Marcos Edgar Fernández-Cuadros, María Jesús Albaladejo-Florín, Sandra Álava-Rabasa, Isabel Usandizaga-Elio, Dolores Martinez-Quintanilla Jimenez, Daiana Peña-Lora, Inmaculada Neira-Borrajo, María Jesús López-Muñoz, Javier Rodríguez-de-Cía & Olga Susana Pérez-Moro
The aim of this study is to evaluate the effectiveness of rectal ozone (O3) in COVID-19 patients with severe pneumonia admitted at Hospital Universitario Santa Cristina, Madrid. In a before-and-after study, four patients admitted with severe bilateral pneumonia due to COVID-19 were treated with rectal ozone and confirmed with (+) RT-PCR for SARS-CoV-2 and evaluated afterwards. The analyzed outcome variables were as follows: (a) clinical improvement (O2 saturation and O2 supply); (b) biochemical improvement (fibrinogen, D-dimer, urea, ferritin, LDH, IL-6, and CRP); (c) radiological improvement. The treatment protocol consisted of 5 sessions (1 session/day) of intra-rectal ozone, applied in a volume of 100 mL and a concentration of 35 μg/mL. The Protocol was previously approved by the Hospital’s Health Care Ethics Committee (CEAS) (Report 15/4/2020) for compassionate use in the face of this exceptional pandemic situation, and prior informed consent was obtained from the patient/legal representative. The patients improved oxygen saturation, as observed by the lower number of desaturations and the lower supply of O2. Biomarkers of inflammation decreased (fibrinogen, D-dimer, urea, ferritin, LDH, IL-6, and CRP). Finally, the radiological signs of bilateral viral pneumonitis improved between 1 and 2 grades based on Taylor’s radiological scale. Rectal ozone decreases O2 supply and improves O2 saturation, decreases inflammation biomarkers, and improves Taylor’s radiological grade in patients with severe COVID-19 pneumonia. Rectal ozone is a safe, effective, cheap, and simple alternative capable of acting on the SARS-CoV-2 virus, and it is presented as an adjunctive therapeutic option to consider in the management of severe bilateral COVID-19 pneumonia.
Management of SARS-CoV-2 virus disease or COVID-19 disease has no proven effective treatments to date. In fact, the Spanish Ministry of Health, in the Technical document entitled “Clinical Management of COVID-19: Hospital Care” states that there is currently no evidence from controlled clinical trials to recommend a specific treatment for the SARS-CoV-2 infection in patients with suspected or confirmed COVID-19. However, this information could change rapidly due to the results of several ongoing clinical trials (https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/documentos/Protocolo_manejo_clinico_ah_COVID-19.pdf).
On the other hand, the pandemic situation means that there is a real risk of saturation of the health system with the need to reorganize it and a probable shortage of material and human resources is expected (https://www.eldiario.es/sociedad/coronavirus-sobrecarga-sanidad-Comunidad-Madrid_0_1004050083.html).
Currently, about 80 clinical trials are being carried out that seek to define the best therapy for the management of SARS-CoV-2 infection, of which only 3 are dedicated to the study of ozone on this disease and its potential therapeutic use . None of the clinical trials consider rectal ozone as a therapeutic option for the management of COVID-19 infection.
The current treatment for COVID-19 is supporting, and respiratory failure due to acute respiratory distress syndrome (ARDS) is the main cause of mortality. A subgroup of patients with severe COVID-19 could develop a hyperinflammation or “cytokine storm” syndrome . Early identification and treatment of hyperinflammation using all existing therapies with acceptable safety profiles is of paramount importance in order to reduce mortality .
Several studies (from Cuba, Italy, Germany, Russia, and Spain) and years of experience have shown that ozone (O3) is capable of modulating inflammation and pain, in addition to having demonstrated a bactericidal, fungicidal, virucidal, and antiparasitic effect [4, 5]. These antimicrobial properties have made ozone recognized as a disinfectant so effective that it is used in many water purification plants worldwide . In this context, in a recent review, Fernández-Cuadros et al. reasonably considered that ozone has a place in the management of the present SARS-CoV-2 pandemic, due to its virucidal, immunomodulatory, stimulating cellular and humoral immunity properties, and as a facilitator of O2 transport in hypoxemic tissues .
In the SARS-CoV-2 infection, three evolutionary stages are recognized (early infection (stage 1), normoxic and hypoxic lung phase (Stage 2a and b), and systemic hyperinflammation or cytokine storm (stage 3)), with characteristic signs and clinical symptoms . In this scenario, Fernández-Cuadros et al. consider that at least 4 biological properties of O3 could allow its use as adjuvant therapy in the different phases of SARS-CoV-2 infection. Ozone could inactivate the virus by direct (O3) or indirect oxidation (ROS (reactive oxygen species) and LOPs (lipid oxidative products)) and could stimulate the cellular and humoral immune system being useful in the early COVID-19 infection phase (stage 1 and 2a). Ozone improves gas exchange, reduces inflammation, and modulates the antioxidant system, making it useful in the hyper inflammation or cytokine storm phase, and in the hypoxemia and / or multi-organ failure phase (stage 2b and stage 3) 
The objective of this article is to show the preliminary results on the effectiveness of rectal O3 in a small series of COVID-19 patients with severe bilateral pneumonia admitted at the Santa Cristina University Hospital in Madrid, Spain.
Material and Methods
A prospective quasi-experimental before-and-after study was performed. The study included 4 severe COVID-19 patients admitted at the Santa Cristina University Hospital, with clinical symptoms and RT-PCR (reverse transcriptase polymerase chain reaction) positive for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). The study was conducted from April to May 2020, and the Hospital’s Health Care Ethics Committee (CEAS Report 15/4/2020) authorized the study and ozone treatment for compassionate use.