EDITORIAL

Ozone as a complement therapy in the treatment of COVID-19

Ozonoterapia como terapia complementar no tratamento da COVID-19

 

Jorge Bomfim Fróes de Farias1, Antonio Pedro Fróes de Farias2,3, Anelize Gimenez de Souza4

 

1Nucleus Reabilitação Cardíaca, Santo Antônio de Jesus, BA - Brasil

2Faculdade de Ciências e Empreendedorismo (FACEMP), Santo Antônio de Jesus, BA - Brasil

3Universidade Federal da Bahia (UFBA), Salvador, BA - Brasil

4Faculdade Nobre (FAN), Feira de Santana, BA - Brasil

 

Received on 2020, April 16; Accepted on: 2020, April 27.

Corresponding author: Jorge Bomfim Fróes de Farias, Av. Barros e Almeida, 114 Centro 44571-013 Santo Antônio de Jesus BA

 

Jorge Bomfim Fróes de Farias: jbfroes@hotmail.com

Antonio Pedro Fróes de Farias: froes_pedro@hotmail.com

Anelize Gimenez de Souza: ane_gimenez@hotmail.com

 

 

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) called “coronavirus 2019” (COVID-19), has become a threat to the general population and health professionals worldwide [1]. The clinical features of COVID-19 is like that of other respiratory viruses, with specifically, fever, generally dry cough, tiredness and, in more severe cases, dyspnea, pulmonary bleeding, severe lymphopenia and renal failure [2].

For diagnosis, the World Health Organization (WHO) recommends the collection of samples from the upper or lower respiratory tract. In the laboratory, the amplification of the genetic material extracted from the saliva or mucus sample is carried out by means of a reverse transcription followed by a polymerase chain reaction (RT-PCR), which involves the synthesis of a double-stranded DNA molecule from of an RNA template, in the search for conserved parts of the coronavirus genetic code. In patients with a confirmed diagnosis, the laboratory test should be repeated to assess the release of viral particles, before leaving the isolation [3].

The clinical manifestation and severity of the disease is directly related to the health condition of the infected individual. Symptoms are often mild as in a common cold or flu and it can progress to pneumonia. Ventilatory support therapy such as oxygen therapy and/or mechanical ventilation is necessary as an intervention method in the most severe cases of the disease [4]. Individuals with chronic respiratory diseases and other comorbidities can present the most severe form of COVID-19 and, for this reason, care with prevention should be emphasized [5].

Although there is no specific recommended antiviral treatment and no vaccine available, several therapeutic approaches have been proposed, such as: lopinavir/ritonavir [6]; chloroquine/hydroxychloroquine [7]; alpha interferon [8]; and remdesivir, an RNA polymerase inhibitor with in vitro activity against several RNA viruses, which have been shown to be effective in preclinical trials in the treatment of coronavirus infections [9].

In this moment of serious global health crisis, we highlight the possibility of using ozone gas or ozone therapy as an adjuvant in the antiviral treatment of COVID-19. Ozone gas (O3) is a molecule that consists of three oxygen atoms in a dynamically unstable structure due to the presence of mesomeric states. The gas is colorless, has a bitter odor and its basic function is to protect humans from the harmful effects of ultraviolet radiation. Ozone is a natural compound that is easily generated in situ from oxygen or air and decomposes into oxygen with a half-life of about 20 minutes [10,11].

Ozone therapy is a technique that uses an oxygen-ozone gas mixture for medicinal purposes. This technique assumes that O3 dissociates quickly and releases a reactive form of oxygen that can oxidize cells, increasing the availability of oxygen and ATP for cellular activity [11]. Ozone increases the rate of glycolysis of red blood cells, stimulating 2,3-diphosphoglycerate, promoting an increase in the amount of oxygen released to the tissues. Additionally, it activates the Krebs cycle, improving the oxidative carboxylation of pyruvate, stimulating the production of ATP. It also leads to a significant reduction in NADH and helps to oxidize cytochrome C. The production of prostacyclin, a potent vasodilator, is also induced by O3 [10,12].

      Ozone is deemed to be a prodrug, since it induces the activation of a biochemical cascade with multiple systemic antioxidant actions (Figure 1) [10,11]. O3 reacts with all biomolecules in cell membranes, including lipids, proteins, carbohydrates and DNA [13]. The unsaturated fatty acid, which is found in cell membrane phospholipids, reacts with O3 to generate hydrogen peroxide (H2O2) and 4-hydroxinonenal aldehyde (4-HNE). H2O2 promotes the transcription factor Nrf2 pathway and protein synthesis, which favor cell survival. Degradation of 4-HNE sends a signal of transient oxidative stress, activating the synthesis of various substances that respond to cellular oxidative stress such as: y-glutamyl transpeptidase, heat shock protein 70 (HSP-70), hemoglobin oxygenase-1 (HO-1); in addition to antioxidant enzymes, such as superoxide dismutase, glutathione peroxidase, catalase and glucose-6-phosphate dehydrogenase (G6PDH). This process represents the basis of the paradoxical phenomenon, for which an oxidizing molecule, such as O3, triggers a potent antioxidant reaction [11-13].

 

 

Adapted from Sciorsci et al. [11]. O3 = Ozone; H2O2 = hydrogen peroxide; 4-HNE = 4-hydroxynonenal; Nrf2 = erythroid nuclear factor 2 related to factor 2; SOD = superoxide dismutase; GSH-Px = glutathione peroxidase; G6PDH = glucose-6-phosphate dehydrogenase; HSP-70 = heat shock protein 70; HO-1 = hemoglobin oxygenase 1.

Figure 1 - The ozone mechanism of action.

 

The use of ozone has been shown to inactivate different microorganisms, such as bacteria, fungi and different viral strains, including the coronavirus [14]. Coronavirus is an enveloped RNA virus where glycoproteins rich in cysteine present in the viral envelope assist in recognition by host cells [3]. Cysteine contains a reduced thiol or sulfhydryl (-SH) group, essential for fusion and entry of the virus into the cell. Sulfhydryl groups are vulnerable to oxidation and, therefore, susceptible to ozone, due to their oxidizing power. Peroxides created by ozone administration oxidize cysteines and show antiviral effects that can serve to reduce viral load [15,16].

The immunological action of ozone is fundamentally directed on monocytes and T lymphocytes, which, once induced, release small amounts of cytokines, such as: interferon-gamma (IFN-g) tumor necrosis factor (TNF) and interleukin-2 (IL-2). The modulating activity of inflammation and the improvement of oxygenation in tissues, in combination with the induction of the activation of antibodies and cytokines, help to structure the immune response to fight several viral types [10,16].

Thus, ozone therapy may be potentially useful for SARS-CoV-2 infection in two therapeutic categories: surface disinfection [14]; or in systemic use as an additional compound, in order to improve the health status of patients and reduce viral load [17]. The mechanism of action has already been proven in other viral infections and involves: 1) induction of adaptation to oxidative stress, with restoration of the balance of the redox state of the cells; 2) induction of IFN-g and pro-inflammatory cytokines; 3) increased blood flow and oxygenation of vital organ tissues; 4) in addition to being able to act as an autovaccine when administered systemically in the form of autohemotherapy [17].

This is a time of vigilance, common sense and scientific investigation [2]. Some clinical studies using ozone therapy are being carried out in China and Italy to determine the effectiveness of this procedure as an adjuvant in the treatment of COVID-19 [18,19]. As there are no specific vaccines or pharmaceutical products for the treatment of this disease, the use of integrative and complementary practices, after a careful assessment of risks and benefits, can assist in the development of protocols to control the infection and disorders caused by SARS-CoV-2.

 

References

 

  1. Lai CC, Shih TP, Ko WC, Tang HJ, Hsueh PR. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents 2020;55(3):1-9. https://doi.org/10.1016/j.ijantimicag.2020.105924 
  2. Strabelli TMV, Uip DE. COVID-19 e o coração. Arq Bras Cardiol 2020. https://doi.org/10.36660/abc.20200209
  3. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD. Features, evaluation and treatment coronavirus (COVID-19). 2020 Apr 06. [Actualization 2020 Apr 06; cited 2020 Apr 22]. http://www.ncbi.nlm.nih.gov/books/NBK554776/#article-52171.s8
  4. Brasil. Diretrizes para diagnóstico e tratamento da COVID-19. Brasília: Ministério da Saúde; 2020. [Cited 2020 Abril 22]. https://portalarquivos.saude.gov.br/images/pdf/2020/April/13/Diretrizes-COVID-13-4.pdf
  5. Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM et al. Comorbidity and its impact on 1590 patients with Covid-19 in China: a nationwide analysis. Eur Respir J 2020. [ahead of print].
  6. Liu F, Xu A, Zhang Y, Xuan W, Yan T, Pan K et al. Patients of COVID-19 may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of COVID-19 progression. Int J Infect Dis 2020;95:183-191. https://doi.org/10.1016/j.ijid.2020.03.013 
  7. Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 2020 :105938 https://doi.org/10.1016/j.ijantimicag.2020.105938 
  8. Kang S, Peng W, Zhu Y, Lu S, Zhou M, Lin W et al. Recent Progress in understanding 2019 novel coronavirus associated with human respiratory disease: detection, mechanism and treatment. Int J Antimicrob Agents 2020:105950. https://doi.org/10.1016/j.ijantimicag.2020.105950 
  9. Gordon CJ, Tchesnokov EP, Feng JY, Porter D.P, Götte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavírus. J Biol Chem 2020;295915):4773-9. https://doi.org/10.1074/jbc.ac120.013056 
  10. Elvis AM, Ekta JS. Ozone therapy: A clinical review. J Nat Sci Biol Med 2011;2(1):66-70. https://doi.org/10.4103/0976-9668.82319 
  11. Sciorsci RL, Lillo E, Occhiogrosso L, Rizzo A. Ozone therapy in veterinary medicine: a review. Res Vet Sci 2020;130:240-6.  https://doi.org/10.1016/j.rvsc.2020.03.026 
  12. Viebahn-Hänsler R. The use of ozone in medicine: mechanisms of action. Munich. 2003. [cited 2020 Abril 23]. http://www.altered-states.net/barry/update247/TheUseofOzoneinMedicine.pdf
  13. Clavo B, Esparragón FR, Abreu DR, Sánchez GM, Llontop P, Bujanda DA et al. Modulation of oxidative stress by ozone therapy in the prevention and treatment of chemotherapy-induced toxicity: review and prospects. Antioxidants 2019;8(12):588. https://doi.org/10.3390/antiox8120588 
  14. Hudson JB, Sharma M, Vimalanathan S. Development of a practical method for using ozone gas as a virus decontaminating agent. Ozone Sci Eng 2009;31(3):216-23. https://doi.org/10.1080/01919510902747969 
  15. Madu IG, Belouzard S, Whittaker GR. SARS-coronavirus spike S2 domain flanked by cysteine residues C822 and C833 is important for activation of membrane fusion. Virology 2009;393:265-71. https://doi.org/10.1016/j.virol.2009.07.038 
  16. Hernández A, Papadakos PJ, Torres A, González DA, Vives M, Ferrando C et al. Dos terapias conocidas podrían ser efectivas como adyuvantes en el paciente crítico infectado por COVID-19. Rev Esp Anestesiol Reanim 2020 Apr 14. [ahead of print]. https://doi.org/10.1016/j.redar.2020.03.004 
  17. ISCO3. Potential use of ozone in SARS-CoV-2/COVID-19. Madri; 2020 March 14. International Scientific Committee of Ozone Therapy ISCO3. [cited 2020 April 5]. Disponível em: http://www.isco3.org
  18. Guangjian N, Hongzhi Y. Clinical study for ozonated autohemotherapy in the treatment of novel coronavirus pneumonia (COVID-19). Tianjin, 2020 Feb. 24. Tianjin University. [cited 2020 April 6]. http://www.chictr.org.cn/showproj.aspx?proj=49947
  19. Huiling H, Tong X. A multicenter randomized controlled trial for ozone autohemotherapy in the treatment of novel coronavirus pneumonia (COVID-19). Tianjin, 2020 Feb 23. Tianjin University. [Acesso em 2020 April 6]. http://www.chictr.org.cn/showprojen.aspx?proj=49747