INTRODUCTION

The first cases of infection by the new human coronavirus (SARS-CoV-2) were registered in December 2019 in the city of Wuhan, China¹. The virus belongs to the family Coronaviridae, the same as the etiological agents of Severe Acute Respiratory Syndrome (SARS-CoV) and the Middle East Respiratory Syndrome (MERS-CoV). COVID-19, a frequently asymptomatic but potentially lethal disease, has spread throughout the world.^2,3 Given its vertiginous spread, the World Organization of Health (WHO) declared COVID-19 a global pandemic on March 11, 2020.

SARS-CoV-2 has a positive and unique RNA strand as its genome⁴. It is a virus whose lipid envelope composition has not yet been determined experimentally, but it is known to be similar to influenza and herpes simplex viruses, containing phosphorylcholine, cholesterol, sphingolipids and “spike” glycoproteins⁵. The latter are essential for the binding of the micro-organism with the host cells, contributing to its high degree of infectivity⁵.

Although its incubation period is estimated to be long, between 2 to 14 days, any infected individual can transmit the disease, even before the onset of symptoms.^6-8 This is because, in the first 10 days after infection, it still in the asymptomatic phase, the virus accumulates in the nasal and oropharyngeal mucosa, in addition to the salivary glands, in whose cells there is a high expression of the transmembrane protein angiotensin-converting enzyme 2 (ACE2), the main receptor of SARS-CoV-2 in the cells⁹. It is inferred , furthermore, that its expression in the salivary glands is greater than in the lungs, which suggests that these sites are reservoirs for the virus before they infect other organs such as lungs, kidneys, and heart.¹⁰

This factor gives saliva a high viral load, which can reach 1.2 × 10./ml of infectious copies, which makes it play a crucial role in the disease transmission route.¹¹In this regard, the current pandemic resulted in many implications for dental practice, since professionals need to be in constant contact with patients’ oral fluids, including saliva and even blood. Moreover, some dental procedures that require the use of water jets, ultrasonic scrapings and low and high-speed handpieces release small saliva particles (≤ 5 μm), also known as aerosols, into the medium, which can transport SARS-CoV-2 as well as other pathogens.^12,13 In general, aerosols have delayed stabilization, which causes them to remain suspended in the air for a period of up to 4 hours after the procedures, in addition to possibility of being transported over distances greater than one meter and eighty.^14,15

In fact, to mitigate cross-infection resulting from contact with contaminated aerosols, it is possible to reduce their production, with the replacement of motorized instruments by manuals or reducing the salivary microbial load through the use of preoperative oral antiseptics⁴. However, in certain cases, high-speed engines and water jets are essential for carrying out the procedures. Therefore, the use of antiseptics is essential to reduce the risk of disease transmission in dental clinics.¹²

One of the most used oral antiseptics in dentistry is chlorhexidine gluconate (0.12%), due to its low toxicity and inhibition of oral biofilm development.¹⁶ However, the National Health Commission of China, through the Diagnosis Directive and Treatment of new Coronavirus Pneumonia, recommended the replacement of the compound by other antiseptics, as previous studies in the United States and England showed that its virucidal potential is limited and little known.^4,17 Thus, many researchers have sought to assess the effectiveness and mechanism of action of other antiseptics that can help control the disease, such as povidone iodine (PVP-I), cetylpyridinium chloride (CPC) and hydrogen peroxide (H.O.), compounds that are already present in the chemical composition of many commercially available mouthwashes.^2.18

The Brazilian National Health Regulatory Agency (Anvisa - Agência Nacional de Vigilância Sanitária), as well as the Federal Council of Dentistry (CFO – Conselho Federal de Odontologia), have recommended mouthwashes with PVP-I (0.2%) or H.O. (0.5% to 1.5%) before the procedures as a complement to the traditional protocol of oral rinses with chlorhexidine (CHX).^19,20 On the other hand, the Brazilian Association of Dental Education (ABENO - Associação Brasileira Ensino Odontológico) maintains the use of CHX as the main antiseptic and only indicates PVP- I (0.2%) and CPC in a titration of 1:4.000 in cases of allergic sensitivity.²¹ It is noteworthy that such recommendations are made based on the mechanism of action of these antiseptics, since their effectiveness against the new coronavirus is still has not been clinically proven³.

Therefore, the present literature review aimed to assess the potential efficacy of different intraoral antiseptics in SARS-CoV-2 infection control in dental clinics.

METHODS

This study is a descriptive and qualitative literature review. The literature review text was structured according to the PRISMA items ³⁵(Main Items for Reporting Systematic Reviews and Meta-analyses), checklist and flowchart for systematic reviews.

Eligibility criteria

Articles with publication date referring to the last five years, which had their full texts published in English and which addressed the efficacy of intraoral antiseptics in SARS-CoV-2 infection control in dental clinics were considered for this review.

Exclusion criteria

Editorials and studies that were based on the authors’ perspectives and that did not address the scientific knowledge regarding the efficacy of intraoral antiseptics in SARS-CoV-2 infection control in dental clinics were excluded.

Information source and search strategy

The databases used in this review included the Latin American and Caribbean Literature on Health Sciences (LILACS), the Cochrane Library, the CAPES Journal Portal, in addition to the Online System for Search and Analysis of Medical Literature (MEDLINE). The following search terms were used “mouth rinse”, “dental care”, “COVID-19”, associated by the Boolean operator AND, and “cetylpyridinium chloride”, “povidone-iodine”, “chlorhexidine” and “hydrogen peroxide”, these, in turn, are associated by the OR operator. A bibliographic search was carried out from June 30 to July 7, 2020.

Selection of studies

In phase 1, three reviewers (F.A.S.M., G.O.J. and A.V.R.F.) selected the articles independently. Disagreements were discussed and sorted out with a fourth reviewer (E.A.A.). Duplicate articles, which were in different databases, were excluded from the review. Articles that appeared to meet the inclusion criteria, as well as articles that lacked information in their abstracts, were selected for full reading in phase 2, in order to determine the work eligibility. A supplementary article was included after checking the reference lists. Data extraction and assessment of the quality of evidence were performed using the GRADE method ³⁶ (Grading of Recommendations Assessment, Developing and Evaluation) in studies that met the inclusion criteria.

Data collection

Three reviewers (F.A.S.M., G.O.J. and A.V.R.F.) independently collected all data. The differences were discussed with a fourth reviewer (E.A.A.). Data were extracted and organized into tables. The following variables were verified: country and place of study, n sample, study design, antiseptic used (including concentration and duration of treatment), antiviral potential against SARS-CoV-2, and authors’ conclusions.

Data were expressed as antimicrobial potential of the antiseptic (family Coronaviridae and other viruses) for the literature reviews included in the study. For in vitro and in vivo studies, the antiviral potential of the antiseptic against SARS-CoV-2 was analyzed.

Risk of bias in individual studies

The reviewers (F.A.S.M., G.O.J. and A.V.R.F.) performed an analysis of the articles independently and any disagreement was sorted out by consulting a fourth reviewer (E.A.A.). The GRADE method (Grading of Recommendations Assessment, Developing and Evaluation) was used to assess the quality of evidence in literature reviews and in vitro and in vivo studies regarding the antiviral activity of antiseptics against SARS-CoV-2. The quality of evidence was checked based on risk of bias, inconsistency, indirect evidence, and inaccuracy.

RESULTS AND DISCUSSION

Selection of studies

In the first stage of the article selection process, 46 potentially relevant articles were selected from the Latin American and Caribbean Literature in Health Sciences (LILACS) electronic, Cochrane Library, CAPES Journal Portal, in addition to the System Online Search and Analysis of Medical Literature (MEDLINE) databases. After reviewing titles and abstracts, 19 articles were excluded as they were in different databases. The abstracts of the remaining 27 articles were read; however, 7 articles were excluded because they were not related to the review topic. Among the 20 selected articles, 7 did not meet the inclusion criteria of this review and were excluded. Thirteen articles were included and 1 complementary article selected after checking the reference lists, totaling 14 articles (Figure 1).

Studies included

The characteristics of studies included in this review are shown in Tables 1, 2 and 3. These were subdivided into three categories: literature reviews (Table 1), in vitro experimental studies (Table 2), and in vivo experimental studies (Table 3).

After analyzing the articles, it was possible to identify four most relevant antiseptics in oral viral load control: CHX, PVP-I, CPC, and H.O..

Chlorhexidine (CHX)

One of the most common antiseptics in dental clinics, CHX has been recommended for medicinal use since the 1950s, being frequently used to control dental biofilm and treat gingivitis.^17,30In low concentrations (0.12%), it has bacteriostatic effect; in higher concentrations (2%), it has bactericidal effect.³⁰ Its mechanism of action involves the lysis of the bacterial cell wall, which usually occurs after thirty seconds of application.^4,17 It has its proven efficacy against gram-positive and gram-negative bacteria, aerobics and anaerobics².

However, its virucidal effects are controversial according to the analysis of the results obtained (Tables 1 and 3). Among the nine literature reviews selected, five addressed CHX characteristics.^2,5,12,13,17 In general, all articles reported its efficacy against lipophilic or enveloped viruses, but not against non-enveloped ones. Experimental studies proving the inactivation of coronavirus species are still scarce². However, two more recent articles reported that coronavirus species showed sensitivity when subjected to the application of CHX solution combined with other compounds, such as ethanol (70%) and cetrimide on inanimate surfaces (Table 1).^5,10

Regarding the elimination of microorganisms present in aerosols, CHX was potentially less effective than PVP-I, having similar efficacy to CPC.^12,17 However, an in vivo study carried out with two patients affected by COVID-19, who were given mouthwash for 30s with 15 mL of 0.12% CHX gluconate, showed that the viral load of SARS-CoV-2 in saliva significantly decreased and maintained is stable for 2 hours after application (Table 3).

Povidone iodine (PVP-I)

PVP-I is used in dentistry for oral decontamination, periodontal and peri-implant treatment, in addition to post-tooth extraction therapy.²⁷ However, its use is restricted, being contraindicated for individuals with iodine allergy, pregnant women, with thyroid disease active and patients on radioactive iodine therapy, as allergic reactions and thyroid dysfunctions have already been reported.^27,31

Its mechanism of action occurs through the release of free iodine, which interrupts microbial metabolic pathways, destabilizes the structural components of cell membranes and leads to irreversible damage to pathogens, as it oxidizes nucleic acid molecules.^3,18 It has proven efficacy against species of influenza, such as H1N1, since it acts to block viral activity by inhibiting hemagglutinin and neuraminidases proteins, thus preventing the binding of the virus to cell receptors as well as the release of the viral particle and consequent infection of new cells³.

The results showed that five review articles indicated the potential efficacy of PVP-I against coronavirus species (Table 1), given that it is characterized by having a larger viral spectrum than CHX, acting against enveloped or non-enveloped viruses.^{2 ,3,5,17,23} Furthermore, three in vitro studies demonstrated the inactivation of SARS-CoV and MERS-CoV by the antiseptic.^2,17,18 Although allergic reactions have been pointed out by some studies, other studies did not find them in the literature evidence of mucosal toxicity or irritation, even with prolonged use (Table 1).^2,3,5,17,31

Regarding SARS-CoV-2, the two in vitro studies already carried out applied different concentrations of PVP-I to virus samples grown in cell media (Table 2). Antiseptic and virus solutions were incubated at room temperature (22ºC) for 15 and 30s. Thus, it was observed that PVP-I was able to completely inactivate the virus after 15 seconds of application, at concentrations of 0.5%, 1%, 1.25% and 1.5%, with no cytotoxicity being observed. ^26.27

On the other hand, only one of the two selected in vivo studies assessed the virucidal potential of PVP-I (1%) (Table 3). This did not demonstrate a significant antiseptic efficacy against the new coronavirus, since a considerable reduction in viral activity in saliva only occurred in 75% of patients assessed and only 1 h after its application (Table 3).²⁹ There were no reports of allergic reactions after rinsing with PVP-I in 0.5% and 1% titrations.^29,30

Cetylpyridinium chloride (CPC)

CPC is a quaternary ammonium cation, soluble in water and highly cationic at neutral pH². It belongs to the group of surface-active agents and is often found in oral antiseptics and disinfectants.^2,24 Furthermore, it is important in dentistry for its antibacterial, antiplaque and antigenivitis properties.²⁴

The virucidal effect of CPC occurs mainly against enveloped viruses by releasing cations that act by breaking the lipid envelope, thus preventing cell infection.³² Its spectrum of action includes influenza virus strains (H1N1, AH3N2, A, B and A resistant to oseltamivir), respiratory syncytial virus, parainfluenza and HIV (Table 2).^{3,12,13,22,24} The action of CPC against coronaviruses was recently demonstrated.³⁴ Of the 36 antiseptics tested by Shen et al. (2019), CPC was ranked the ninth most relevant against four species of coronaviruses, including the virus that causes MERS.^33.34

There are no records of in vitro or in vivo experiments verifying the effectiveness of CPC against SARS-CoV-2. However, due to its mechanism of action, which is similar to that of some drugs used against the new coronavirus, the use of CPC-based mouthwashes is recommended in case of any need to change the traditional preoperative protocol (CHX 0.12%), as in patients allergic to CHX.^13,24The occurrence of allergic reactions to CPC is rare, although there are reports of pigmentation of the tongue and teeth.²³

Hydrogen peroxide (H.O.)

Widely used in concentrations at 1 to 3% as a tooth whitening agent, H.O. causes disruption of lipid membranes by releasing oxygen free radicals, making it very effective against enveloped viruses.^2,5

Although higher concentrations (> 5%) can induce damage to soft and hard tissues of the body, little damage is reported within the concentration range used in dental clinics⁵. In addition to this, its inactivation in the oral mucosa is rapid due to the presence of catalase enzyme, physiologically produced by the body and by bacteria of the oral microbiota, which reduces its possibility of causing allergic reactions⁵.

Some studies discussed the virucidal potential of H.O., including three literature reviews and one in vitro study (Tables 1 and 2). Some authors recommended its use due to antioxidant properties.^2,5,25 Caruso et al. (2020) highlighted that mouth and nasal rinses with antiseptic can improve the local innate response to viral infections due to oxidative stress caused by it (Table 1).²⁵

Regarding efficacy against SARS-CoV-2, Bidra et al. 2020 assessed the virucidal effect of H.O. at two concentrations (1.5% and 3%), verifying a minimal reduction in viral titer after 30s of interaction of H.O. with the virus (Table 2).²⁶ Thus, H.O. was less effective than PVP-I used in the study, since PVP-I at concentrations of 0.5%, 1.25% and 1.5% completely inactivated SARS-CoV-2 after 15s of interaction.

Assessment of the quality of evidence (GRADE)

Table 4 shows the assessment of the quality of evidence performed by the GRADE method.³⁶Literature reviews showed moderate quality of evidence due to the risk of bias in some selected articles. Although many articles discuss the relevance of antiseptic activity against viruses related to SARS-CoV-2 such as SARS-CoV and MERS-CoV, some studies do not present results in randomized clinical trials, with a significant number of patients.^2,5,12,17,25The absence of these data compromises the quality of evidence and can hinder decision-making related to the use of these antiseptics in dentists’ practice.

Furthermore, the in vivo studies analyzed showed very low quality of evidence, presenting methodological limitations and inconsistency of results (Table 4). The very low quality of evidence is associated with a reduced number of subjects in the studies ^16,28, differences in the results presented by patients²⁸ and the lack of testing to confirm the suggested results.²⁹ Although the pandemic was a major factor for the development of research around the world, it is extremely important that other studies with a lower risk of bias are carried out to determine the real effectiveness of these intraoral antiseptics in COVID-19 control in dental clinics.

On the other hand, in vitro studies showed high quality of evidence, demonstrating the antiviral activity of PVP-I against SARS-CoV-2.^26,27 These data are promising and may contribute to future randomized clinical trials capable of investigating the action of PVP-I in preventing SARS-CoV-2 contamination.

CONCLUSION

Routine dental procedures constantly release saliva aerosols containing pathogens into the medium, potentially increasing the risk of cross-infection. Therefore, considering that the main route of transmission of SARS-CoV-2 through contact with contaminated saliva, the use of preoperative oral antiseptics in dental clinics is essential to control transmission, as they can considerably decrease the salivary viral load.

Little conclusive evidence has been found regarding the efficacy of different oral antiseptics against SARS-CoV-2. However, PVP-I and CHX showed promising results in SARS-CoV-2 infection control in some studies. However, it is necessary to carry out randomized clinical studies to prove the real effectiveness of these antiseptics in combating SARS-CoV-2 infections.

Acknowledgments

We would like to thank the Universidade Federal do Piauí for the financial support.

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