019.
The new virus was called SARS-CoV-2 and the cause of the disease was “COVID-19”, which stands for “Coronavirus disease 2019” . Many of these patients deteriorated rapidly and required intubation and mechanical ventilation.
Mortality rates are assumed to be around 3.7%. There is currently no effective treatment [2,3].
Therapeutic strategies for dealing with the infection are only supportive. Prevention, aimed at reducing transmission speeds within the community, is our best weapon.
• Macrophage Activation Syndrome : A life-threatening complication characterized by hypercytokinemia (cytokine storm) with multiorgan failure. It is characterized by the uncontrolled activation and proliferation of T lymphocytes and macrophages, producing extensive tissue damage such as endothelial lesions leading to the production of microthrombi. Laboratory abnormalities include a decrease in white blood cells, platelets, and hemoglobin.
There is a production of a high level of transaminases, a marked increase in ferritin and evidence of activation of intravascular coagulation. The protagonist of this storm is mainly interleukin 6 (IL-6) which promotes the differentiation of B lymphocytes. The cytokine storm also stimulates the production of acute phase proteins and also plays a role in thermoregulation, in the maintenance of bone and central nervous system function. During inflammatory diseases, infections, autoimmune diseases, cardiovascular diseases and some cancers, there is an increase in IL-6.
• Antiphospholipid syndrome : it is a disease of the autoimmune system that manifests itself clinically as recurrent venous or arterial thrombosis.
This also alters the homeostatic regulation of blood clotting. D-dimer is elevated in most patients with pneumonia and other clotting markers are abnormal. Thrombocytopenia is also observed, which appears to be associated with a worse prognosis.
Analytically, it affects the presence of high levels of ferritin in the blood. They appear to respond to an acute inflammatory process. Liver enzymes also tend to be elevated. The Fe2 + released into the blood, in the presence of hydrogen peroxide, produces hydroxyl radicals (Fenton reaction).
This is extremely toxic, causing oxidative damage, mainly lung, but also systemic. Damage to lung tissue stimulates the monocyte-macrophage system which contributes significantly to the inflammatory process. Taking into account all the therapeutic properties of ozone, which will be explained below, it can be proposed as an adjunct therapy for patients with COVID-19.
—– Haber-Weiss / Fenton reaction
The Haber-Weiss reaction is a chemical reaction that produces hydroxyl radicals (· OH) starting from hydrogen peroxide (H2O2) and superoxide (· O2-).
This reaction can occur inside cells, representing a potential source of oxidative stress. 
It owes its name to the chemist Fritz Haber and his student Joseph Joshua Weiss who first described it. 
The overall reaction, catalyzed by iron ions, is as follows:
·O2– + H2O2 → ·OH + OH– + O2
It is divided into two different phases, in which in the first there is the reduction of ferric ions to ferrous ions
Fe 3+ + O 2 – → Fe 2+ + O 2
Fe2+ + H2O2 → Fe3+ + OH– + ·OH
Under the name of “Haber-Weiss reaction” there is also a second type of reaction, less known than the previous one, in which the hydrogen peroxide reacts with the hydroxyl radical forming superoxide: 
H2O2 + ·OH → H2O + ·O2– + H+
1^ Dziubla, Butterfield, p.12
2 ^ F. Haber e J. Weiss, About the Catalysis of Hydroperoxide, in Natural Sciences, vol. 20, n.51, 1932, pp. 948-950, DOI: 10.1007 / BF01504715.
3^ Dziubla, Butterfield, p.66
4 ^ Haber – Weiss reaction, on IUPAC Gold Book. Retrieved November 23, 2016.
Ozone therapy and its positive effects in the treatment of patients with COVID-19
Among the therapeutic effects of ozone therapy that favors the positive evolution of patients with COVID-19 are:
– Ozone improves oxygen metabolism by increasing cellular oxygenation. Improvement of hexose-monophosphate shunt, due to activation of 2,3-DPG which, by binding to the β chain of hemoglobin (Hb), causes a shift to the right of the Hb dissociation curve.
This increases the release of oxygen in the hypoxic tissues. There is also an improvement in the glycolytic pathway on erythrocytes by significantly increasing their ATP content [11,13], recovering the elasticity of the red blood cell membrane thus improving blood rheology and capillarity .
There is a significant improvement in blood flow and oxygenation of ischemic tissues thanks to ozone treatment [27-30].
This is due to nitric oxide (NO), S-nitrosothiols cooperating with carbon monoxide (CO) and released prostacyclin [31,32].
Several preclinical and clinical studies have demonstrated the effect of ozone in modulating NO levels and its importance in the protection of vascular endothelial cells [32-34].
– Ozone is able to induce the release and modulation of interferons and related cytokines. In addition, it stimulates the antioxidant defense systems, counteracting the state of hyperinflammation, cytokine storm and oxidative stress suffered by patients with COVID-19.
This is achieved by increasing Nrf2 factors and restoring cellular redox balance [35,36]. There is also the activation of heme oxygenase-1 (HO-1) by increasing the release of CO and bilirubin. This helps reduce inflammation .
Several preclinical and clinical studies report a decrease in proinflammatory cytokines such as IL-1, IL-6, TNFα, as well as ICAM-1, MCP-1, among others [24,38-45]. Ozone has been able to modulate phagocytic cells in peripheral blood and the mechanisms on how the messengers can activate the immunological response leading to therapeutic biological effects [46,47].
This is a very positive effect on COVID-19 infection. The inflammatory response is a hallmark of severe SARS-CoV-2 infection, the cytokine storm can lead to the death of these patients.
The protective effect of ozone therapy was achieved due to its anti-inflammatory property through modulation of the receptor similar to the nucleotide-binding oligomerization domain containing the pyrine domain 3 (NLRP3) inflammasome, increasing the antioxidant activity of Nrf2 and inhibiting apoptosis [48,49].
The NLRP3 inflammasome is a critical component of the innate immune system that mediates the activation of caspase-1 and the secretion of proinflammatory cytokines IL-1β / IL-18 in response to microbial infection and cell damage.
On the other hand, the activation of the Toll-Like Receptor (e.g. TLR4) by SARS-CoV-2 causes a biochemical cascade that begins with the formation of pro-IL-1 cleaved by caspase-1 and followed by activation of the inflammasome.
IL-1 is secreted outside macrophages, mediating lung inflammation, fever and fibrosis and causing severe respiratory problems . Ozone preconditioning has been shown to protect the rat kidney from reperfusion injury by modulating the TLR4-NF-κB pathway .
– COVID-19 patients suffer from microthrombi due to increased viscosity and erythrocyte aggregation, among other factors. Ozone has an antiplatelet effect, increases some prostacyclines (such as PGI2) leading to vasodilation, as well as modulating antithrombin III [31,51].
All these effects, together with better blood circulation, can help to decrease the hypercoagulation phenomena present in these patients.
– Ozone can block the ability of the virus to replicate by balancing the cellular redox state by controlling Nrf2 [52,53]. Entry of SARS-CoV-2 cells depends on the angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2).
The SARS peak protein S will bind to ACE2. After attachment to ACE2, viral entry requires protein S priming, which is performed by protein S that cuts TMPRSS2. TMPRSS2 activity is essential for viral spread and pathogenesis in the infected host and TMPRSS2 inhibitors have been investigated as a potential therapeutic target for SARS-CoV-2.
Nrf2 activators play an important role in reducing viral pathogenesis by inhibiting virus entry through TRMPSS2 inhibition [54,55]. Nrf2 activators may offer several ways to regain control of important pathways to increase endurance and slow viral replication.
Application of an NRF2 activating agent, ACE2 mRNA was 3.5-fold down-regulated and TMPRSS2 was 2.8-fold down-regulated in human liver-derived HepG2 cells . Exacerbated lung damage in Nrf2 – / – mice was associated with increased lung expression of inflammatory cytokines (TNF-α, IL-1β, IL-6) and with a decrease in lung antioxidant and detoxifying enzymes compared to Nrf2 + / mice. + .
Furthermore, pretreatment with the Nrf2-ARE inducer sulforaphane significantly attenuated respiratory syncytial virus (RSV) -induced bronchopulmonary inflammation, epithelial damage and lung viral expression in Nrf2 + / + mice .
The study results confirmed an association of oxidative stress in the pathogenesis of RSV and provide compelling evidence for an important regulatory role of Nrf2-ARE as a host defense mechanism against RSV disease.
Another study found an inverse relationship between Nrf2 expression levels and influenza A viral entry and replication within nasal epithelial cells .
In response to experimentally applied mechanical ventilation, higher levels of alveolar and pulmonary vascular permeability and inflammatory responses were found in Nrf2 – / – mice than in Nrf2 + / + mice .
In mice, Nrf2 deficiency caused increased ovalbumin-driven airway inflammation and hyperreactivity. In this study, the best allergic response in Nrf2 – / – mice was associated with more pronounced pulmonary mucus cell hyperplasia, eosinophilic infiltration, increase in Th2 cytokines IL-4 and IL-13, and suppression of more antioxidants than in Nrf2 mice. + / + .
In an experimental sepsis model, Nrf2 deficiency increased the inflammation and mortality of mice against bacterial endotoxin (LPS), caecal ligation, and puncture-induced septic shock .
This indicates that Nrf2 is a new sepsis modifier that determines survival by mounting an appropriate innate immune response.
The data, therefore, suggest that Nrf2-ARE activators exert protective effects on LPS-induced inflammation and have suggested their potential therapeutic role for inner sepsis syndrome.
Taking into account that ozone stimulates Nrf2 [28,36,37,63], this could be an important physiological mechanism for blocking the endogenous reduplication of COVID-19 by preventing contact with SARS-CoV-19 receptors through the downregulation of ACE2 and TMPRSS2, inactivating the virus’ ability to enter cells .
The rebalancing of the cellular REDOX state obtained with ozone therapy is also important in the induction of cytokine synthesis in monocytes and lymphocytes and in the release of HO-1 and heat shock proteins which are powerful activators of the immune system [12, 64].
In summary, the positive aspect of ozone therapy is the ability to activate different defense mechanisms that cooperate to regain a normal redox system and a modulation of the NFκB / Nrf2 pathway. Today ozone therapy represents the most practical approach to integrate standard therapies to achieve homeostasis. Therefore, due to the therapeutic effects of ozone, it can be proposed as an adjunct therapy in SARS-CoV-2.
- Ozone therapy can be used to treat COVID-19.
- Ozone can achieve a balance between Nrf2 and NF-κB, modulating oxidative stress and pro-inflammatory cytokines.
- Ozone counteracts hyper-inflammation, cytokine storm and oxidative stress.
- Ozone improves oxygen metabolism, blood flow and oxygenation of ischemic tissues.
Studies and application of Oxygen Ozone therapy
Although ozone is a weak inducer, lymphocytes and monocytes reinfused during the main autohemotherapy, ozonated blood autohemotherapy (MAH – GAE), migrating through the lymphoid system are able to activate APC cells (cells presenting the antigen) as dendritic and macrophages present in the lymph nodes leading to the stimulation of the immune system ( Ref5 L .; Martinez-Sanchez, G .; Bordicchia, M .; Malcangi, G .; Pocognoli, A .; Morales-Segura, MA; Rothchild, J .; Rojas, A. Is ozone pre-conditioning effect linked to Nrf2 / EpRE activation pathway in vivo? A preliminary result. Eur. J. Pharmacol. 2014 , 742, 158–162 .)
Exploiting these properties, Cespedes et al ( Ref 6 Cespedes-Suarez J., Martin-Serrano Y., Carballosa-Peña MR, Dager-Carballosa DR Response of patients with chronic Hepatitis B in one year of treatment with Major Autohemotherapy. J Ozone Ther . 2018; 2 DOI: 10.7203 / jo3t.2.3.2018.11459 ) successfully used autohemotherapy (AHT) for the treatment of some patients with chronic hepatitis B; obtaining after one year of therapy not only the negativity of the surface antigen associated with undetectable values of the viral load with the presence of antibodies against the surface antigen itself, but also the restoration of normal values of transaminases, which demonstrate a functional recovery liver.
Gli stessi autori (Ref 7 Javier Cespedes-Suarez et al. “The immune response behavior in HIV-AIDS patients treated with Ozone therapy for two years” Journal of Ozone Therapy, Vol.2, No.3, 2018: / 1 9) treated 32 patients with HIV-1 AIDS with ozone therapy for two years, and the results were also a significant decrease in viral RNA to undetectable values and an increase in the number of CD4 and CD8 lymphocytes, with an improvement in the picture clinician of patients, thus demonstrating that autohemotherapy acted as a modulator of the immune system and as an enhancer of current antiretroviral therapy; however, unlike the work on hepatitis B, there are no data on the restoration of homeostasis of the immune system, nor on the presence of neutralizing antibodies, nor on the decrease in viral DNA reservoirs over time, which were instead observed even after 8 years in the Dr. Ensoli’s therapeutic vaccine in relation to the presence of anti-Tat neutralizing antibodies (Ref 8 Continued Decay of HIV Proviral DNA Upon Vaccination With HIV-1 Tat of Subjects on Long-Term ART: An 8-Year Follow-Up StudySgadari C et al. Front Immunol 2019; 13;10:233 doi: 10.3389/fimmu.2019.00233).
Excellent results with ozone therapy were obtained in 5 symptomatic patients infected with Ebola, (the high lethality (65%) hemorrhagic fever virus) in Sierra Leone in one week with complete remission of symptoms by Robert Jay Rowen et al ( Ref 9 Robert Jay Rowen et al RAPID RESOLUTION OF HEMORRHAGIC FEVER (EBOLA) IN SIERRA LEONE WITH OZONE THERAPY Afr. J. Infect. Dis. (2016) 10 (1): 49– 54 ).
It has also been observed that ozone therapy is able to kill the SARS1 virus in monkey cells in vitro as well as being of benefit in patients with bronchopneumonia and neurological complications ( Ref 10 Oxygen-ozone immunoceutical therapy in COVID-19 outbreak: facts and figures “Giovanni Ricevuti, Marianno Franzini, Luigi Valdenassi Ozone Therapy 2020; 5: 9014; Ref 11 The neuroinvasive potential of SARS ‐ CoV2 may play a role in the respiratory failure of COVID ‐ 19 patients Yan ‐ Chao Li et al. J Med Virol. 2020 Feb 27. doi: 10.1002 / jmv.25728 ), SARS2 COVID19 has a sequence homology of 82% with SARS 1, so these data, taken together, represent a rationale for curing Covid 19 with ozone therapy (Ref 12: “Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan”Chan JFEmerg Microbes Infect. 2020 Jan 28;9(1):221-236. doi: 10.1080/22221751.2020.1719902. eCollection 2020”).
In 1988 Bocci discovered that ozone can initially act as an inducer of cytokines such as IFNγ, IL-1, 2, 6, 7, 8, 10, tumor necrosis factor α (TNFα), granulocyte-macrophage colony stimulating factor (GM-CSF ) and transforming growth factors (TGF-β), using an optimal concentration of ozone at 70 µg / ml / g of blood, to then immediately activate the mechanisms to block oxidative stress (add Ref Bocci V “Does Ozone Therapy Normalize the Cellular Redox Balance? “Medical Hypotheses (1996) 46, 150-154)
Both HIV and Ebola viruses have in common with COVID19 that they produce a storm of cytokines in the infected organism leading to a dysregulation of the immune system with serious or fatal consequences.
Thanks to its antiviral and immunomodulating properties, ozone is able to counteract these serious effects by restoring homeostasis.
Ozone is the best agent available for water sterilization ( Ref 13 WHO. Disinfectants and Disinfection By-Products. Available en: https://www.who.int/water_sanitation_health/dwq/S04.pdf .).
Ozone therapy is not only highly effective, but also has a good tolerance, also due to the absence of side effects; in addition, no pathogens resistant to ozone treatment have ever been found.
Considering its wide spectrum of action, and all its properties, ozone therapy can be used for the treatment of Covid-19.
The Italian Society of Oxygen Ozone Therapy (SIOOT), thanks to the study of Prof. Marianno Franzini, Luigi Valdenassi, Giovanni Ricevuti, Salvatore Chirumbolo, Markus Depfenhart, Dario Bertossi, Umberto Tirelli, proposed to the Italian ISS (Istituto Superiore di Sanità) to use oxygen ozone therapy (O2-O3) in patients suffering from COVID-19.
The ISS declared on March 24, 2020 that it is possible to use oxygen ozone therapy to treat infectious diseases and therefore also patients with COVID-19 in the light of scientific evidence consolidated in the literature.
The proposal was approved, numerous works show that ozone is capable of killing viruses and bacteria, it has been tested that kills the Sars virus in monkey cells. Other published works demonstrate the effectiveness of Oxygen Ozone to treat bronchopneumonia.
In hospitals, treatment was performed under the responsibility of the physician, after obtaining the informed consent of the patient and the hospital ethics committee.
Since 1992, the Ministry of Health has certified systemic oxygen ozone therapy, antiviral and antibacterial therapy. In the case of Covid-19, it attacks the external part of the virus preventing it from replicating in the body. There are no viruses and bacteria that resist oxygen ozone therapy.
We studied the therapeutic effect of 4 cycles of systemic oxygen-ozone therapy (GAE) in 50 Covid-19 subjects admitted to intensive care with acute respiratory failure syndrome (ARDS), aged over 60 years, all of male and undergoing non-invasive mechanical ventilation in intensive care.
After treatment with a gaseous mixture of oxygen and systemic ozone (GAE), a significant and immediate improvement in the inflammation and oxygenation indices was found within the first 9 days, although 14-20 days were expected. A significant reduction in inflammatory and thromboembolic markers (CRP, IL-6, D-dimer) was observed.
Furthermore, an improvement in the main respiratory indices was highlighted, such as the gas exchange and respiratory parameters SatO2% (oxygen saturation), the PaO2 / FiO2 ratio (arterial partial pressure of oxygen in the blood / inspired fraction of oxygen).
Our results show that systemic oxygen ozone therapy results in a quick recovery from acute respiratory failure syndrome with an improvement in the main respiratory and blood gas indices, followed by a reduction in intubation times (approximately one or two weeks). .
This study pushes the scientific community to investigate and further study the proposed therapeutic methodology for the treatment of patients with Covid-19.
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