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Three patients present to a hospital emergency department in Ibiza, Spain, with severe COVID-19 pneumonia and respiratory failure and are given an unproven -- and possibly dangerous -- treatment: oxygen-ozone (O₂-O₃) therapy -- also called ozonated autohemotherapy, which has been used to and involves intravenous infusion of ozonated autologous whole blood.

The FDA has called ozone Furthermore, in April 2020, a federal court entered a permanent halting a purported "ozone therapy" center in Dallas from offering unproven treatments for COVID-19, after the company claimed that the treatments were able to "eradicate" the virus and were 95% effective in preventing the illness even for individuals who had tested positive.

As described in this , published on Aug. 17, 2020, of three patients in Spain, the clinicians drew 200 mL of autologous whole blood from the antecubital vein into a standard plastic disposable blood collection bag (certified SANO₃ bag) with 35 mL of anticoagulant citrate dextrose solution. The team enriched the blood with 200 mL of gas mixture O₂-O₃ with an ozone concentration of 40 μg/mL obtained using an ozone generator with CE0120 certificate type IIb. This was followed by reinfusion of the ozonized blood using the same vein over approximately 10 minutes.

Patient 1

Patient 1, a 49-year-old man, body mass index (BMI) of 31, reported having 1 week of ongoing abdominal pain, and that over the course of the previous day he had increasing shortness of breath. Examination finds a soft abdomen with no distension.

Upon auscultation of his chest, clinicians noted bilateral crackles with reduced air entry and ordered a computed tomography (CT) scan of the chest and abdomen, which identified lung infiltrates in both lungs, compatible with COVID-19 pneumonia. Laboratory tests show elevated levels of:

• Ferritin (1,609 ng/mL)

• D-dimer (1,900 ng/dL)

• C-reactive protein (CRP, 17.3 mg/dL)

• Lactate dehydrogenase (LDH, 536 IU/L)

Clinicians took a nasopharyngeal swab; real-time polymerase chain reaction (RT-PCR) analysis identified the sample as positive for viral RNA, and the man is admitted to the intensive care unit (ICU). Over the following 24 hours, his condition improves and he is transferred to the general ward.

However, during the following day, the patient's oxygen levels declined, followed by respiratory distress, with a PaO2/FiO2 [partial pressure of arterial oxygen/percentage of inspired oxygen] ratio of 235. Clinicians put the patient on a non-rebreather face mask with oxygen on FiO2 of 0.8, and noninvasive ventilation (NIV) is not required. An x-ray revealed diffuse bilateral infiltrates.

For the next 3 days, the patient received two sessions of ozone autohemotherapy daily q 12 hours. He had a rapid clinical response, as evidenced by a marked improvement in respiratory rate and an increased PaO2/FiO2 ratio, with decreased FiO2 to 0.31% (3 L) after 1 day. After 2 sessions of ozone therapy, the patient's ferritin levels dropped from over 2,000 to 246 ng/mL, and his D-dimer levels dropped from 1,900 to 323 ng/mL.

On day 4, the patient was discharged home.

Patient 2

The second patient, a 61-year-old man, BMI of 29, presented a week after developing a persistent fever of over 39°C. He reported having long-standing hypertension and becoming progressively short of breath over the previous 2 days. Chest auscultation showed crackles with reduced air entry over the right hemithorax. CT of the chest–abdomen revealed right upper infiltrates suggestive of COVID-19 pneumonia. Baseline PaO2/FiO2 was 253.

Laboratory tests showed high levels of:

• Ferritin (2,200 ng/mL)

• D-dimer (3,660 ng/mL)

• CRP (10 mg/dL)

• LDH (816 IU/L)

The patient remained in the general ward, where he received oxygen at an FiO2 of 0.6 via face mask, and he did not require NIV.

For the following 2 days, he received two sessions of ozone autohemotherapy over a period of 24 hours. On day 3, clinicians noted a decline in the FiO2 of 0.31% (3 L) with improved PaO2 to 90 mmHg, and decreased levels of laboratory markers.

The patient was discharged home on day 3 after a total of four sessions of O₂-O₃ therapy. Post-discharge, clinicians reported that the patient's LDH levels dropped from 816 U/L at baseline to 469 U/L by day 6 after the start of ozone therapy. Likewise, his CRP levels began falling progressively after initiation of ozone therapy, from 10 mg/dL at the time of presentation to approximately 4 mg/dL on day 3 and about 0 mg/dL on day 21.

Patient 3

The third patient, a 64-year-old woman with a BMI of 20, presented with progressive shortness of breath over 3 days. Clinicians diagnosed her with COVID pneumonia, and took a nasopharyngeal swab sample. Laboratory tests showed high levels of:

• Ferritin (656 ng/mL)

• D-dimer (657 ng/dL)

• CRP (5 mg/dL)

• LDH (452 IU/L)

RT-PCR analysis of the swab was positive for viral RNA; baseline PaO2/FiO2 is 243. The patient is admitted to the general ward, where she received oxygen at an FiO2 of 0.8 via face mask; NIV is not required. Clinicians immediately initiated O₂-O₃ therapy.

Treatment was followed by rapid recovery as demonstrated by the patient's clinical and laboratory profiles, which were similar to those of Patients 1 and 2. Her D-Dimer levels dropped from 657 to approximately 130 ng/mL 1 day after ozone therapy and remained at 100 -200 ng/mL for the next 4 days.

CRP levels fell to 1 mg/dL on day 2 and continued to decline for the patient's remaining time in the hospital. She received six sessions of O₂-O₃ therapy in total, and was discharged to home on day 4 after ozone therapy.

Discussion

Clinicians reporting these three cases noted that in all the patients, four to six sessions of ozonated autohemotherapy was associated with early discharge from the hospital without the need for invasive ventilation.

The authors noted that there is no effective treatment for COVID-19 pneumonia and only limited understanding of the pathogenesis of the virus, resulting in a growing use of novel methods. Ozone is known to have antipathogenic activity and can induce the release and modulation of interferons and related cytokines, such as interleukin (IL)-2, interferon-gamma, tumor necrosis factor, and colony-stimulating factors; ozone can also modulate and stimulate phagocytic function, which may explain its potential benefits in treatment of COVID-19 infection, the case authors speculated.

They explained that medical ozone generators produce 1-5% ozone gas in 95-99% oxygen from pure oxygen, and that therapeutic applications generally use concentrations of 10-70 μg/mL. As described, the process of "ozonated autohemotherapy" involves systemic delivery of ozone therapy by adding it to a sample of a patient's blood and then reinfusing it.

When blood is exposed to this gas mixture , oxygen equilibrates with the extracellular and intra-erythrocytic water before becoming bound to hemoglobin until it is fully oxygenated, the authors explained. They added that since ozone is approximately 10 times more soluble than oxygen, it reacts immediately with any soluble compounds and biomolecules such as ascorbic acid, urate, free cysteine, glutathione molecules, and albumin thiol groups, and then disappears.

The theory, the authors said, is that the reaction process – i.e., reactive oxygen species and lipid ozonation products – generates com­pounds that act as "ozone messengers," thus theoretically providing ozone's presumed biological effects. Ozone can deliver sufficient energy and oxygen to the tissues through several mechanisms: (1) by activating the ; (2) by elevating 2,3-diphosphoglyceric acid content in erythrocytes; and (3) by stimulating erythrocyte oxygen metabolism.

Angiotensin-converting enzyme 2 is an entry receptor for COVID-19 that can be blocked by control of the nuclear factor erythroid 2-related factor 2 (Nrf2), which controls the activity of this receptor, the case authors continued. They suggested that ozone's rapid activation of Nrf2 activation may help block endogenous COVID-19 reduplication by preventing contact with this receptor. In addition, the authors said, ozone therapy could theoretically decrease the hypercoagulation phenomena associated with COVID-19 by of blood, which has been reported to be beneficial in ischemic vascular diseases.

And because there is an associated such as PGI₂, there may be benefits in microthrombosis, the case authors said.

They also suggested that given the significant rates of kidney damage in COVID-19 patients, potential renal protection may represent another treatment benefit of ozone, which modulates local accumulation of neutrophils, expression of interleukin-6, tumor necrosis factor-alpha and albumin , and . There may also be , given that cytokine modulation helps prevent deterioration associated with the inflammatory response that characterizes severe infection, the case authors further speculated.

They explained that severe oxidative stress is known to activate nuclear transcriptional factor kappa B (NFκB), resulting in an inflammatory response and tissue injury via the production of cyclooxygenase-2, prostaglandin E₂, and cytokines. Moderate oxidative stress, however, activates another nuclear transcriptional factor -- nuclear factor erythroid 2-related factor 2 (Nrf2). This then can induce the transcription of antioxidant response elements, which in turn may result in the production of antioxidant enzymes, which like free antioxidants, help protect cells from oxidation and inflammation.

Thus, the authors state, ozone therapy may also activate Nrf2 via moderate oxidative stress, and suppress NFκB and inflammatory responses.

Regarding use of ozone therapy overall, the case authors pointed to a of the mechanisms of action involved in the method unrelated to COVID-19 that noted that during the last 4 decades, "millions" of O₃ autohemotransfusion procedures were performed in Europe "without any problem," and that the "recorded four deaths were due to direct intravenous administration of O₂-O₃, a practice prohibited since 1984." Ozone therapy in general is commonly used in Russia, Ukraine, and China, those authors noted.

Also unrelated to the novel coronavirus, a published by the Spanish Association of Medical Professionals in Ozone Therapy noted "growing interest" in the technique among medical professionals, as assessed by MedLine/PubMed searches showing 235 clinical studies; the association noted that the European Medicines Agency includes ozone as an authorized active substance and has active projects in research.

Conclusions

The case authors concluded by stating that while O₂-O₃ therapy appeared to lead to improvement in these three COVID-19 patients with severe respiratory failure, the method remains unproven, and the only way to know whether it is indeed effective is to conduct large controlled clinical trials to study the efficacy and safety compared with standard supportive care in terms of the need for invasive ventilation and length of stay in the hospital and ICU.

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