Persistent COVID-19: Post-acute coronavirus disease 2019 (COVID-19) syndrome, or long COVID, refers to a condition marked by prolonged symptoms that extend beyond the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, in some cases appearing weeks or months after the first infection.1 Regarding epidemiology, it is estimated that approximately 10% to 20% of individuals infected with COVID-19, regardless of severity, experience this condition. Although there are no strong data on genetic or epigenetic predispositions or predispositions that may determine a greater likelihood of contracting it, Long COVID is a clinical condition more present in middle-aged women and in those patients who experienced more symptoms in the first week of infection.1,2 The exact pathophysiological mechanisms remain unclear; however, some authors suggest that the excessive and sustained release of proinflammatory cytokines after COVID-19 infection promotes very heterogeneous symptoms due to a subsequent and progressive immune dysregulation. This aspect had already been observed and proposed in other immunoinflammatory pathologies that can be triggered by a viral infection, in fact Long COVID is known to present pathophysiological mechanisms like other conditions such as chronic fatigue syndrome/myalgic encephalomyelitis or fibromyalgia.3,4 Recent studies have also shown that COVID is one of the few viruses able to cross the blood-brain barrier and deposit in the central nervous system, generating a long- term neurotoxic effect that triggers systemic responses including neuromuscular system involvement that could lead to chronic fatigue associated with this pathology. Exaggerated levels of systemic inflammation (“cytokine storm”) can also sensitize glial cells, increasing the risk of neurological manifestations such as encephalitis and stroke.3 Hypercoagulability and cardioembolic events, resulting from virus-related cardiac lesions, are manifestations that could lead to an increased incidence of stroke and other neurological diseases following COVID-19 infection. Oxidative damage has also been proposed as a persistent element in these patients; however, it has not yet been possible to determine to what extent this may be triggered late.4 From a symptomatologic point of view, as mentioned above, patients experience very heterogeneous symptoms ranging from myalgia, brain fog, dyspnea, palpitations and neurocognitive alterations to dermatological alterations, and above all chronic fatigue, which is the most frequently described symptom in the more than 400 million people affected. In addition to chronic fatigue, psychological symptoms are also quite frequent, with aspects such as anxiety and depression (30–40%) that trigger insomnia and obsessive-compulsive symptoms, all of which are very common in patients affected by fibromyalgia. The clinical symptoms and pathophysiological mechanisms associated with persistent COVID-19 mark a dualism with fibromyalgia that is worth exploring.4,5 From the point of view of clinical treatment, there are different suggestions and recommendations on the monitoring of the main symptoms, but there is no definitive treatment, and the clinical trials published so far are oriented towards multidisciplinary clinical approaches. This clinical condition poses, on the one hand, a medical-social problem and, on the other hand, a therapeutic challenge, since current treatments are insufficient, and the clinical alterations associated with this condition significantly deteriorate the quality of life of those affected.4,5 Medical ozone: Fundamentals: Ozone treatment in medicine is an emerging treatment for pathologies involving redox imbalance, chronic hypoxia, inflammation and immune deficiencies. The objective is to provoke controlled and innocuous “micro-oxidation” that modulates the antioxidant systems (Figure 1).6Figure 1: Summary of the clinical rationale for ozone treatment in patients with Long COVID.This infographic illustrates the key concepts presented in the article. Long COVID is characterized by prolonged symptoms such as chronic fatigue, inflammation, oxidative stress, and immune dysregulation. Ozone treatment is proposed as a complementary therapeutic approach due to its immunomodulatory, antioxidant, and oxygenation-enhancing properties. The figure highlights the systemic routes of administration — major blood ozonation and rectal insufflation — and the physiological mechanisms through which ozone may contribute to the improvement of symptoms and overall patient function. Created with ChatGPT, Paint, and Adobe Photoshop Express. COVID: Coronavirus disease; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.Systemic ozone treatment is administered mainly by two routes: indirect intravenous, or major blood ozonation according the proposed WFOT (World Federation of Occupational Therapists) nomenclature and rectal insufflation.7 In the first case, a small amount of blood is extracted from the patient, treated with a mixture of ozone diluted in oxygen and re-injected to the patient. In the second case, the rectal insufflation of oxygen and ozone is directly into the rectum by means of a suitable catheter. The objective, in both cases, is to accelerate the cellular metabolic response in order to obtain healing of lesions, improve the release of oxygen to tissue and modulate the immune system.6,8 In addition, there are two other non-systemic ways to administer medical ozone: topical and subcutaneous infiltration. In the first case, it is administered by means of ozonized oils and in the second case it is administered directly in the painful region by means of direct infiltration and normally under ultrasound guidance. Because this type of delivery is usually quite painful, before it is performed, the patient is subjected to local anesthetics such as mepivacaine.8 Medical applications of ozone: Currently, multiple clinical applications of medical ozone are known due to its anti-inflammatory, antioxidant, immunostimulant and germicidal properties. In the field of musculoskeletal diseases, its use is widely documented in the treatment of herniated discs, acute and chronic low back pain, arthritis, arthrosis and tendinopathies. In vascular diseases, numerous studies and systematic reviews have supported its use in peripheral arterial disease, chronic venous insufficiency and diabetic foot. In dentistry, dermatology and oncology, its complementary use is widely justified in order to improve the quality of life during conventional treatments and to support fatigue and pain.6 General biological effects: Ozone reactions in the body lead to the production of reactive oxygen species, mainly hydrogen peroxide (H2O2) and products of lipid oxidation. Most of the H2O2 is sequestered by erythrocytes, which are activated to enhance oxygen delivery to tissues. Lipid oxidation products activate the NRF2 pathway, upregulating the expression of genes located in the DNA region called Antioxidant Response Elements.9,10 Numerous preclinical studies have shown that by regulating the redox system, stimulating the production of endogenous antioxidant enzymes such as glutathione peroxidase and superoxide dismutase. Furthermore, it is known from other authors that the medical ozone has a general protective and germicidal function, inactivating bacteria, viruses and fungi by membrane and protein oxidation.6 The described effects on immunomodulatory function are centered on the proliferation of cytokines (interferon, tumor necrosis factor, and interleukins), while the improvement in oxygenation and tissue perfusion are due to the release of oxygen from hemoglobin and mitochondrial function.6 Adverse effects and contraindications of ozone: The biological effects described above are achieved with specific therapeutic concentrations, since it has been demonstrated that in high or inadequate doses, ozone may not have the desired effects.8 Conventionally this drug is considered safe and with few adverse effects, however, infrequent symptoms associated with the type of administration have been described. When ozone is injected, the patient may experience pain, burning or bruising and local inflammation. However, according to the authors, these symptoms are more related to the administration technique than to the action of the drug. In sensitive individuals, cases of dizziness and mild nausea have been reported, with symptoms disappearing within a few hours.6,8 Although no serious adverse effects have been observed, there are certain absolute contraindications for the administration of ozone. In patients with G6PD deficiency, severe hyperthyroidism, blood clotting diseases, or who have suffered recent episodes of cerebral hemorrhage or acute myocardial infarction, its use is not recommended.8 Systemic ozone treatment in fibromyalgia and persistent COVID-19: Fibromyalgia is a significantly limiting chronic immunoinflammatory disease, whose main symptoms are chronic pain, chronic fatigue, unrefreshing sleep and cognitive deficits. At present, there is no fully effective treatment.10 Its etiopathogenesis is complex, and it is not associated with any inflammation or lesion visible or detectable with clinical tests, which makes diagnosis and treatment difficult. However, numerous authors have suggested and observed an underlying redox imbalance in affected patients. From the point of view of treatment, there is currently no single pathway that can be corrected, so the approach must be multidisciplinary and aimed at treating the symptoms rather than the pathology.11 Due to the systemic anti-inflammatory characteristics of ozone, numerous trials have been carried out with fibromyalgic patients, obtaining encouraging and very promising results, especially in aspects such as pain, sleep, mental acuity and fatigue. Several reviews show a good tolerability to ozone treatment and clinical, functional, analytical and radiological improvements in fibromyalgic patients undergoing treatment with ozone.10,11 Because on the one hand both fibromyalgia and Long COVID are complex syndromes determined by symptomatic overlap, namely in fatigue, chronic pain and cognitive symptoms, on the other hand, both diseases are triggered by viral processes and finally systemic inflation is a common feature of both, therapeutic strategies could benefit from a shared approach. Currently, only three studies have been found on medical ozone, delivered by major blood ozonation, former autohemotherapy, in patients with persistent COVID-19, however, the improvements are significant, in both studies, especially in pain, fatigue and functional capacity. According to He et al.,12 the combination of conventional treatment with medical ozone not only improved symptoms in patients with PASC more effectively than conventional treatment alone, but no adverse effects were observed, which promotes medical ozone as a new treatment option for this condition. Tirelli et al.,13 similarly, observed in a sample of 100 patients with persistent COVID undergoing ozone treatment, that 67% recovered normal function and showed improvement in pain and discomfort in the form of post-acute COVID-19 syndrome associated fatigue regardless of sex and age. Finally, Soldatenko et al.,14 in a sample of 140 patients, observed that the group undergoing ozone treatment as a coadjutant to pharmacological treatment showed a significant reduction in oxidative stress and a remarkable improvement in mental status, with 95% of patients in the ozone treatment group experiencing complete or near complete resolution of clinical symptoms associated with Long COVID, with no adverse effects described. These findings suggest that systemic ozone treatment may be an effective and pathogenically relevant strategy for the comprehensive outpatient management of post-acute COVID-19 syndrome. Based on the above, medical ozone could contribute to improving the quality of life and benefit the immunoinflammatory response of patients with persistent COVID-19. Therefore, we propose to conduct an open pilot study to evaluate the efficacy, tolerability, and biological and thermographic changes of ozone treatment via rectal insufflation as an added adjunctive treatment in patients with persistent COVID-19. Conclusion: The cited literature suggests the need to delve deeper into this area through new experimental studies that can more convincingly justify the relationship between the clinical features associated with this chronic condition and the effects of medical ozone treatment.
Pérez et al. (Fri,) studied this question.