A retrospective observational study on the efficacy of chlorine dioxide for the prophylaxis of symptoms similar to those of COVID19 in relatives living with patients with this disease
To date, there is no effective prophylactic agent to prevent COVID-19. However, the development of symptoms similar to covid19 could be prevented with an aqueous solution of chlorine dioxide (ClO2). This retrospective study evaluated the efficacy of an aqueous solution of ClO2 (CDS) as a prophylactic agent in 1.163 relatives living with COVID19 positive / suspected patients.
Prophylactic treatment consisted of 0,0003% chlorine dioxide solution orally for at least fourteen days. Family members in whom no reports of the development of COVID19-like symptoms were found in the medical history were considered successful cases. The efficacy of CDS in preventing covid19-like symptoms was 90,4% (1.051 of 1.163 family members did not report any symptoms). Comorbidities, sex, and severity of the patient's illness did not contribute to the development of symptoms similar to covid19 (P = 0,092, P = 0,351, and P = 0,574, respectively). However, older relatives were more likely to develop symptoms similar to those of covid19 (ORa = 4,22, P = 0,002). There was no evidence of alterations in blood parameters or in the QTc interval in relatives who consumed CDS. Recent findings on chlorine dioxide justify the design of clinical trials to evaluate its efficacy in preventing SARS-CoV-2 infection.
KEY WORDS: Chlorine Dioxide, prophylaxis, COVID19, Pandemic
INTRODUCTION
The coronavirus disease 2019 (COVID19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is a disease that is transmitted directly or indirectly through aerosols and whose significant symptoms include mild to mild pneumonia. severe (da Rosa Mesquita et al. 2021; Yu et al. 2020). It has been shown that a high percentage of infections (mean 16,6%) occurs mainly in households (Liu et al. 2020; Madewell et al. 2020), especially because houses are closed environments that make it difficult to maintain social distance, there is reduced use of personal protective equipment and it is not possible to completely isolate a sick family member (Madewell et al. 2020). Due to global problems and the rapid spread of this disease, there are research groups dedicated to testing drugs that help prevent and improve the prognosis of the disease (for example, Ivermectin, Bryant et al., 2021; Vitamin D, Martineau & Forouhi, 2020; and Hydroxychloroquine, Rajasingham et al., 2021). However, the global crisis continues and it is necessary to test other substances that could effectively prevent the spread of SARS-CoV-2 and develop COVID19.
Aqueous solutions of chlorine dioxide (ClO2) have antimicrobial potential due to the denaturation of specific viral capsid proteins (Kály-Kullai et al. 2020). For example, ClO2 was shown to have the ability to inactivate Influenza Virus caused by oxidation of tryptophan residue 153 at the receptor binding site (Ogata 2012). Taking into account the composition of the spike protein of SARS-CoV-2 (12 tryptophan, 54 tyrosine and 40 cysteine residues), it can be assumed that ClO2 also has the potential to inactivate this virus (Insignares-Carrione , Bolano Gómez and Ludwig Kalcker 2020). There are many unique properties that make ClO2 an ideal and nonspecific antimicrobial: ClO2 has been shown to be a size-selective antimicrobial agent that can rapidly neutralize microorganisms (Noszticzius et al. 2013). Furthermore, it can be used in animals and humans without adverse effects in adequate concentrations due to its inability to penetrate tissues (Kály-Kullai et al. 2020; Noszticzius et al. 2013).
The current situation of COVID-19 has shown the importance of having antiviral compounds that act quickly. Currently, there is no drug (prophylactic or therapeutic) approved by the Food and Drug Administration (FDA) against COVID-19, and that has demonstrated high efficacy (Gupta, Sahoo and Singh 2020; Meo, Klonoff and Akram 2020; Shamshina
A retrospective observational study on the efficacy of chlorine dioxide for the prophylaxis of symptoms similar to those of COVID19 in relatives living with patients with this disease
Rogers 2020). Therefore, it is essential to investigate new compounds that can help reduce the impact of the current pandemic. This study analyzed clinical information from healthy people who consumed an aqueous solution of ClO2 as a prophylactic agent when living with COVID19 positive / suspected patients. The efficacy of ClO2 in preventing the development of symptoms similar to those of COVID19 was evaluated.
II. METHODS
Basic and clinical information
This retrospective study was carried out from the clinical records of 1,163 healthy subjects (without symptoms similar to those of covid19), hereinafter referred to as relatives, who live with positive / suspected COVID19 patients (sick) in different cities (mainly Querétaro) from Mexico; from May 30, 2020 to January 15, 2021. The inclusion criteria were the following: 1) relatives who lived in the same house with a sick patient diagnosed by the reverse transcriptase (RT) viral nucleic acid test in real time to SARS-CoV-2 (Park et al. 2020) and complementary tests such as the antigen detection test (Zainol Rashid et al. 2020), serology test for specific antibodies to immunoglobulin M (IgM) and immunoglobulin G ( IgG) against SARS-CoV-2 (Xiang et al. 2020), computed tomography (Long et al. 2020), chest radiography (Smith et al. 2020), or clinical manifestations such as fever, cough, dyspnea, malaise and fatigue (from Rosa Mesquita et al. 2021); 2) family members who voluntarily requested prophylactic management at home and who, after being informed of the benefits and possible side effects of ClO2 consumption, signed the informed consent. Baseline information (sex, age, and comorbidities) and clinical information (date of request for prophylactic management, partial oxygen saturation [SpO2] and symptoms similar to those of covida19) were collected from the medical records. In addition, the severity status of the patient's disease (mild, moderate or severe) was included.
Prophylactic Management: Chlorine Dioxide Solution
ClO2 production is not yet regulated by any regulations in Mexico. Chemists-pharmacists or professional chemical engineers make ClO2 by oxidation of sodium chlorite (NaClO2) using hydrochloric acid (HCl) as activator, ensuring the concentration and safety of the product. Being a chemical compound, exposure to light and a temperature above 11 ° C changes its composition (Kály-Kullai et al. 2020). Family members were informed that they should keep the CDS in the refrigerator (4-10 ° C) and store it in closed amber jars. Family members began oral prophylactic management in daily doses (0,3 mg / kg) of 0,0003% Aqueous Chlorine Dioxide Solution (CDS, 10 ml of ClO2 at 3000 ppm in 1000 ml of water), divided into ten shots of 100 ml / hour. This dose had been reported as adequate for human use (Lubbers and Bianchine 1984; Lubbers, Chauhan and Bianchine 1981; Smith and Willhite 1990); Furthermore, it is ten times below the "No Observed Adverse Effect Level" (NOAEL), almost 20 times below the "Lowest Observed Adverse Effect Level" (LOAEL), and almost 300 times below the lethal dose 50 ( LD50; Insignares-Carrione et al., 2020; United States Environmental Protection Agency, 2000). Due to Mexican regulations during the pandemic, family members stayed home for at least 14 days or compensated for the sick patient's symptoms. Medical records show daily follow-up for a minimum of 20 days for each family member.
Incidence of symptoms similar to those of Covid19 and monitoring of general physical well-being
Family-reported symptoms were used to calculate the incidence of Covid19-like symptoms during clinical follow-up. Family members who reported any symptoms were considered as an unsuccessful case of prophylactic management. To assess general physical well-being during the administration of prophylaxis, 27 family members underwent a complete blood count (red blood cells, white blood cells and platelets) and a metabolic panel test (blood urea nitrogen, creatinine, alkaline phosphatase alanine aminotransferase , aspartate aminotransferase, gamma-glutamyl transferase, glucose, total proteins, albumin, sodium, potassium, chloride, bilirubin, cholesterol and triglycerides) before (at least three months) and after the consumption of CDS. The typical values of the general Mexican adult population were used as reference values (Díaz Piedra et al. 2012; Olay Fuentes et al. 2013). Additionally, data from 50 electrocardiograms (ECG) performed on relatives after CDS consumption were collected to assess the QTc interval (measured manually), using Bazzet's QT correction formula (Dahlberg et al. 2021).
Statistic analysis
Descriptive statistics were used to get an overview of the basic characteristics of the reference information. Age was classified into five groups: 1-12, 13-19, 20-34, 35-64,> 64 years. The incidence of symptoms similar to those of covid19 was calculated by dividing the number of relatives with any symptoms by the total number of relatives in prophylactic treatment. A logistic regression model was fitted to analyze the association of age, sex, family size, comorbidities, and disease severity of the ill patient with reported symptoms. Multicollinearity was analyzed and ruled out. The adjusted odds ratio (aOR) and their 95% confidence intervals are presented. The hazard ratio (RR) was calculated to compare the prophylactic efficacy of CDS with current prophylactic drugs, and we used data from a meta-analysis of Ivermectin (Bryant et al. 2021), which has shown the highest efficacy to date. moment. Wilcoxon rank sum tests were performed to compare results between blood tests (complete blood count and metabolic panel test) before and after CDS consumption. To compare the QTc interval of family members who consume CDS versus COVID19 patients treated with Hydroxychloroquine, an Analysis of Variance (ANOVA) was performed. A p value <0,05 was considered statistically significant. To reduce information bias in this study, the treating physician did not participate in digitization or statistical analysis. All analyzes were performed with STATA v.15.1. (StataCorp 2017)
Ethical approval
The Ethics Committee of the Juridical Medical Center waived the need for ethical approval and obtaining consent for the collection, analysis and publication of the data obtained retrospectively because it was a non-interventional study in which the information was captured from old medical records , maintaining the anonymity of each person and because all patients signed the informed consent before treatment.
Data availability
The data sets used and analyzed during the present study are available from the corresponding author upon reasonable request.
reasonable request.
III. RESULTS
Background of the study participants
Information was collected from 1,163 family members belonging to 554 family nuclei, in 13 states of the Mexican Republic, mainly Querétaro (52.25%) and Mexico City (12.61%). The sample consisted of 567 women (48,75%), 442 men (38,00%) and 154 without information (13,24%), with a mean baseline of 40,37 (range 2-89) years. One hundred and eighty-one relatives declared concomitant diseases, predominantly hypertension (17,39%), diabetes (15,76%) and respiratory diseases (bronchitis, asthma and chronic pneumonia; 7,06%). Other conditions such as cancer, kidney failure, hypothyroidism, heart disease, and arthritis were reported in less than 1%.
Incidence of Covid19-like symptoms
The calculated incidence of Covid19-like symptoms was 9,63%. In total, 112 relatives (67 women [59,82%], 41 men [36,61%] and four without information [3,57%]) reported at least one sporadic-mild symptom similar to covid19 between 4 and 5 days after the request for prophylactic treatment with CDS (Table 1). Thirteen relatives (1,12%) reported side effects (diarrhea, headaches, gastritis, nausea, dizziness or sore throat) after taking CDS, and two of the unsuccessful cases (1,78%) suspended prophylactic management for moderate headaches and gastritis. In these 112 sick family members, the CDS intake dose was increased immediately after symptom onset was reported to a therapeutic dose (0,6 mg / kg) until symptom resolution (between two and four days) . None of the family members who presented symptoms similar to those of covid19 died.
The reported comorbidities were not statistically significant for the development of symptoms similar to those of covid19 (p = 0,092). There was no statistical evidence that the sex of the family member and the severity of the sick patient's illness contributed independently and were associated with the presence of symptoms (P = 0,351 and P = 0,574). However, both variables were added to the model to adjust for confounding factors. When adjusting for the sex and severity of the patient's illnesses, family members of all age categories were more likely to have symptoms similar to covid19 compared to younger patients, but they were only statistically significant in 35 at 64 years (aOR = 4,22, 95% CI: 1,71, 10,41, p = 0,002) and in those over 64 years (aOR = 3,64, 95% CI: 1,30 , 10,16, p = 0,014). When comparing the prophylactic efficacy of ivermectin (mean 86%; Bryant et al., 2021) versus CDS, we found that family members who consume CDS are 31% less likely to develop symptoms similar to those of covid19 (RR = 0,69, 95% CI: 0,54-0,89, P = 0,003).
General well-being of the patient
No analyzed parameter of the complete blood count (Table 2) was outside the mean values before or after. Mean Cell Volume (MCV) was different (Wilcoxon rank sum test, P <0,02), being higher after prophylactic management with CDS, although it was not outside the normal upper limit. In the metabolic test (Table 2), blood glucose was above the expected values before and after (mean, 102,65 mg / dL and 103,79 mg / dL, respectively). However, there were no differences between both periods, neither in this metabolite nor in the others evaluated. The mean QTc was 400,08 ms (95% CI: 394,34 ms, 405,76 ms), and no ECG showed a prolonged QTc (Fig. 1). However, the ECG of a male showed a QTc = 442 ms. The QTc interval of relatives was significantly lower (ANOVA, P <0,001) compared to the QTc of patients treated with conventional COVID19 treatment (Hydroxychloroquine and Azithromycin; Chorin et al., 2020; Ramireddy et al., 2020) .
IV. DISCUSSION
This retrospective study collected information from 1,163 family members who lived with sick patients and who used CDS prophylactically. In this study, the incidence of covid19-like symptoms was 9,63%, which is lower than the reported overall estimated home secondary attack rate (16,6%, 95% CI: 14,0%, 19,3%; Madewell et al., 2020). It is clear that people commonly take protective measures in public places such as washing their hands and wearing masks, but neglect personal protection at home because they consider it a “safe” place, which has generated a high incidence of contagion among relatives (Madewell et al. 2020). That is why researchers are making a great effort to find an effective prophylactic alternative against COVID19.
Some studies had evidence of the prophylactic effect of COVID19. Vitamin D supplementation during the COVID19 pandemic has been suggested as a preventive measure due to its beneficial effect on the immune system (Verdoia and De Luca 2021). However, the effectiveness was only 40% (Martineau and Forouhi 2020). On the other hand, ivermectin has been extensively studied to demonstrate its prophylactic efficacy against SARS-CoV-2 infection (Alam et al. 2020; Elgazzar et al. 2020; Kory et al. 2021). The results of a meta-analysis were used to compare the efficacy of CDS against ivermectin. We showed that the prophylactic efficacy of CDS was slightly higher than that reported for ivermectin (90,4% vs 86%, respectively). Despite using similar exposure variables and outcomes, the conditions and design of the compared studies were different. Due to the limited evidence available for ClO2 / CDS in humans, we consider it necessary to conduct randomized control trials or prospective cohorts to compare the effect of these two substances in analogous groups.
One of the most studied prophylactic drugs is hydroxychloroquine (Rajasingham et al. 2021; Rathi et al. 2020). However, it has not shown a statistically significant risk reduction (HR = 0,72, 95% CI: 0,44, 1,16; P = 0,18; Rajasingham et al., 2021). In addition, hematological alterations, changes in liver and kidney function (Agrawal, Goel and Gupta 2020; Galvañ et al. 2007) and prolongation of the QTc interval (Chorin et al. 2020; Christos-Konstantinos et al. 2017; Ramireddy et al. 2020). ) have been reported to use this drug. Contrary to what we reported in the present study, blood tests did not reveal any systemic disturbances after CDS consumption, similar to previously reported (Lubbers and Bianchine 1984; Smith and Willhite 1990). Regarding cardiac function, the use of Hydroxychloroquine combined with azithromycin in patients with COVID19 induces a longer QTc interval (459 ± 36 ms, Ramireddy et al., 2020; and 463 ± 32 ms, Chorin et al., 2020 ). In this study, only one relative presented the QTc interval (442 ms) at the limit (431-450 ms), a limit established as usual for 1% of the population (Christos-Konstantinos et al. 2017). In the rest of the family members, the QTc interval was within normal ranges during prophylactic management with CDS. COVID19 infection has been associated with prolonged QTc, independent of several clinical factors related to QTc prolongation. The risk of prolonged QTc has been reported to increase in patients treated with hydroxychloroquine and azithromycin, regardless of the presence or absence of SARS-CoV-2 infection (Rubin et al. 2021), and could lead to a high risk of malignant arrhythmia (Christos-Konstantinos et al. 2017). We did not find alterations in the QTc interval in healthy individuals who consumed CDS prophylactically. The design of clinical trials in which detailed follow-up is carried out to evaluate any possible effect of Chlorine Dioxide on the QTc interval is recommended.
With regard to the risk associated with sex, women are the main caregivers of other household members, which could put them at risk in the event of a sick relative (Wenham, Smith and Morgan 2020). A higher risk of COVID19 infection has been reported in women than in men (RR = 1,66, 95% CI: 1,39, 2,00) with the wife being the most affected compared to a family member who does not is a spouse due to intimacy or direct contact (for example, sleeping in the same room) with her husband (Liu et al. 2020). However, in this study, no evidence was found that women are at higher risk of infection than men. With regard to age, we did not find statistical evidence on the development of symptoms similar to covid19 in younger age groups. Family members older than 35 years were at the highest risk, being those with the highest probability of developing COVID19 worldwide (Liu et al. 2020; Madewell et al. 2020). Although comorbidities such as diabetes and hypertension have been recognized as risk factors for the development of COVID19, (Liu et al. 2020) we did not find statistical differences in the present study. This may be due to incorrect clinical data or due to the prophylactic effect of CDS. However, this remains to be clarified in further studies of specific design.
This study shows that the cases of failure started with symptoms similar to covid19 between 4 and 5 days after the request for prophylactic treatment. This is consistent with previous studies where the highest transmissibility rate occurs at the end of the first week of infection (To et al. 2020). The unsuccessful cases reported sporadic and mild symptoms, mainly: headache, sore throat, cough, fever, malaise, diarrhea, dizziness, abdominal pain and fatigue, which have already been reported as symptoms of COVID19 in other studies (Madewell et al. 2020). ; da Rosa Mesquita et al. 2021). However, without a confirmatory diagnosis of COVID19, it is impossible to ensure that family members were infected with SARS-CoV-2.
ClO2 in other application and dosage forms has been classified as a dangerous compound due to some reported side effects. In addition, some reported cases have been due to sodium hypochlorite (NaClO2) instead of ClO2. In general, social media has been inundated with misinformation through unwarranted news about ClO2. Even the health authorities have issued erroneous information (without scientific basis) about this compound in different media. While some of this information may be harmless, another portion may be dangerous and may affect the development and implementation of potential treatments (Osuagwu et al. 2021), such as this compound. Our results show that CDS at the dose used is safe and has no serious side effects, even when used at higher doses (none of the unsuccessful cases reported side effects after increasing the dose). This is also supported as no blood parameters were outside the normal range after 14 days of prophylactic treatment. In this study, we only reported thirteen family members with side effects, which disappeared after dose adjustment.
LIMITATIONS
Our study has some limitations. The first of all is that it is a retrospective observational study, which means that conclusive evidence of the effectiveness of the CDS cannot be established because we could only use the information available in the medical records of the relatives, and we could not have any control . on the variables. Second, there is a misinformation bias as family members report initial and clinical information. Third, many relatives did not undergo diagnostic or confirmatory tests for SARS-Cov-2 due to the economic situation and the high cost of these in Mexico. Therefore, it was impossible to establish with certainty that family members who reported any symptoms similar to covid19 had COVID19. Fourth, the results of the studies used to compare our results are obtained from different populations and collected under other conditions, so these comparisons should be interpreted with caution. Fifth, the general interpretation of the findings may be restricted due to a lack of additional information (eg, personal care, eating habits, proximity and relationship with patients, etc.). These and other variables must be taken into account in future studies.
SAW. CONCLUSION
This is the first study to try to determine the effectiveness of an aqueous solution of chlorine dioxide in preventing the development of symptoms similar to those of COVID19. We demonstrate 90,4% efficacy in preventing the outbreak of COVID19-like symptoms under the given conditions. The blood test did not reveal any systemic abnormalities after the consumption of CDS. Our results suggest that the correct use of ClO2 as a solution is safe for human consumption in an adequate concentration and dose. Therefore, we consider that the recent findings on chlorine dioxide justify conducting RCTs to assess its efficacy against SARS-CoV-2. Furthermore, this may open up a new field of research on the potential use of new compounds to solve current and future public health problems. Finally, we invite more research groups to consider this solution for future studies.
REFERENCES
1) Agrawal, Sumita, Akhil Dhanesh Goel, and Nitesh Gupta. 2020. "Emerging Prophylaxis Strategies against COVID-19."
Monaldi Archives for Chest Disease 90: 169–72.
2) Alam, Mohammed Tarek, Rubaiul Murshed, Pauline Francisca Gomes, Zafor Md. Masud, Sadia Saber, Mainul Alam Chaklader, Fatema Khanam, Monower Hossain, Abdul Basit Ibne Momen Momen, Naz Yasmin, Rafa Faaria Alam, Amrin Sultana, and Rishad Choudhury Robin. 2020. "Ivermectin as Pre-Exposure Prophylaxis for COVID-19 among Healthcare Providers in a Selected Tertiary Hospital in Dhaka - An Observational Study." European Journal of Medical and Health Sciences 2 (6): 1–5.
3) Bryant, Andrew, Theresa Lawrie, Edmund Fordham, Mitchell Scott, Sarah Hill, and Tony Tham. 2021. “Ivermectin for
Prevention and Treatment of COVID-19 Infection: A Systematic Review and Meta-Analysis. " PREPRINT (Version 1) Available at Research Square 1–25.
4) Chorin, Ehud, Lalit Wadhwani, Silvia Magnani, Matthew Dai, Roi Bar-cohen, Edward Kogan, Chirag Barbhaiya, Anthony
Aizer, Douglas Holmes, Scott Bernstein, Michael Spinelli, David S. Park, Carugo Stefano, and Larry A. Chinitz. 2020. "QT
Interval Prolongation and Torsade de Pointes in Patients with COVID-19 Treated with Hydroxychloroquine / Azithromycin. "
Heart Rhythm 17: 1425–33.
5) Christos-Konstantinos, Antoniou, Dilaveris Polychronis, Manolakou Panagiota, Galanakos Spyridon, Magkas Nikolaos, Gatzoulis Konstantinos, and Tousoulis Dimitrios. 2017. "QT Prolongation and Malignant Arrhythmia: How Serious a Problem?" European Cardiology Review 12 (2): 112–20.
6) Dahlberg, Pia, Ulla Britt Diamant, Thomas Gilljam, Annika Rydberg, and Lennart Bergfeldt. 2021. "QT Correction Using Bazett's Formula Remains Preferable in Long QT Syndrome Type 1 and 2." Annals of Noninvasive Electrocardiology 26: e12804.
7) Díaz Piedra, Pablo, Gabriela Olay Fuentes, Ricardo Hernández Gómez, Daniel Cervantes-Villagrana, José Miguel Presno-Bernal, and Luz Elena Alcántara Gómez. 2012. “Determination of Hematic Biometry Reference Intervals In
Mexican population. " Latin American Journal of Clinical Pathology and Laboratory Medicine 59 (4): 243–50.
8) Elgazzar, Ahmed, Basma Hany, Shaimaa Abo Youssef, Mohy Hafez, Hany Moussa, and Abdelaziz Eltaweel. 2020. "Efficacy and Safety of Ivermectin for Treatment and Prophylaxis of COVID-19 Pandemic." PREPRINT (Version 2) Available at Research Square 1–13.
9) Galvañ, Vicente Giner, María Rosa Oltra, Diego Rueda, María José Esteban, and Josep Redón. 2007. "Severe Acute Hepatitis Related to Hydroxychloroquine in a Woman with Mixed Connective Tissue Disease." Clinical Rheumatology 26 (6): 971–72.
10) Gupta, Dhyuti, Ajaya Kumar Sahoo, and Alok Singh. 2020. "Ivermectin: Potential Candidate for the Treatment of Covid 19." Brazilian Journal of Infectious Diseases 24 (4): 369–71.
11) Insignares-Carrione, Eduardo, Blanca Bolano Gómez, and Andreas Ludwig Kalcker. 2020. "Chlorine Dioxide in COVID-19: Hypothesis about the Possible Mechanism of Molecular Action in SARS-CoV-2." Journal of Molecular and Genetic Medicine 14 (5): 1–8.
12) Kály-Kullai, K., M. Wittmann, Z. Noszticzius, and László Rosivall. 2020. “Can Chlorine Dioxide Prevent the Spreading of Coronavirus or Other Viral Infections? Medical Hypotheses. " Physiology International 107 (1): 1–11.
13) Kory, Pierre, Gianfranco Umberto Meduri, Joseph Varon, Jose Iglesias, and Paul E. Marik. 2021. “Review of the Emerging
Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. " American Journal of Therapeutics 28 (3): e299–318.
14) Liu, Tao, Wenjia Liang, Haojie Zhong, Jianfeng He, Zihui Chen, Guanhao He, Tie Song, Shaowei Chen, Ping Wang, Jialing Li, Yunhua Lan, Mingji Cheng, Jinxu Huang, Jiwei Niu, Liang Xia, Jianpeng Xiao , Jianxiong Hu, Lifeng Lin, Qiong Huang, Zuhua Rong, Aiping Deng, Weilin Zeng, Jiansen Li, Xing Li, Xiaohua Tan, Min Kang, Lingchuan Guo, Zhihua Zhu, Dexin Gong, Guimin Chen, Moran Dong, and Wenjun Ma. 2020. "Risk Factors Associated with COVID-19 Infection: A Retrospective Cohort Study Based on Contacts Tracing." Emerging Microbes and Infections 9 (1): 1546–53.
15) Long, Chunqin, Huaxiang Xu, Qinglin Shen, Xianghai Zhang, Bing Fan, Chuanhong Wang, Bingliang Zeng, Zicong Li, Xiaofen
Li, and Honglu Li. 2020. "Diagnosis of the Coronavirus Disease (COVID-19): RRT-PCR or CT?" European Journal of Radiology
126: 108961.
16) Lubbers, JR, and JR Bianchine. 1984. "Effects of the Acute Rising Dose Administration of Chlorine Dioxide, Chlorate and Chlorite to Normal Healthy Adult Male Volunteers." Journal of Environmental Pathology, Toxicology and Oncology:
Official Organ of the International Society for Environmental Toxicology and Cancer 5: 215-228.
17) Lubbers, Judith R., Sudha Chauhan, and Joseph R. Bianchine. 1981. "Controlled Clinical Evaluations of Chlorine Dioxide, Chlorite and Chlorate in Man." Toxicological Sciences 1 (4): 334–38.
18) Madewell, Zachary J., Yang Yang, Ira M. Longini, Elizabeth Halloran, and Natalie E. Dean. 2020. "Household Transmission of SARS-CoV-2: A Systematic Review and Meta-Analysis." JAMA Network Open 3 (12): e2031756.
19) Martineau, Adrian R., and Nita G. Forouhi. 2020. "Vitamin D for COVID-19: A Case to Answer?" The Lancet Diabetes and Endocrinology 8: 735–36.
20) Meo, SA, DC Klonoff, and J. Akram. 2020. “Efficacy of Chloroquine and Hydroxychloroquine in the Treatment of COVID-
- ”European Review for Medical and Pharmacological Sciences 24 (8): 4539–47.
21) Noszticzius, Zoltán, Maria Wittmann, Kristóf Kály-Kullai, Zoltán Beregvári, István Kiss, László Rosivall, and János Szegedi.
- "Chlorine Dioxide Is a Size-Selective Antimicrobial Agent." PLoS ONE 8 (11): e79157.
22) Ogata, Norio. 2012. "Inactivation of Influenza Virus Haemagglutinin by Chlorine Dioxide: Oxidation of the Conserved Tryptophan 153 Residue in the Receptor-Binding Site." Journal of General Virology 93: 2558–63.
23) Olay Fuentes, Gabriela, Pablo Díaz Piedra, Ricardo Hernández Gómez, Daniel Cervantes-Villagrana, José Miguel Presno-
Bernal, and Luz Elena Alcántara Gómez. 2013. "Determination of Reference Intervals for Clinical Chemistry in the Mexican Population." Latin American Journal of Clinical Pathology and Laboratory Medicine 60 (1): 43–51.
24) Osuagwu, Uchechukwu L., Chundung A. Miner, Dipesh Bhattarai, Khathutshelo Percy Mashige, Richard Oloruntoba, Emmanuel Kwasi Abu, Bernadine Ekpenyong, Timothy G. Chikasirimobi, Piwuna Christopher Goson, Godwin O. Ovenseri-Bogbomo, Raymond Lanmond Ogbgsi Donald Charwe, Tanko Ishaya, Obinna Nwaeze, and Kingsley Emwinyore Agho. 2021.
"Misinformation about COVID-19 in Sub-Saharan Africa: Evidence from a Cross-Sectional Survey." Health Security 19 (1): 44–56.
25) Park, Myungsun, Joungha Won, Byung Yoon Choi, and Justin C. Lee. 2020. "Optimization of Primer Sets and Detection Protocols for SARS-CoV-2 of Coronavirus Disease 2019 (COVID-19) Using PCR and Real-Time PCR." Experimental and Molecular Medicine 52 (6): 963–77.
26) Rajasingham, Radha, Ananta S. Bangdiwala, Melanie R. Nicol, Caleb P. Skipper, Katelyn A. Pastick, Margaret L. Axelrod, Matthew F. Pullen, Alanna A. Nascene, Darlisha A. Williams, Nicole W. Engen , Elizabeth C. Okafor, Brian I. Rini, Ingrid A. Mayer, Emily G. McDonald, Todd C. Lee, Peter Li, Lauren J. MacKenzie, Justin M. Balko, Stephen J. Dunlop, Katherine H.
Hullsiek, David R. Boulware, and Sarah M. Lofgren. 2021. "Hydroxychloroquine as Pre-Exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial." Clinical Infectious Diseases: An Official
Publication of the Infectious Diseases Society of America 72 (11): e835–43.
27) Ramireddy, Archana, Harpriya Chugh, Kyndaron Reinier, Joseph Ebinger, Eunice Park, Michael Thompson, Eugenio Cingolani, Susan Cheng, Eduardo Marban, Christine M. Albert, and Sumeet S. Chugh. 2020. “Experience with Hydroxychloroquine and Azithromycin in the Coronavirus Disease 2019 Pandemic: Implications for Qt Interval
Monitoring. " Journal of the American Heart Association 9 (12): e017144.
28) Rathi, Sahaj, Pranav Ish, Ashwini Kalantri, and Shriprakash Kalantri. 2020. "Hydroxychloroquine Prophylaxis for COVID-19
Contacts in India. " The Lancet Infectious Diseases 20 (10): 1118–19.
29) da Rosa Mesquita, Rodrigo, Luiz Carlos Francelino Silva Junior, Fernanda Mayara Santos Santana, Tatiana Farias de Oliveira, Rafaela Campos Alcântara, Gabriel Monteiro Arnozo, Etvaldo Rodrigues da Silva Filho, Aisla Graciele Galdino dos Santos, Euclides José Oliveira da Cunha, Saulo Henrique Salgueiro de Aquino, and Carlos Dornels Freire de Souza. 2021.
"Clinical Manifestations of COVID-19 in the General Population: Systematic Review." The Central European Journal of Medicine 133 (377): 382.
30) Rubin, Geoffrey A., Amar D. Desai, Zilan Chai, Aijin Wang, Qixuan Chen, Amy S. Wang, Cameron Kemal, Haajra Baksh, Angelo Biviano, Jose M. Dizon, Hirad Yarmohammadi, Frederick Ehlert, Deepak Saluja, David A. Rubin, John P. Morrow, Uma Mahesh R. Avula, Jeremy P. Berman, Alexander Kushnir, Mark P. Abrams, Jessica A. Hennessey, Pierre Elias, Timothy J. Poterucha, Nir Uriel, Christine J. Kubin, Elijah Lasota, Jason Zucker, Magdalena E. Sobieszczyk, Allan Schwartz, Hasan
Garan, Marc P. Waase, and Elaine Y. Wan. 2021. “Cardiac Corrected QT Interval Changes among Patients Treated for
COVID-19 Infection during the Early Phase of the Pandemic. " JAMA Network Open 4: 1–14.
31) Shamshina, Julia L., and Robin D. Rogers. 2020. "Are Myths and Preconceptions Preventing Us from Applying Ionic Liquid Forms of Antiviral Medicines to the Current Health Crisis?" International Journal of Molecular Sciences 21 (17): 1–16.
32) Smith, David L., John-Paul Grenier, Catherine Batte, and Bradley Spieler. 2020. “A Characteristic Chest Radiographic
Pattern in the Setting of the COVID-19 Pandemic. " Radiology: Cardiothoracic Imaging 2 (5): e200280.
33) Smith, Roger P., and Calvin C. Willhite. 1990. "Chlorine Dioxide and Hemodialysis." Regulatory Toxicology and Pharmacology 11 (1): 42–62.
34) StataCorp. 2017. "Stata Statistical Software: Release 15."
35) To, Kelvin Kai Wang, Owen Tak Yin Tsang, Wai Shing Leung, Anthony Raymond Tam, Tak Chiu Wu, David Christopher Lung, Cyril Chik Yan Yip, Jian Piao Cai, Jacky Man Chun Chan, Thomas Shiu Hong Chik, Daphne Pui Ling Lau, Chris Yau Chung Choi, Lin Lei Chen, Wan Mui Chan, Kwok Hung Chan, Jonathan Daniel Ip, Anthony Chin Ki Ng, Rosana Wing Shan Poon, Cui Ting Luo, Vincent Chi Chung Cheng, Jasper Fuk Woo Chan, Ivan Fan Ngai Hung, Zhiwei Chen, Honglin Chen, and Kwok
Yung Yuen. 2020. “Temporal Profiles of Viral Load in Posterior Oropharyngeal Saliva Samples and Serum Antibody
Responses during Infection by SARS-CoV-2: An Observational Cohort Study. " The Lancet Infectious Diseases 20 (5): 565–74.
36) US Environmental Protection Agency. 2000. "Toxicological Review of Chlorine Dioxide and Chlorite." CAS Nos. 10049-04-4 and 7758-19-2 (September): 1–49.
37) Verdoia, M., and G. DeLuca. 2021. “Potential Role Pf Hypovitaminosis D and Vitamin D Supplementation during COVID-XNUMX.
19 Pandemic. " QJM: An International Journal of Medicine 114 (1): 3–10.
38) Wenham, Clare, Julia Smith, and Rosemary Morgan. 2020. "COVID-19: The Gendered Impacts of the Outbreak." The Lancet 395 (10227): 846–48.
39) Xiang, Fei, Xiaorong Wang, Xinliang He, Zhenghong Peng, Bohan Yang, Jianchu Zhang, Qiong Zhou, Hong Ye, Yanling Ma,
Hui Li, Xiaoshan Wei, Pengcheng Cai, and Wan Li Ma. 2020. "Antibody Detection and Dynamic Characteristics in Patients with Coronavirus Disease 2019." Clinical Infectious Diseases 71 (8): 1930–34.
40) Yu, Xiaoqi, Dong Wei, Yongyan Chen, Donghua Zhang, and Xinxin Zhang. 2020. "Retrospective Detection of SARS-CoV-2 in Hospitalized Patients with Influenza-like Illness." Emerging Microbes and Infections 9: 1–12.
41) Zainol Rashid, Zetti, Siti Norlia Othman, Muttaqillah Najihan Abdul Samat, Umi Kalsom Ali, and Kon Ken Wong. 2020.
"Diagnostic Performance of COVID-19 Serology Assays." Malaysian Journal of Pathology 42 (1): 13–21.
A STUDY OF:
Manuel Aparicio-Alonso1, Carlos A. Domínguez-Sánchez2, Marina Banuet-Martínez3
1,2,3 Legal Medical Center, Querétaro, Mexico
