Dr. Manuel Aparicio-Alonso, Carlos A. Domínguez-Sánchez* and Marina Banuet-Martínez Deparment of Natural Sciences, Jurica Medical Center, Queretaro, Mexico

Summary;

As of December 2019, the first case of COVID-19 was reported in Wuhan, China, and spread rapidly around the world. This disease has caused millions of deaths and to date there is no fully effective drug against this disease. 

This study evaluated the negative and positive effects of chlorine dioxide (ClO2) as an alternative therapy for the treatment of COVID-19. Data were collected from the medical records of 1136 patients treated for COVID-19 with three different protocols of an aqueous ClO2 solution at a mean dose of 1.41 mg/kg. 

The average time to symptom resolution was 4.84 days, and full treatment lasted 15.87 days. In addition, 6.78% of patients had mild and sporadic adverse reactions such as headache, dizziness, vomiting, diarrhoea and nausea. 

There were no side effects that endangered the health of the patients.

Blood tests revealed no systemic abnormalities after ClO2 consumption. Liver enzymes, glucose, total cholesterol and triglycerides returned to normal at the end of treatment. 

Without complications, 99.03% of patients were discharged. 

Our findings show that, when used at the appropriate concentration and dosage, ClO2 as a solution effectively treats COVID-19 while being safe for human consumption.

Introduction

The disease reported in late 2019 (COVID-19), caused by the novel SARS-CoV-2 coronavirus, is characterised mainly by acute respiratory symptoms accompanied by fever, malaise, headache and, occasionally, digestive and nervous symptoms [1,2]. 

These symptoms are caused by excessive inflammatory responses [3,4] and coagulopathies due to endothelial damage caused by the SARS-CoV-2 Spike protein [5]. 

Since the early 2020`s, when the World Health Organization declared it, the COVID-19 pandemic has severely affected most countries in terms of morbidity and mortality, as well as in terms of the economic and social cost of the measures taken to curb the pandemic. One of the main challenges posed by this disease has been finding effective drugs to treat COVID-19 [6]. 

Chlorine dioxide (ClO2) is a soluble gas that is used in different countries to disinfect drinking water [7-9] due to its antimicrobial activity [10]. When both air and water are present, ClO2 is distributed between the two phases in an equilibrium relationship determined by temperature and atmospheric pressure [11]. 

ClO2 is known to denature tyrosine and tryptophan residues due to oxidation [10,12], and also has a modulating action on the immune system by inhibiting NF-kB transcription [13,14]. In this context, it is possible to assume that ClO2 can react with the SAR-CoV-2 Spike protein (composed of 54 tyrosine, 12 tryptophan and 40 cysteine residues) and inactivate the virus [15]. 

In addition, by neutralising reactive oxygen molecules and cytokines with ClO2 [16,17], it is possible to control the excessive inflammation associated with severe COVID-19 [1]. 

Although cysteine, tyrosine and tryptophan residues can also be found in human tissues, ClO2 is much less toxic to humans or animals than to bacteria and viruses due to its size selectivity [16,18] and due to the content of antioxidants such as glutathione in mammalian cells [19].

While ClO2 has been categorised as a hazardous compound when used for other applications in other forms and doses, due to some reported non-lethal side effects [19], it is important to consider that most of these cases are clinical reports of poisoning with other chemical substances like sodium chlorite (NaClO2) or sodium hypochlorite (Bleach, NaClO), and not ClO2. 

Regardless, health authorities have issued misleading information that lacks scientific evidence on the toxicity of this chemical compound, thus affecting the development and implementation of ClO2 as a possible treatment for COVID-19. 

To date, none of the drugs approved or cleared on an emergency basis by the Food and Drug Administration (FDA) to treat COVID-19 have demonstrated high effectiveness in reducing symptoms, hospitalisation and death. It is therefore critical to evaluate new compounds that can reduce the impact of the current pandemic, such as Ivermectin [20,21]. 

Evidence on the safety and efficacy of ClO2 is just beginning to be accepted in the medical community, although official regulatory institutions do not yet accept it. Here, we examined medical data from 1,136 patients with COVID-19 who used ClO2 solutions (CDS) as an alternative treatment. We evaluated the side effects produced by CDS consumption and its potential effectiveness in preventing serious illness and death.

Materials and Methods 
Data collection: Baseline and clinical information Clinical records of 1,136 COVID-19 positive/suspected patients (treated by the same physician) who voluntarily requested home therapeutic management in Mexico were reviewed; these records spanned from 30 May 2020 to 15 January 2021. 

Inclusion criteria for the clinical registries were as follows: 

1) patients diagnosed by molecular testing (real-time reverse transcriptase (RT-PCR) for SARSCoV-2, antigen detection, specific immunoglobulin M (IgM) and immunoglobulin G (IgG) against SARS-CoV-2), computer-assisted computed tomography of the lungs, chest radiographs or a combination of clinical manifestations such as headache, fever, cough, sore throat, dyspnoea, malaise and fatigue [1,22]; 

2) patients informed about the benefits and possible side effects of ClO2 consumption before starting treatment and who had signed the informed consent form. 

Variables collected from medical records were: sex, age, comorbidities, previous medications, date of onset, date of discharge or date of death, side effects following CDS consumption, millilitres of ClO2 consumed per day (“ClO2 per day”), partial oxygen saturation (SpO2), oxygen supplementation (O2 L/min) and COVID-19-like symptoms. In addition, six variables were calculated for each patient from the collected data: duration of COVID-19-like symptoms (“symptom days”), duration of treatment (“treatment duration”), millilitres of ClO2 consumed during treatment (“total ClO2“), ClO2 dose during treatment (“ClO2 dose”), ClO2 cost per day (“cost per day”) and total ClO2 cost during the entire treatment (“total cost”). 

In addition, patients’ disease severity (mild, moderate or severe) was determined according to the parameters established in the Coronavirus Disease Treatment Guidelines (COVID-19) [23] and the interim algorithms for COVID-19 care of the Mexican Social Security Institute [24].

Two groups of patients were analysed: 

1) Multi-drug patients: people taking drugs normally used to treat COVID-19 (Azithromycin, Dexamethasone, Ivermectin and Hydroxychloroquine) plus a chlorine dioxide solution, and 

2) ClO2-only patients: people treated with a chlorine dioxide solution only. All patients were treated at home by their relatives or nurses according to the treating physician’s instructions. 

Two types of oral aqueous ClO2 solutions at 3000 ppm (3 mg/ml) were used to treat COVID-19: Protocol C (ClO2 in 1000 ml of water, divided into ten 100 ml intakes given orally every hour, daily) and Protocol F (ClO2 in 500 ml of water, divided into ten 50 ml intakes given orally every 15 minutes, 1-5 times daily). 

For intravenous use, Protocol Y (ClO2 in 500 ml of sterile 0.9% saline plus 5 ml of 10% calcium gluconate and 10 ml of 7.5% sodium bicarbonate, administered at an average rate of 70 ml per hour). All patients started treatment with Protocol F and, depending on the severity of the disease, were placed on Protocols C, F or Y until symptoms resolved. After the disappearance of symptoms, they continued on Protocol C as maintenance until treatment ended (14-21 days depending on disease severity). 

The ClO2 in form of CDS used by patients for oral use was made by oxidising 28% sodium chlorite (NaClO2) and 4% hydrochloric acid (HCl) as an activator [19]. For intravenous use, ClO2 was produced by the membrane electrolysis method [9]. According to the instructions given to each patient, the ClO2 solution was kept in a closed bottle, protected from direct sunlight and kept below 11°C [19,25].

General physical condition of patients: 

Symptoms reported voluntarily by patients were used to calculate the incidence of each symptom similar to COVID-19. Patients who died during the course of the disease were considered as unsuccessful treatment cases. The clinical condition of patients was assessed in a subset of 57 patients (mainly severe COVID-19 cases) for whom data on a complete blood count and a metabolic biomarker test were available before and after treatment. 

As reference values, we used those reported for the healthy Mexican adult population [26,27]. 

Statistical analysis 

An initial analysis of the data using descriptive statistics provided an overview of the baseline information of the patients included in this study. Prior to proper data analysis, the distribution of each variable was examined. 

Variables deviated from a normal distribution and there was evidence of heteroscedasticity; therefore, we used Kruskal-Wallis tests to compare ClO2 values per day, symptom days, treatment duration, total ClO2 administered, ClO2 dose, cost per day and total cost between disease severity (mild, moderate and severe). 

Duration of symptoms and duration of treatment among comorbidities were also analysed using Kruskal-Wallis tests. The Wilcoxon signed-rank test was used to compare symptom days and treatment duration between multidrug and ClO2-only patients, as well as to compare results between blood tests (complete blood counts and metabolic biomarker panel tests) before and after treatment. 

Treatment efficacy was assessed by dividing unsuccessful cases by the total number of patients. A log-transformed linear regression model was fitted to analyse the association of treatment duration to end of symptoms with SpO2 and O2 L/min. Logistic regression was fitted to analyse the association of age, sex and comorbidities with disease severity. 

A p-value of p <0.05 was considered statistically significant. Continuous outcomes were measured as the mean difference and 95% confidence intervals (CI). To reduce reporting bias in this study, the treating physician was not involved in the digitisation or statistical analysis. 

All analyses were performed using Rv.3.6.1 [28]. 

Ethical approval The Ethics Committee of the Jurica Medical Centre waived the need for ethical approval and the need to obtain consent for the collection, analysis and publication of retrospectively collected data because this was a non-interventional study in which information was captured from old medical records, maintaining the anonymity of each individual and because all patients signed an informed consent prior to treatment. Data availability Data sets used and analysed during the present study are available upon reasonable request from the corresponding author.

Results Descriptive analysis of patients Primary data were collected from 1,136 patients (Table 1) in 30 states of Mexico, mainly in Queretaro (53.07%), Mexico City (10.22%) and Jalisco (5.11%). Of the entire sample set, 487 (42.87%) patients were diagnosed as COVID-19 positive by molecular testing or diagnostic imaging; the remaining 649 patients (57.13%) were diagnosed due to COVID-19-like symptoms. At the end of treatment, 213 (18.75%) patients underwent specific antibody testing for SARS-CoV-2, and 154 (72.30%) tested positive (93 for IgG and 61 for IgM). 

Patients were classified according to severity of illness into three groups: mild, moderate and severe, according to symptoms and SpO2. The study included 551 (48.50%) males, 525 (46.21%) females and 60 (5.28%) for whom there was no information on sex. 

Severity was associated with sex (x2=16.89, df=2, P=0.0002); men were 1.8 times more likely than women to develop a severe case of COVID-19 (RR=1.8, 95% CI: 1.33-2.42, P<0.001). The mean age was 46.72 (range 1-93) years, and COVID-19 was more prevalent in the 40-49 and 50-60 age groups (19.01%, 21.04%; respectively). 

The risk of developing severe disease was determined by age (x2=82, dF=7, P<0.0001), increasing by 4% for each year of life (OR=1.04, 95% CI: 1.03-1.05, P<0.001). 

The risk of developing more severe disease was highest after the age of 30 years (Figures S1 and S2). A total of 25 different symptoms were reported by patients, with the most frequent symptoms (table S1) being headache (49.65%), malaise (44.45%), sore throat (37.41%), fever (22.89%), dry cough (17.34%), weakness (14.70%), chest pain (12.32%), dyspnoea (9.5%), anosmia (9.15%) and ageusia (8.71%). The average duration of symptoms was 4.84 days (95% CI: 4.32-5.36 days) and differed according to severity of illness (mild: 2.52 to 3.33 days, moderate: 7.89 to 12.21 days and severe: 6.73 to 9.95 days; Kruskal-Wallis, x2=234.89, df=2, P<0.001) (Table 2).