BioScience Trends Advance Publication P1

Correspondence DOI: 10.5582/bst.2022.01495

Can nasal irrigation with chlorine dioxide be considered as a

potential alternative therapy for respiratory infectious diseases?
The example of COVID-19
§ § §
Jing Cao1, , Yirong Shi1, , Min Wen1, , Yuanyuan Peng1, Qiqi Miao1, Xiaoning Liu1,
Mingbin Zheng2, Tetsuya Asakawa2,*, Hongzhou Lu2,3,*
1
Department of Nursing, National Clinical Research Center for Infectious Diseases, Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China;
2
Institute of Neurology, National Clinical Research Center for Infectious Diseases, Third People's Hospital of Shenzhen, Shenzhen, Guangdong, China;
3
Department of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Third People's Hospital of Shenzhen, Shenzhen,
Guangdong, China.

SUMMARY Chlorine dioxide (ClO2) is a high-level disinfectant that is safe and widely used for sterilization. Due
to the limitations on preparing a stable solution, direct use of ClO2 in the human body is limited. Nasal
irrigation is an alternative therapy used to treat respiratory infectious diseases. This study briefly
summarizes the available evidence regarding the safety/efficacy of directly using ClO2 on the human
body as well as the approach of nasal irrigation to treat COVID-19. Based on the available information,
as well as a preliminary experiment that comprehensively evaluated the efficacy and safety of
ClO2, 25-50 ppm was deemed to be an appropriate concentration of ClO2 for nasal irrigation to treat
COVID-19. This finding requires further verification. Nasal irrigation with ClO2 can be considered as
a potential alternative therapy to treat respiratory infectious diseases, and COVID-19 in particular.

Keywords chlorine dioxide (ClO2), nasal irrigation, COVID-19, SARS-CoV-2, respiratory infectious diseases

Chlorine dioxide (ClO 2) is an oxidizing agent that and medical equipment have been well documented.
is commonly used as a high-level disinfectant. It is However, there is a limitation to directly using ClO2 on
effective at killing pathogenic microorganisms including human body, namely the limited availability of a stable
bacteria, viruses, fungi, and spores, and it has almost no ClO2 solution that can be stored for a prolonged period.
toxic effects on human or animal cells in daily use (1). A ClO2 solution often needs to be prepared before using
ClO2 has a molecular structure with 19 electrons in the via a chemical reaction of precursors such as sodium
outer layer, which contributes to its oxidizing action and chlorite (NaClO2) or use of an effervescent tablet. Such
penetration. It can adsorb to and penetrate the surface of "activation" procedures are inconvenient. Importantly,
microorganism without markedly destroying the integrity the concentration and stability of the obtained ClO2
of the microbial shell (such as the cytoderm or protein solution are not easily controlled, thereby limiting the use
capsid), and it markedly acts on enzymes containing of ClO2 to disinfect the human body. Fortunately, a stable
sulfhydryl groups. The mechanism of disinfection by ClO2 solution (free of activation) has recently become
ClO2 is via: i) Rapid damage to tyrosine on the capsid of available, and this offers hope for the direct use of ClO2
the bacterium or virus, thereby suppressing their specific in the human body.
adsorption; ii) Suppression of protein synthesis; and
iii) Killing these microorganisms, which account for its 1. Use of ClO2 for human disinfection
sterilizing action (2). In the context of SARS-CoV-2,
ClO2 directly affects the spike protein and RNA of the Many previous animal studies have demonstrated the
virus, ultimately killing the virus (3). Hence, ClO2 has safety of ClO 2 as a sanitizer. Ma et al. verified the
been long used for sterilization, both for sterilization efficacy, toxicity, and safety of ClO2 in vitro and in
of equipment and environments as well as for human vivo (8). Their in vitro experiments found that ClO2 at
disinfection, such as dental oral cleaning (4-6) and 5-20 ppm resulted in a 98.2% reduction in bacteria and
wound cleaning (7). Its disinfecting action in home fungi. ClO2 at 200 ppm (37℃, 2 min) killed most strains
environments, the water supply, environmental surfaces, of influenza A and B and enterovirus 71. In terms of

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P2 BioScience Trends Advance Publication

toxicity, cellular viability was 74.0% at 600 ppm, and most studies similarly concerning the environment.
40.3% at 800 ppm. In in vivo experiments, inhalation of There are only limited studies in humans (Table 1).
ClO2 at 0-20 ppm (24 h) or oral administration of ClO2 Aparicio-Alonso et al. orally administered ClO2 at 3 ppm
at 0-40 ppm (90 days) did not cause any pathological as a prophylactic agent to family members living with
changes in the heart, lungs, liver, kidneys, or spleen COVID-19 patients in Mexico (9). They found that ClO2
of mice. Oral administration of ClO2 at 0-40 ppm also was effective at preventing COVID-19, and no adverse
did not cause any pathological changes in these organs. events were reported. In another study, Aparicio-Alonso
Use of 0.1 mL of ClO2 at 50 ppm did not lead to ocular et al. orally administered a mean dose of 1.41 mg/kg to
irritation in rabbits (8). These experiments verified the treat COVID-19 patients (10). They found that CIO2
biosafety of ClO2 in different animals. helped to resolve COVID-19 symptoms and reduce the
However, evidence regarding the direct use of ClO2 in duration of treatment. Only 6.78% of patients reported
humans is limited due to the aforementioned limitation. mild and sporadic uncomfortable reactions such as
By far, the most common context is dental disinfection. headaches, dizziness, vomiting, diarrhea, and nausea.
Early in 2008, a Japanese team used 0.1% ClO2 (1,000 They hence concluded that ClO2 might be considered as
ppm) mouthwash to treat healthy subjects with halitosis a safe alternative therapy with which to treat COVID-19.
(4). They found that halitosis was alleviated, and no There are only 2 studies reporting toxic reactions.
adverse events were reported (5). Later, the same team Bathina et al. reported an unusual case of reversible
used ClO2 at 1,000 ppm (7 days of mouthwash) in 15 acute kidney injury due to chlorine dioxide poisoning
subjects with halitosis. They found that accumulation due to consumption of 250 mL of stable ClO 2 (11).
of plaque, coating of the tongue, and the count of Recently, Medina-Avitia et al. reported a 55-year male
Fusobacterium nucleatum in saliva decreased. Only three who developed acute kidney injury and disseminated
subjects reported "dislike of the smell and taste of ClO2". intravascular coagulation due to the oral administration
Recently, an Indian team also used ClO2 at 1,000 ppm of CIO2 to prevent and treat COVID-19. After treatment
for disinfection in patients who underwent periodontal with hemodialysis, the kidney injury was reversed
surgery (mouthwash bid for 14 days). They found (12). These cases imply that: i) Oral administration of
that all of the patients were able to tolerate the ClO2 CIO2 in a short period, in a large dose, or to patients
mouthwash. No discomfort was reported (6). Noszticzius with underlying illnesses might be risk factors for the
et al. used ClO2 at 300 ppm as an antimicrobial agent development of acute kidney injury and ii) this ClO2-
for the wounds of patients with deep venous thrombosis related kidney injury is reversible.
or diabetic foot (7). They found that ClO2 at 300 ppm
displayed efficacy in killing all bacteria. It helped with 2. Using nasal irrigation as an alternative therapy for
wound healing without causing any toxic reactions. They COVID-19
contended that ClO2 might be a good disinfectant for use
in all living organisms (Table 1). Since there is no specific treatment for COVID-19, many
In terms of using ClO2 in the context of COVID-19, alternative therapies have been considered. High titers

Table 1. The concentrations of ClO2 in representative studies directly using ClO2 in the human body

Concentration
Studies/Country Subjects Intervention Safety Efficacy
of ClO2 (ppm)

Shinada et al., 15 healthy subjects 7 days of 1,000 No adverse events reported Relief of halitosis
2008/Japan mouthwash

Shinada et al., 15 healthy subjects 7 days of 1,000 Three subjects reported "dislike Accumulation of plaque, coating
2010/Japan mouthwash of the smell and taste" of the tongue, and the count of
Fusobacterium nucleatum in saliva
decreased

Noszticzius et al., One patient with Direct 300 No adverse events reported Effective at wound disinfection and
2013/Hungary thrombosis and administration helped with wound healing
two patients with of ClO2 to the
diabetic foot wound

Kale et al., Patients who 14 days of 1,000-2,000 No adverse events reported ClO2 contributed to the promotion of
2020/India underwent mouthwash early wound healing after periodontal
periodontal surgery
surgery

Aparicio-Alonso Family members 14-day oral 3 ppm No obvious adverse reactions ClO 2 reduced COVID-19-related
et al., 2021/ living with patients administration reported symptoms and contributed to
Mexico with COVID-19 prevention of the COVID-19

Aparicio-Alonso Family members 14-day oral 3 ppm Only 6.78% of patients ClO 2 reduced COVID-19-related
et al., 2021/ living with patients administration (1.41 mg/kg) reported mild and sporadic symptoms and contributed to
Mexico with COVID-19 uncomfortable reactions prevention of the COVID-19
such as headaches, dizziness,
vomiting, diarrhea, and nausea.

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 BioScience Trends Advance Publication P3

of SARS-CoV-2 can be detected in the upper airways of

asymptomatic/symptomatic COVID-19 patients (13),
with higher viral loads found in nasal swabs compared
to pharyngeal swabs. Nasal irrigation has hence been
considered as an alternative therapy to treat COVID-19.
During the early days of the COVID-19 pandemic,
Casale et al. (14), Ramalingam et al. (15), and Panta
et al. (16) proposed that nasal irrigation may be a
potential treatment for COVID-19. Later, Huijghebaert
et al. reported that early nasal irrigation with saline
may ameliorate COVID-19 symptoms (17). Yilmaz et
al. found that nasal irrigation with hypertonic alkaline
significantly reduced the viral load in patients with
COVID-19 (18). Later, Yildiz et al. found that nasal
saline irrigation with triamcinolone acetonide may relieve
COVID-19-related hyposmia (19). Baxter et al. found
that nasal irrigation with povidone-iodine or sodium
bicarbonate helped to reduce disease severity and the
duration of hospitalization in patients with COVID-19
(20). These studies seem to prove the efficacy of nasal
irrigation to treat COVID-19. However, whether nasal
Figure 1. Results of a preliminary experiment exploring the doses
irrigation can be used as a potential alternative therapy
of ClO2 for nasal irrigation in 5 healthy participants. (A) Schematic
for COVID-19 requires further investigation because diagram of nasal irrigation used in a preliminary experiment. (B)
of the small samples in those studies. Moreover, those Results of the preliminary experiment with regard to discomfort.
studies involved the early beta and delta strains; whether At a ClO2 concentration of 25 ppm, 3 participants felt comfort and
2 participants felt mild discomfort. At a ClO2 concentration of 50
nasal irrigation is effective against the omicron strain
ppm, two participants felt comfort and three participants felt mild
warrants investigation. discomfort. At a ClO2 concentration of 100 ppm, one participant felt
Based on the aforementioned evidence, ClO2, is moderate discomfort, three participants felt severe discomfort, and one
a safe and efficient disinfectant, and it is particularly participant felt extreme discomfort. Hence, 25-50 ppm was considered
to be an appropriate concentration range for nasal irrigation and was
useful as an agent for nasal irrigation to treat respiratory
used in subsequent experiments.
infectious diseases, and COVID-19 in particular.

3. Deduction of an appropriate dose of ClO2 for nasal 4). In a preliminary experiment performing nasal
irrigation irrigation in 5 healthy subjects, 25 and 50 ppm did not
cause any intolerable discomfort, whereas 100 ppm may
The first consideration is safety. The dose, concentration, cause discomfort due to the smell (Figure 1).
and method of administration are known to be the most 5). If using ClO2 at 50 ppm for nasal irrigation (100
crucial factors associated with the safety of ClO2 in the mL, bid), the nasal irrigation dose is 10 mg (for a 50 kg
context of COVID-19 (3). Hence, the dose/concentration adult), about 2/3 of the dose in the study by Aparicio-
of ClO 2 must be carefully and comprehensively Alonso et al. (3). This is 30 times lower than the LOAEL
determined by balancing efficacy, safety, and ease and 450 times lower than the LD50
of solution preparation. Several aspects need to be 6). When preparing a ClO2 solution, concentrations
considered to deduce the appropriate dose: of 25 and 50 ppm are easily handled and stored.
1). Hatanaka et al. reported that exposure to ClO2 at Accordingly, 25-50 ppm was deemed to be an
24 ppm for 10 s can kill 99.99% of SARS-CoV-2 (1). appropriate concentration range for nasal irrigation
This suggests that SARS-CoV-2 is extremely sensitive to with ClO2 in terms of safety and efficacy. Indeed, the
ClO2. current authors are now conducting a subsequent study
2). Aparicio-Alonso et al. reported that oral to evaluate the safety and efficacy of nasal irrigation
administration of ClO2 at 3 ppm in a dose of 0.3 mg/kg/ with ClO2 at 25 or 50 ppm. The forthcoming results
day was safe (9). Assuming the body weight of an adult should help to provide evidence regarding whether nasal
is 50 kg, oral consumption of 15 mg/day ClO2 is safe. irrigation with ClO2 can be used as an alternative therapy
This is 20 times lower than the lowest observed adverse to treat COVID-19, as well as the other respiratory
effect level (LOAEL) and 300 times lower than the LD50. infectious diseases such as influenza.
3). Ma et al. found that ClO2 at 50 ppm did not cause
ocular irritation in rabbits, which proved that 50 ppm Acknowledgments
causes no mucosal irritation. Thus, it is safe for the nasal
mucosa. The authors would like to thank Shenzhen Caseche

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P4 BioScience Trends Advance Publication

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Shenzhen (approval number 2022-182-03). The study Deshpande P, Ch R, Prayaga A, Uppin M. An unusual case
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These authors contributed equally to this work.
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