A retrospective observational study of Chlorine

Dioxide effectiveness to covid19-like symptoms

prophylaxis in relatives living with COVID19 patients
Manuel Aparicio-Alonso
Centro Medico Jurica https://orcid.org/0000-0002-0188-9871
Carlos Dominguez-Sanchez (  [email protected] )
Centro Medico Jurica https://orcid.org/0000-0002-5659-355X
Marina Banuet-Martinez
Centro Medico Jurica https://orcid.org/0000-0002-7869-2049

Research Article

Keywords: Chlorine Dioxide, prophylaxis, COVID19, Pandemic

DOI: https://doi.org/10.21203/rs.3.rs-703538/v1

License:   This work is licensed under a Creative Commons Attribution 4.0 International License.
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Abstract
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 effectiveness of an aqueous solution of ClO2 (CDS) as a
prophylactic agent in 1,163 family members living with positive/suspected COVID19 patients.
Prophylactic treatment consisted of 0.0003% chlorine dioxide solution (CDS) 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 relatives did not report any symptoms). The comorbidities, sex and
severity of the illness of the sick patient 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 covid19-like symptoms (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. The recent findings regarding Chlorine
Dioxide justify designing clinical trials to assess its efficacy for preventing SARS-CoV-2 infection.

Introduction
The coronavirus disease of 2019 (COVID19), caused by the Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2), is a pathology transmitted directly or indirectly through aerosols and whose
significant symptoms include mild to severe pneumonia.1,2

It has been shown that a high percentage of infections (mean 16.6%) occurs mainly in family nuclei,3,4
mostly because houses are closed environments that make it hard to maintain social distance, there is a
reduced use of personal protective equipment, and it is not possible to completely isolate a sick family
member.4 Attributable to the global problems and the rapid spread of this disease, there are research
groups dedicated to testing drugs that contribute to prevent and improve the prognosis of the disease
(e.g. Ivermectin,5 Vitamin D,6 and Hydroxychloroquine7). 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 the
viral capsids’ specific proteins.8 For example, ClO2 was shown to have the ability to inactivate Influenza
Virus caused by oxidating tryptophan 153 residue in the receptor-binding site.9 Considering SARS-CoV-2
spike protein composition (12 tryptophan, 54 tyrosine, and 40 cysteine residues), it can be assumed that
ClO2 also has the potential to inactivate this virus.10 There are a lot of unique properties that make ClO2
an ideal, non-specific antimicrobial: It has been demonstrated that ClO2 is a size-selective antimicrobial
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agent that can neutralize microorganisms rapidly.11 Furthermore, it can be used in animals and humans
without adverse effects in proper concentrations because of its incapability to penetrate the tissues.8,11

The current COVID-19 situation has shown the importance of having antiviral compounds available to act
quickly. Nowadays, there is no drug (prophylactic or therapeutic) approved by the Food and Drug
Administration (FDA) against COVID-19, and that had demonstrated high effectiveness.12–14 For this
reason, it is essential to investigate new compounds that can help to 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 positive/suspected COVID19 patients. We
evaluated the effectiveness of ClO2 in preventing the development of covid19-like symptoms.

Materials And Methods

Baseline and clinical information

This retrospective study was carried out using clinical records of 1,163 healthy subjects (without covid19-
like symptoms), from now on referred to as relatives, who live with positive/suspected COVID19 patients
(sick patients) in different cities (mainly Queretaro) in Mexico; from May 30, 2020, to January 15, 2021.
The inclusion criteria were as follows: 1) relatives living in the same house with a sick patient diagnosed
by Real-Time Reverse Transcriptase (RT)-PCR Viral Nucleic Acid Test to SARS-CoV-215 and
complementary tests like antigen detection test,16 serology test for specific immunoglobulin M (IgM) and
immunoglobulin G (IgG) antibodies against SARS-CoV-2,17 computed tomography,18 chest radiography,19
or clinical manifestations such as fever, cough, dyspnea, malaise, and fatigue;1 2) relatives whose
voluntarily requested prophylactic management at home and that, after were informed of the benefits and
possible secondary effects of ClO2 consumption, signed informed consent. Baseline (sex, age, and
comorbidities) and clinical (date of prophylactic management request, partial oxygen saturation [SpO2]
and covid19-like symptoms) information were collected from medical records. Moreover, the sick patient’s
disease severity status (mild, moderate or severe) was included.

Prophylactic Management: Chlorine Dioxide Solution

The production of ClO2 is not governed by any regulations in Mexico yet. Chemist-pharmacists or
professional Chemical-Engineers made the ClO2 by oxidation of sodium chlorite (NaClO2) using
hydrochloric acid (HCl) as an activator, ensuring the product’s concentration and safety. Being a chemical
compound, exposure to light and temperature above 11 °C changes its composition.8 Relatives were
informed to keep the CDS in the refrigerator (between 4-10 °C) and stored in closed amber jars. Relatives
began the oral prophylactic management in daily doses (0.3 mg/kg) of 0.0003% Chlorine Dioxide

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aqueous Solution (CDS, 10 ml of ClO2 at 3000 ppm in 1000 ml of water), divided into ten intakes of 100
ml/hour. This dose had been reported as adequate for human use;20–22 additionally, is ten times below
the “No Observed Adverse Effect Level” (NOAEL), almost 20 times below the “Lowest Observed Adverse
Effect Level” (LOAEL), and nearly 300 times below the lethal dose 50 (LD 50).10,23 Due to Mexico’s
regulations during the pandemic, relatives stayed at home for at least 14 days or offset symptoms of the
sick patient. Medical records show a daily follow-up for a minimum of 20 days of each relative.

Covid19-like symptoms Incidence and tracking overall physical well-being

Reported symptoms by relatives were used to calculated de incidence of covid19-like symptoms during
the clinical follow-up. Relatives who reported any symptom were considered as a non-successful case of
prophylactic management. To evaluate general physical well-being during prophylactic administration, 27
relatives that had 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 protein, albumin, sodium,
potassium, chloride, bilirubin, cholesterol, and triglycerides) before (at least three months) and after CDS
consumption, were included. Typical values from the general Mexican adult population were used as
reference values.24,25 Additionally, data of 50 electrocardiograms (ECG) performed to the relatives after
CDS consumption were collected to assess the QTc interval (manually measured), using the Bazzet QT
correction formula.26

Statistical analysis

Descriptive statistics were used to have an overall view of the basic features of the baseline information.
Age was categorized in five groups: 1-12, 13-19, 20-34, 35-64, >64 years. The incidence of covid19-like
symptoms was calculated by dividing the number of relatives with any symptom by the total number of
relatives in prophylactic management. We fitted a logistic regression model to analyze the association of
age, sex, family size, comorbidities, and the sick patient’s disease severity with the symptoms reported.
Multicollinearity was analyzed and discarded. Adjusted odds ratio (aOR) and its 95% confidence intervals
are presented. Risk Ratio (RR) was calculated to compare the prophylactic effectiveness of CDS with
current prophylactic drugs, and we use an Ivermectin meta-analysis data 5, which has presented the
highest effectiveness so far. Wilcoxon rank-sum tests were performed to compare outcomes between
blood tests (complete blood counts and metabolic panel test) before and after CDS consumption. To
compare the QTc interval of relatives that consume CDS against COVID19 patients treated with
Hydroxychloroquine, we performed an Analysis of Variance (ANOVA). A p-value <0.05 was considered
statistically significant. To reduce information bias in this study, the treating physician was not involved
in digitization or statistical analysis. All analyses were conducted using STATA v.15.1.27

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Ethical approval

For this type of study (retrospective), formal consent is not required28. Each subject included in this study
signed informed consent before starting the prophylactic management.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author
upon reasonable request.

Results
Background of study participants

Information was collected from 1,163 relatives belonging to 554 family nuclei, in 13 Mexico’s states,
mainly from Queretaro (52.25%) and Mexico City (12.61%). The sample comprised 567 women (48.75%),
442 men (38.00%) and 154 without information (13.24%), with a mean at the onset of 40.37 (range 2-89)
years. One hundred eighty-one relatives reported concomitant diseases, predominantly hypertension
(17.39%), diabetes (15.76%) and respiratory diseases (bronchitis, asthma and chronic pneumonia;
7.06%). Other conditions like cancer, renal failure, hypothyroidism, heart diseases and arthritis were
reported in less than 1%.

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
covid19-like symptom between 4-5 days after the request for prophylactic management with CDS (Table
1).

TABLE 1. Covid19-lik symptoms (mild, moderate and severe) that were reported by relatives

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 n %

Relatives that reported covid19-like symptoms

Total (non-success cases) 112 9.63

Female 67 59.82

Male 41 36.61

No informed sex 4 3.57

Covid19-like symptom (sporadic-mild)

Headache 36 3.10

Throat pain 24 2.06

Cough 23 1.98

Fever 22 1.89

Malaise 14 1.20

Diarrhea 12 1.03

Dizziness 11 0.95

Abdominal Pain 10 0.86

Fatigue 10 0.86

Nasal Congestion 10 0.86

Nasal Secretion 10 0.86

Nausea 9 0.77

Chest Pain 8 0.69

Dyspnea 7 0.60

Ageusia 4 0.34

Vomit 4 0.34

Anosmia 3 0.26

Gastritis 3 0.26

Appetite Loss 3 0.26

Joint Pain 3 0.26

Myalgia 1 0.09

Disorientation 1 0.09

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 Sneeze 1 0.09

Relatives that reported moderate covid19-like symptoms and suspended CDS

Total 2 0.17

Covid19-like symptom (moderate)

Headache 1 0.08

Gastritis 1 0.08

Relatives that reported severe covid19-like symptoms

Total 0 0

Relatives that reported secondary effects after CDS consumption

Total 13 1.12

Thirteen relatives (1.12%) reported secondary effects (diarrhea, headaches, gastritis, nausea, dizziness or
throat pain) posterior to CDS intake, and two of the non-success cases (1.78%) suspended the
prophylactic management due to moderate headaches and gastritis. In those 112 ill relatives, the CDS
consumption dosage was increased immediately after the symptom onset was reported to a therapeutic
dose (0.6 mg/kg) until symptoms’ resolution (between two and four days). None of the relatives who
presented covid19-like symptoms died.

The reported comorbidities were not statistically significant for covid19-like symptoms development (P =
0.092). There was no statistical evidence that relative’s sex and sick patient’s disease severity 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. Adjusting for sex and sick patient’s
diseases severity, relatives of all age categories had higher odds of present covid19-like symptoms
compared to younger patients, but only statistically significant in those of 35-64 years (aOR = 4.22,
95%CI: 1.71, 10.41, P = 0.002) and more than 64 years (aOR = 3.64, 95%CI: 1.30, 10.16, P = 0.014). When
comparing the prophylactic effectiveness of Ivermectin (average 86%5) against CDS, we observed that
relatives who consume CDS are 31% less likely to develop covid19-like symptoms (RR = 0.69, 95% CI =
0.54-0.89, P = 0.003).

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No parameters analyzed of the complete blood count (Table 2) were outside the average values before or
after. The Mean Cell Volume (MCV) was different (Wilcoxon rank-sum test, P < 0.02), being greater after
prophylactic management with CDS, although it was not outside the normal upper limit. In the metabolic
test (Table 2), blood glucose was above expected values before and after (mean, 102.65 mg/dL and
103.79 mg/dL, respectively). Nevertheless, 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 prolonged QTc (Fig. 1). Although, one male’s ECG showed a QTc = 442 ms. 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).29,30

TABLE 2. Complete blood count and metabolic parameters of 27 relatives before and after the CDS
prophylactic management to prevent covid19-like symptoms development

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Parameter BEFORE CDS AFTER CDS p- Reference
value values

mean±SD mean±SD α=
0.05

Red blood cells (106/µL) 5.02 ± 0.59 4.69 ± 0.89 0.22 4.39 -
6.10

Hemoglobine (gr/dL) 17.44 ± 7.26 14.11 ± 2.69 0.13 13.80 -

18.50

Hematocrit (%) 45.59 ± 12.80 42.73 ± 7.85 0.36 35.40 -

49.40

MCV (fL) 80.05 ± 22.56 90.36 ± 8.23 0.02* 84.40 -

100.00

MCH (pg) 36.82 ± 17.50 30.97 ± 2.40 0.45 27.10 -

33.5

MCHC (gr/dL) 30.79 ± 5.44 32.11 ± 1.45 0.84 31.60 -

34.80

Platelets (103) 264.21 ± 59.78 239.62 ± 39.11 0.27 147 - 384

MPV (fL) 9.47 ± 1.75 9.60 ± 1.39 0.73 9.60 -

13.40

White blood cells (103) 6.93 ± 1.73 6.94 ± 1.81 0.79 3.84 -
9.79

Neutrophils (%) 62.31 ± 7.29 61.05 ± 7.77 0.39 39.60 -

76.10

Lymphocytes (%) 29.42 ± 6.37 29.51 ± 8.48 0.73 15.50 -

48.60

Monocytes (%) 5.43 ± 2.13 5.97 ± 1.81 0.43 3.40 -

10.10

Eosinophils (%) 2.21 ± 2.43 1.88 ± 1.70 0.91 0.30 -

4.50

Basophils (%) 0.56 ± 0.56 0.41 ± 0.48 0.35 0.00 -

1.60

Lactic Dehydrogenase (UI/L) 147.43 ± 24.30 194.95 ± 72.57 0.22 139 - 205

Aspartate aminotransferase 26.21 ± 8.43 27.41 ± 9.47 0.34 12 - 35

(UI/L)

Alaline aminotransferase 31.08 ± 13.27 26.72 ± 13.09 0.22 9 - 47

(UI/L)

Gamma-glutamyl Transferase 33.77 ± 21.88 43.18 ± 29.18 0.28 13- 82

(UI/L)

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 Sodium (mmol/L) 139.24 ± 1.56 138.78 ± 1.72 0.79 136 - 145

Chloride (mmol/L) 104.00 ± 3.78 103.94 ± 4.11 0.69 102 - 112

Potassium (mmol/L) 4.37 ± 0.38 4.48 ± 0.48 0.44 3.70 -

5.20

Glucose (mg/dL) 102.65 ± 15.76 103.79 ± 20.40 0.73 < 100

Urea (mg/dL) 34.57 ± 16.91 45.18 ± 47.43 0.16 19 - 58

Blood Urea Nitrogen (mg/dL) 19.19 ± 8.61 18.87 ± 15.54 0.04 9 - 27

Creatinine (mg/dL) 0.90 ± 0.20 0.90 ± 0.23 0.74 0.77 -

1.32

Cholesterol total (mg/dL) 191.25 ± 66.91 174.09 ± 58.41 0.76 < 200

Triglycerids (mg/dL) 151.78 ± 75.02 141.71 ± 63.80 0.28 < 150

Total Bilirubin (mg/dL) 0.64 ± 0.39 0.73 ± 0.36 1 0.22 -

1.04

Direct Bilirubin (mg/dL) 0.16 ± 0.13 0.31 ± 0.20 0.64 0.12- 0.42

Indirect Bilirubin (mg/dL) 0.48 ± 0.37 0.42 ± 0.32 1 0.09 -

0.65

Alkaline phosphatase (UI/L) 79.94 ± 30.42 78.55 ± 29.11 0.48 40 - 130

Total Protein (g/dL) 7.03 ± 0.66 6.99 ± 1.14 0.26 6.50- 8.10

Seric Albumin (g/dL) 4.14 ± 0.53 4.19 ± 0.85 0.71 3.50 -

5.20

Abbreviations: MCV, mean cell volume; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular
hemoglobin concentration; MPV, mean platelets volume; SD, standard deviation.
*Statistical significance

Discussion
This retrospective study collected information from 1,163 relatives who lived with sick patients and who
consumed CDS prophylactically. In this study, the incidence of the covid19-like symptoms was 9.63%,
which is lower than the estimated overall household secondary attack rate reported (16.6%, 95% CI:
14.0%, 19.3%).4 It is clear that people commonly take protective measures in public places such as
washing their hands and wearing face masks, but neglect personal protection at home because they
consider it a “safe” place, which has generated a high incidence of infection among relatives.4 This is
why researchers are making a great effort to find an effective prophylactic alternative against COVID19.

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A few studies had proof of the COVID19 prophylaxis effect. Vitamin D supplementation during the
COVID19 pandemic has been suggested as a preventive measure due to its beneficial effect on the
immune system.31 However, the effectiveness was only about 40%.6 On the other hand, Ivermectin has
been studied extensively to prove its prophylactic efficiency against SARS-CoV-2 infection.32–34 The
results of a meta-analysis were used to compare the effectiveness of CDS against Ivermectin. We show
that CDS prophylactic effectiveness was slightly higher than the reported for Ivermectin (90.4% vs 86%,
respectively). Despite using similar exposure and outcome variables, the conditions and design of the
compared studies were different. Due to the few available evidence of ClO2/CDS in humans, we consider
it necessary to carry out randomized control trials or prospective cohorts to compare the effect of these
two substances in analogous groups.

One of the most studied drugs proposed as prophylactic is Hydroxychloroquine.7,35 However, it has not
shown statistically significant hazard reduction (HR =0.72, 95% CI: 0.44, 1.16; P = 0.18).7 Furthermore,
hematological alterations, liver36 and kidney37 function changes, and prolonged QTc interval29,30,38 have
been reported using this drug. Contrary to what we report in the present study, blood tests did not reveal
any systemic alteration after CDS consumption, similar to previously reported.21,22 Regarding cardiac
function, the use of Hydroxychloroquine combined with azithromycin in COVID19 patients, induces a
longer QTc interval (459 ± 36 ms29 and 463 ± 32 ms30). In this study, only one relative presented the QTc
interval (442 ms) in the borderline (431-450 ms), a limit established as usual for 1% of the population.38
In the rest of the relatives, the QTc interval was within normal ranges during prophylactic management
with CDS. COVID19 infection has been associated with prolonged QTc, regardless of various clinical
factors related to QTc prolongation. It has been reported that the risk of having prolonged QTc, increases
in patients treated with Hydroxychloroquine and Azithromycin, regardless of the presence or absence of
SARS-CoV-2 infection,39 and could lead to a high risk of malignant arrhythmia.38 We did not find
alterations in the QTc interval in healthy individuals who consumed CDS prophylactically. The design of
clinical trials in which a detailed follow-up is carried out is recommended to evaluate any possible effect
of Chlorine Dioxide on the QTc interval.

Concerning the risk associated with sex, women are the primary caregivers of other household members,
which could put them at risk in the event of a sick familiar.40 It has been reported a higher risk of infection
for COVID19 in females than in males (RR= 1.66, 95% CI: 1.39, 2.00) being the wife the most affected
compared with a non-spouse family member because of intimacy or direct contact (e.g. sleeping in the
same room) with her husband.3 However, in this study, no evidence was found that women have a higher
risk of infection than men. Regarding age, we did not find statistical evidence on covid19-like symptoms
development in younger age groups. Relatives older than 35 were at higher risk, being those with the
highest probability of developing COVID19 worldwide.3,4

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Even though comorbidities such as diabetes and hypertension have been recognized as risk factors for
COVID19 development,3 we did not find statistical differences in the present study. This may be due to
incorrect clinical data or due to CDS prophylactic effect. However, this remains to be clarified in additional
specific-designed studies.

This study shows that non-success cases started with covid19-like symptoms between 4-5 days after the
request for prophylactic management. This is consistent with previous studies where the highest
transmissibility rate is at the end of the first week of infection.41 Non-success cases reported sporadic
and mild symptoms, mainly: headache, throat pain, cough, fever, malaise, diarrhea, dizziness, abdominal
pain, and fatigue, which have already been reported as COVID19 symptoms in other studies.1,4
Nonetheless, without a confirmatory COVID19 diagnostic, it is impossible to ensure that the relatives were
infected with SARS-CoV-2.

ClO2 in other application forms and dosage have been categorized as a hazard compound due to a few
reported side effects. Additionally, some reported cases have been due to sodium hypochlorite (NaClO2)
instead of ClO2. In general, social networks have been flooded with misinformation through unjustified
news about ClO2. Even 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 possible
treatments,42 such as this compound. Our results show that CDS in the used dosage is safe and does not
have severe side effects, even if used in higher doses (none of the non-success cases reported secondary
effects after dose increase). This also is supported since no blood parameter was out of the normal
range after 14 days of prophylactic management. In this study, we only report thirteen relatives with
secondary effects, which disappear after dosage adjustment.

Limitations

Our study has some limitations. The first of all is that this 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 over the variables. Second, misinformation bias exists since baseline and clinical information is
reported by relatives. 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 the relatives who reported any covid19-like symptoms had COVID19. Fourth,
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the studies’ results used to compare our results are obtained from different populations and were
collected under other conditions, so these comparisons should be interpreted with caution. Fifth, the
overall interpretation of the findings may be restrained due to the lack of additional information (e.g.
personal care, eating habits, proximity and relationship with patients, etc.). These and other variables
should be taken into account in future studies.

Conclusion
This is the first study to try to determine the effectiveness of a Chlorine Dioxide aqueous Solution in
preventing the development of symptoms similar to COVID19. We demonstrated a 90.4% effectiveness of
preventing the outbreak of covid19-like symptoms under the given conditions. The blood test did not
reveal any systemic alteration after CDS consumption. Our results suggest that the correct use of ClO2 as
a solution is safe for human consumption in an adequate concentration and dosage. Hence, we consider
that the recent findings regarding Chlorine Dioxide justify implementing RCTs to evaluate 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.

Declarations
The Ethics Committee of the Centro Medico Jurica waived the need for ethical approval and the need to
obtain consent for the collection, analysis, and publication of retrospectively obtained data because it is 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 informed consent before treatment.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article

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Figures

Figure 1

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QTc interval (ms) of 50 relatives (females and males) after prophylactic management with CDS to
prevent covid19-like symptoms development.

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