key: cord-0981384-h7i1jpda
authors: Chirumbolo, Salvatore; Franzini, Marianno; Simonetti, Vincenzo; Valdenassi, Luigi; Ricevuti, Giovanni; Bertossi, Dario; Pandolfi, Sergio
title: Oxygen‐ozone autohemotherapy against COVID‐19 needs to fit highly experienced, customized, and standardized protocols to succeed
date: 2021-01-27
journal: J Med Virol
DOI: 10.1002/jmv.26806
sha: e0c7f8b99d31399db77abc0529e9d7c23cee9fe6
doc_id: 981384
cord_uid: h7i1jpda

nan

Oxygen-ozone autohemotherapy against COVID-19 needs to fit highly experienced, customized, and standardized protocols to succeed To the Editor, We read the recent paper by Araimo et al. published in the latest issue of this journal and found some crucial flaws, which raised the comments we are forwarding here.

The authors reported that they treated, with different best available therapies (BATs) and BAT plus oxygen-ozone autohemotherapy (O 3 -AHT), 28 patients (14 + 14), each selected from a cohort of 91 subjects undergoing a "snapshot" analysis, from a larger population of 152 enrolled individuals involved in their probiotics project. 1 They further reported that they have carried out an interventional, randomized, prospective, and double-arm trial, but did not explain their selection approach. Actually, the authors appear to have performed a "cherry picking" randomized selection of 28 patients from the largest cohort of 152 recruited subjects (Clinical Trial NCT04366089), that is, they selected a second cohort of COVID-19 stage-III positive subjects (initially n = 91, then 63 excluded, so n = 28), in which half of them (14 subjects) were treated with BAT plus O 3 -AHT (screening study). 1 We are still wondering if the 152 patients who were hospitalized COVID-19 positive patients, suffering from severe pneumonia or not and if they entered an intensive care unit (ICU). Actually, the same authors stated that they selected 152 patients as an amount necessary to achieve the more correct statistic sample size, considering 76 (non 14) patients for each group (α = .05, power 80%, δ = −.15). 1 In Araimo et al. paper, the number of patients who were investigated was largely lower than a rigorous sample size calculation from statistics. We are wondering why the authors selected a very narrow cohort of subjects, when their protocol planned a higher number of participants, without providing further good explanations. Moreover, they referred to 85 patients in the Abstract, whereas the number was 91 in the text, without any sound reason. Maybe, the participation in the research paper of such numerous experts, crashed with some difficulty in the communication within the different paper co-authorships.

Again, the primary and secondary endpoints reported by Araimo et al. showed some discrepancy. They evaluated the data of patients undergoing orotracheal intubation despite BAT (primary endpoint) and the data of crude mortality at 7, 14, and 30 days (secondary endpoint); but the authors never went ahead in the therapy protocol, as they stopped O 3 -AHT at 1 week itself without any sound and reliable explanation. 1 In this circumstance, the reader cannot be ensured if carrying out O 3 -AHT further, patients ameliorated their clinical stage, as demonstrated by a previously published paper from ours. 2 Furthermore, they reported that their primary endpoint was the 15% reduction of COVID-19 positive patients upon admission on ICUs, 1 but then they did not discuss this outcome further, they did not report if reached and how, neither in the text nor in the conclusion. 1 Interestingly, their primary outcome did not deal with major changes in laboratory and clinical markers upon therapy, which left investigators disinterested to follow up patients during their study and have a sound experimental conclusion. 1 In addition, we observed that information about sample enrollment and stratification, as well as statistical confounders and therapeutic regimens used, showed some critical issues.

As a matter of fact, in their recruitment eligibility criteria they selected hospitalized adults undergoing spontaneous breathing, supported either by Venturi's mask or with a high flow nasal cannula or continuous positive airway pressure, 1 but they did not stratify correctly how many patients were spontaneously breathing and how many with assisted ventilation. Doubts, therefore, remain about their correct selection of the COVID-19 clinical stages to be included in the treatment. Patients underwent a statistical homogenization when the authors stated different ventilation needs. These patients were each equally administered with azithromycin 500 mg/day, hydroxychloroquine 200 mg for 2 days, and tocilizumab ® 8 mg/kg twice a day and a time lapse of half a day upon admission, without any thorough stratification and differential BAT protocol recommended for each patient, depending on their own clinical stage and pneumonia computed tomography (CT) evaluation. 1 Therefore, we are persuaded that all the 28 patients underwent the same clinical diagnosis and entered the same, homogeneous therapy protocol, without any differential diagnosis and different ages ever reported. 1 Actually, patients' age was not properly reported (≥18 years is a poor indicator to have insights about patients' age distribution) and data on chest CT were completely missing.

The most striking bias emerged from reading this study with regard to O 3 -AHT. 

The peer review history for this article is available at https://publons. 

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