Global Journal of Medical Research: F
Diseases

Volume 23 Issue 2 Version 1.0 Year 2023
Type: Double Blind Peer Reviewed International Research Journal
Publisher: Global Journals
Online ISSN: 2249-4618 & Print ISSN: 0975-5888

Relationship between COVID-19 and use of Chlorine Dioxide GasReleasing Agents in Elementary Schools
By Yoshinori Kubo, Takanori Miura, Kaoru Obinata, Ken Hisata, Mitsuyoshi Suzuki,
Eisuke Inage, Naotake Yanagisawa, Hiromichi Shoji, Norio Ogata, Jo Shibata,Takashi Shibata & Toshiaki Shimizu
Juntendo University

Abstract- Chlorine dioxide has an inactivating effect on various types of viruses in vitro, including
severe acute respiratory syndrome coronavirus 2. Therefore, chlorine dioxide gas can be used asa new preventive measure against coronavirus disease 19 (COVID-19). However, no studies
have been conducted to investigate the relationship between the incidence of COVID-19 andchlorine dioxide. We retrospectively studied the occurrence of COVID-19 in 164 public
elementary schools under the jurisdiction of boards of education located in urban areas inJapan, provided with chlorine dioxide gas-releasing agents or not, from January to March 2022.
The odds of developing COVID-19 were lower (odds ratio: 0.934, 95% confidence interval:
0.895–0.975) in schools provided with chlorine dioxide gas-releasing agents than in schools
without them. This suggested a relationship between the use of chlorine dioxide-releasing agentsand the incidence of COVID-19. Further studies are needed to prove a causal relationshipbetween them.
Keywords: chlorine dioxide, COVID-19, infection prevention, elementary school, viral infectivity.
GJMR-F Classification: DDC Code: E

RelationshipbetweenCOVID19anduseofChlorineDioxideGasReleasingAgentsinElementarySchools
Strictly as per the compliance and regulations of:© 2023. Yoshinori Kubo, Takanori Miura, Kaoru Obinata, Ken Hisata, Mitsuyoshi Suzuki, Eisuke Inage, Naotake Yanagisawa,
Hiromichi Shoji, Norio Ogata, Jo Shibata, Takashi Shibata & Toshiaki Shimizu. This research/review article is distributed under theterms of the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0). You must give appropriate credit toauthors and reference this article if parts of the article are reproduced in any manner. Applicable licensing terms are athttps://creativecommons.org/licenses/by-nc-nd/4.0/.

Relationship between COVID-19 and use of
Chlorine Dioxide Gas-Releasing Agents in
Elementary Schools

types of viruses in vitro, including severe acute respiratory
syndrome coronavirus 2. Therefore, chlorine dioxide gas canbe used as a new preventive measure against coronavirus
disease 19 (COVID-19). However, no studies have been
conducted to investigate the relationship between theincidence of COVID-19 and chlorine dioxide. We
retrospectively studied the occurrence of COVID-19 in 164
public elementary schools under the jurisdiction of boards ofeducation located in urban areas in Japan, provided withchlorine dioxide gas-releasing agents or not, from January to
March 2022. The odds of developing COVID-19 were lower(odds ratio: 0.934, 95% confidence interval: 0.895–0.975) inschools provided with chlorine dioxide gas-releasing agentsthan in schools without them. This suggested a relationshipbetween the use of chlorine dioxide-releasing agents and theincidence of COVID-19. Further studies are needed to prove a
causal relationship between them.

Keywords: chlorine dioxide, COVID-19,
prevention, elementary school, viral infectivity.

S

I.

infection

Introductionince December 2019, coronavirus disease 19(COVID-19) caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) (Shang etal., 2020; Zhou et al., 2020) has been a global publichealth problem (Chen et al., 2020; Xu et al., 2020).
Although pediatric patients with COVID-19 often have amilder course than adults, the COVID-19 infection has
had a negative impact on children in terms of lostlearning opportunities, malnutrition, poverty, anddisruption of health services such as routine childhood
immunizations (UNICEF, 2022). In the first and second
waves of COVID-19 in Japan, the proportion of cases
under 20 years of age was less than 15% (Imamura etal., 2021), and children did not suffer from secondary
infections (Ko et al., 2022). However, in the sixth wave of
the omicron variant, the proportion of cases under 20
Author α σ ρ Ѡ § χ ν € : Department of Pediatrics, Juntendo University
Faculty of Medicine, Tokyo 113-8421, Japan.
e-mail: y.kubo.hj@juntendo.ac.jp
Author α σ ρ Ѡ § χ ζ £ € : Department of Mass Infection Prevention,
Juntendo University, Tokyo 113-8421, Japan.
Author α σ Ѳ ζ £: Taiko Pharmaceutical Co., Ltd., Osaka 550-0005,
Japan.
Author: Medical Technology Innovation Center, Juntendo University,
Tokyo 113-8421, Japan.

years of age rose to 35% (Aizawa et al., 2022). Standard
infection control measures include routine precautions
such as hand washing, wearing masks, andenvironmental cleaning. Thorough implementation ofthese measures is important for the prevention of
infection. However, it has been reported that young
children often not wash properly their hands and handwashing is less effective. (Harada, 2004)
In addition, in terms of environmental cleaning,
it is practically impossible to clean areas where handcontact occurs with high frequency, and standard
precautions alone are not sufficient to prevent infection.
Despite the prevalence of highly infectious variants in all
age groups, parents are hesitant to vaccinate theirchildren (Horiuchi et al., 2021; Yoda & Katsuyama,2021). Therefore, to reduce the adverse effects of
COVID-19 on children and prevent the spread of
infection, it is desirable to reduce the incidence of
COVID-19 through new preventive measures.
SARS-CoV-2 is transmitted among humanbeings primarily through close contact in confined
spaces, droplets of respiratory origin, and contaminatedsurfaces (Cheng et al., 2020; Lai et al., 2020; Sungnak
et al., 2020). SARS-CoV-2 can remain on the surface ofthe vector for several days (Chin et al., 2020; vanDoremalen et al., 2020) and is stable for several hours if
aerosolized (van Doremalen et al., 2020). Therefore,
environmental factors can have a significant impact ontransmission in buildings where people are in close
proximity, such as schools (Azuma, Kagi, et al., 2020;
Azuma, Yanagi, et al., 2020). Especially in Japan, during
the sixth wave of SARS-CoV-2 infection, the proportionof infections in children in schools, nursery schools, andkindergartens increased, while the proportion of
infection in the family, the main source of infection,
decreased (Aizawa et al., 2022). Therefore, schools are
considered an important place for the prevention of
COVID-19 in children.
Chlorine dioxide (CD) exists as a diffusible gas
at room temperature that can be distributed over a wide
area (Gates, 1998). The effectiveness of lowconcentration CD gas, which poses almost no risk to thehuman body, was demonstrated in an in vitro© 2023Global Journals

1

Global Journal of Medical Research ( FD ) Volume XXIII Issue II Version I

Abstract- Chlorine dioxide has an inactivating effect on various

Year 2023

Yoshinori Kubo α, Takanori Miura σ, Kaoru Obinata ρ, Ken Hisata Ѡ, Mitsuyoshi Suzuki ¥, Eisuke Inage §,Naotake Yanagisawa χ, Hiromichi Shoji ν, Norio Ogata Ѳ, Jo Shibata ζ, Takashi Shibata £& Toshiaki Shimizu €Year 2023

Relationship between COVID-19 and use of Chlorine Dioxide Gas-Releasing Agents in Elementary Schools

Global Journal of Medical Research ( FD ) Volume XXIII Issue II Version I

2experiment in a closed space in which 0.01 ppmv CD
gas inactivated more than 99% of all floating viruses(Ogata et al., 2016). More than 99% of the viruses
adhering to the surface of objects were also inactivatedby 0.007 ppmv CD gas (Morino et al., 2013).In vivo
experiments suggested that 0.03 ppmv CD gas
prevented influenza infection in mice (Ogata & Shibata,2008). In vitro experiments using a CD gas-releasing
agent have also shown inactivation of the avian
influenza virus A (H7N9) (Sun et al., 2022). Further,studies in humans have suggested that the use of CD
gas-releasing agents is effective against viral infections(Mimura et al., 2010; Ogata & Shibata, 2009).
Although CD gas-releasing agents can be
expected to be useful for COVID-19 prophylaxis, nostudies have been conducted to investigate therelationship between COVID-19 infection and CD gasreleasing agents. Therefore, the purpose of this study
was to conduct a retrospective study of the relationshipbetween the use of CD gas-releasing agents and theincidence of COVID-19 in elementary schools.
II.

Material and Methodsa) DesignThis
multicenter,retrospective
study
investigated the relationship between the incidence of
COVID-19 and the use of CD gas-releasing, fromJanuary to March 2022, using a database created by theCity Board of Education. This study was approved by
the Juntendo University School of Medicine Medical
Research Ethics Committee (Research Project No. E220382).
b) Subjects
The subjects of this study were first- to sixthgrade (approximately 6 to 12 years old) male andfemale students in public elementary schools under thejurisdiction of a municipal board of education in an
urban area in Japan. Since there was no precedent forthis study, the sample size could not be calculated. No
exclusion criteria were established as this was an
exploratory study.
c) CD gas-releasing agent
CD gas-releasing agents (Cleverin® pro Gel
Large type for 50m2(Taiko Pharmaceutical Co.) andCleverin Pro Pouch type for 30 m2, Taiko
Pharmaceutical Co., Ltd., Japan) are made by adding
sodium dihydrogen phosphate to sodium chlorite andsolidifying the mixture by adding superabsorbent
polymers, which then generate and release CD gas
continuously for several months. Those agents, which
can be safely used in an inhabited environment, were
provided free of charge by Taiko Pharmaceutical Co.,
Ltd. to city school boards for marketing purposes. They
were further distributed by city school boards toelementary schools that requested them from January© 2023Global Journals

2022 through March 2022. It was recommended thatthose agents be provided in classrooms at a rate of one
unit per 30 m2 or 50 m2 in the case of Cleverin Pro
Pouch type or Placeable type, respectively.
d) Incidence of COVID-19
The number of infections of COVID-19 wasinvestigated in all elementary schools from January to
March 2022. The parents of the children were requested
to notify the schools when the PCR test for COVID-19
was positive, when the antigen test was positive, or
when a physician determined that COVID-19 wasstrongly suspected. These reports were compiled by theelementary schools and reported to the city's board ofeducation. The city school board created a database of
the CD gas-releasing agents provided and the numberof COVID-19 infections.
e) Statistical analysis
The distribution by a number of elementary
school students was shown as the median (25th–75th
percentile values), since the Kolmogorov-Smirnov
normality test did not allow for a normal distribution. The
association between the use of CD gas-releasing agentsand the incidence of COVID-19 was analyzed using
crude odds ratios of the subjects who suffered fromCOVID-19. Incidence as cases were defined as thenumber of reported COVID-19 incidences, and controls(non-incidence) were defined as the number of children
minus the number of reported COVID-19 infections. The
significance level was p<0.05, and IBM SPSS
Statistics® ver. 28 was used for statistical analysis.
III.

Results

A summary of the elementary schools analyzed
in this study is shown in Table 1. Sixty-eight elementary
schools (n = 34,810) did not use any CD gas-releasing
agent, whereas 96 (n = 38,714) used those agents.
Table 2 shows the odds ratio for incident
COVID-19. Elementary schools that did not use chlorine
dioxide-releasing agents had higher odds (odds ratio:
0.934, 95% confidence interval: 0.895–0.975) of COVID19 incidence than those that did.
IV.

Discussion

This exploratory study investigated therelationship between the use of CD gas-releasing
agents in classrooms and COVID-19 infections inelementary schools and showed that elementary
schools that used those agents had significantly lower
odds ratios for COVID-19 incidence than those that didnot.
A previous study showed that in an intervention
study of Ground Self-Defense Forces personnel, agroup that used those CD gas-releasing agents in aroom had significantly lower numbers of cases ofinfluenza-like illnesses than the non-intervention groupRelationship between COVID-19 and use of Chlorine Dioxide Gas-Releasing Agents in Elementary Schools

V.

References Références Referencias
1.

2.

3.

4.

Conclusion

A retrospective study in an urban elementary
schools in Japan suggested that the use of chlorine
dioxide gas-releasing agents may be linked to the
reduced development of COVID-19 infections. Further
studies are needed to prove a causal relationship.

5.

Acknowledgement
We are appreciative to the elementary school
officials and the school board for providing the data forthis study.
Funding
The study was conducted and supported by ajoint laboratory established by Juntendo University andits funder, Taiko Pharmaceutical Co., Ltd.
Abbreviations
SARS-CoV-2, severe acute respiratory syndrome
coronavirus 2; COVID-19, coronavirus disease 19; CD,chlorine dioxide.

6.

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© 2023Global Journals

Year 2023

Conflict of Interest
Yoshinori Kubo, Takanori Miura, Norio Ogata,
Jo Shibata, and Takashi Shibata received a salary from
Taiko Pharmaceutical Co., Ltd., which manufactures thechlorine dioxide gas-releasing agents (Cleverin®) usedin this study. Yoshinori Kubo, Takanori Miura, Kaoru
Obinata, Ken Hisata, Mitsuyoshi Suzuki, Eisuke Inage,
Naotake Yanagisawa, Jo Shibata, Takashi Shibata,Toshiaki Shimizu belong to the Department of Mass
Infection Prevention, which is funded by Taiko
Pharmaceutical Co., Ltd.

3

Global Journal of Medical Research ( FD ) Volume XXIII Issue II Version I(Mimura et al., 2010). In addition, a retrospective
observational study of elementary school students
reported significantly lower cumulative absenteeism
rates in classes where those CD gas-releasing agentswere used than in classes where they were not used
(Ogata & Shibata, 2009). The results of this study
support the findings of these previous studies. A
potential mechanism by which the CD gas-releasing
agent suppressed COVID-19 infections is that CD gas,
once dissolved in water, reduces the binding activity of
the SARS-CoV-2 spike protein as demonstrated in invivo experiments (Ogata & Miura, 2020, 2021). It has
been suggested that this mechanism can reduce theviral infectivity of SARS-CoV-2 (Hatanaka et al., 2021). In
summary, these findings suggest that the use of CD
gas-releasing agents in elementary school classrooms
could be linked to lower COVID-19 infections instudents.
The strength of this study is that it was a
relatively large survey of many public elementary
schools in the city. However, this study has several
limitations. First, chlorine dioxide-releasing agents were
distributed only to elementary schools that requested
them, which may have biased the characteristics of thetarget population. Second, we did not have access to
information from elementary schools located outside
urban areas. Therefore, caution should be exercisedwhen generalizing the results of this study. Moreover,
the odds ratio could not be adjusted for confounding
factors. Third, the route of infection was not considered.
Hence, future randomized controlled trials should be
conducted to evaluate the efficacy of CD gas-releasing
agents against COVID-19.

Relationship between COVID-19 and use of Chlorine Dioxide Gas-Releasing Agents in Elementary Schools

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Table 1: Characteristics

Not used
Used

68
96

Number of students per elementary school
Total

Median25th

75th

34,81038,714

466
332

279
236

668
526

Year 2023

Number of
Elementary
Schools5

Table 2: Odds ratio for incident COVID-19
CD gas-releasing
agent
Not used
Used

COVID-19
Number of
Number of
Incidences
Controls
4,787
5,019

30,02333,695

Odds ratio

95%CI

Reference
0.934

0.895-0.975

p-value0.0017© 2023Global Journals

Global Journal of Medical Research ( FD ) Volume XXIII Issue II Version I

Chlorine dioxide
releasing agent