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. 2020 Sep 16;9(9):CD013627.
doi: 10.1002/14651858.CD013627.pub2.

Antimicrobial mouthwashes (gargling) and nasal sprays administered to patients with suspected or confirmed COVID-19 infection to improve patient outcomes and to protect healthcare workers treating them

Martin J Burton  1 , Janet E Clarkson  2 , Beatriz Goulao  3 , Anne-Marie Glenny  4 , Andrew J McBain  5 , Anne Gm Schilder  6   7 , Katie E Webster  8 , Helen V Worthington  9
Affiliations

Antimicrobial mouthwashes (gargling) and nasal sprays administered to patients with suspected or confirmed COVID-19 infection to improve patient outcomes and to protect healthcare workers treating them

Martin J Burton et al. Cochrane Database Syst Rev. .

Abstract

Background: COVID-19 infection poses a serious risk to patients and - due to its contagious nature - to those healthcare workers (HCWs) treating them. If the mouth and nose of patients with infection are irrigated with antimicrobial solutions, this may help the patients by killing any coronavirus present at those sites. It may also reduce the risk of the active infection being passed to HCWs through droplet transmission or direct contact. However, the use of such antimicrobial solutions may be associated with harms related to the toxicity of the solutions themselves or alterations in the natural microbial flora of the mouth or nose.

Objectives: To assess the benefits and harms of antimicrobial mouthwashes and nasal sprays administered to patients with suspected or confirmed COVID-19 infection to both the patients and the HCWs caring for them.

Search methods: Information Specialists from Cochrane ENT and Cochrane Oral Health searched the Central Register of Controlled Trials (CENTRAL 2020, Issue 6); Ovid MEDLINE; Ovid Embase and additional sources for published and unpublished trials. The date of the search was 1 June 2020. SELECTION CRITERIA: This is a question that urgently requires evidence, however at the present time we did not anticipate finding many completed RCTs. We therefore planned to include the following types of studies: randomised controlled trials (RCTs); quasi-RCTs; non-randomised controlled trials; prospective cohort studies; retrospective cohort studies; cross-sectional studies; controlled before-and-after studies. We set no minimum duration for the studies. We sought studies comparing antimicrobial mouthwash and/or nasal spray (alone or in combination) at any concentration, delivered with any frequency or dosage to suspected/confirmed COVID-19 patients.

Data collection and analysis: We used standard Cochrane methodological procedures. Our primary outcomes were: 1) RECOVERY* (www.recoverytrial.net) outcomes in patients (mortality; hospitalisation status; use of ventilation; use of renal dialysis or haemofiltration); 2) incidence of symptomatic or test-positive COVID-19 infection in HCWs; 3) significant adverse event: anosmia (or disturbance in sense of smell). Our secondary outcomes were: 4) change in COVID-19 viral load in patients; 5) COVID-19 viral content of aerosol (when present); 6) other adverse events: changes in microbiome in oral cavity, nasal cavity, oro- or nasopharynx; 7) other adverse events: allergy, irritation/burning of nasal, oral or oropharyngeal mucosa (e.g. erosions, ulcers, bleeding), long-term staining of mucous membranes or teeth, accidental ingestion. We planned to use GRADE to assess the certainty of the evidence for each outcome.

Main results: We found no completed studies to include in this review. We identified 16 ongoing studies (including 14 RCTs), which aim to enrol nearly 1250 participants. The interventions included in these trials are ArtemiC (artemisinin, curcumin, frankincense and vitamin C), Citrox (a bioflavonoid), cetylpyridinium chloride, chlorhexidine, chlorine dioxide, essential oils, hydrogen peroxide, hypertonic saline, Kerecis spray (omega 3 viruxide - containing neem oil and St John's wort), neem extract, nitric oxide releasing solution, povidone iodine and saline with baby shampoo. AUTHORS' CONCLUSIONS: We identified no studies for inclusion in this review. This is not surprising given the relatively recent emergence of COVID-19 infection. It is promising that the question posed in this review is being addressed by a number of RCTs and other studies. We are concerned that few of the ongoing studies specifically state that they will evaluate adverse events such as changes in the sense of smell or to the oral and nasal microbiota, and any consequences thereof. Very few interventions have large and dramatic effect sizes. If a positive treatment effect is demonstrated when studies are available for inclusion in this review, it may not be large. In these circumstances in particular it may be a challenge to weigh up the benefits against the harms if the latter are of uncertain frequency and severity.

Trial registration: ClinicalTrials.gov NCT04352959 NCT04341688.

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Conflict of interest statement

Martin J Burton: none known. Janet E Clarkson: none known. Beatriz Goulao: none known. Anne‐Marie Glenny: none known. Andrew McBain: Andrew McBain conducts research and advises companies in the areas of antimicrobials, microbiome and microbial control. Anne GM Schilder: in her roles of Director of NIHR UCLH BRC Hearing Theme and National Specialty Lead of NIHR CRN ENT, Professor Schilder advises companies in the hearing field about design and delivery of clinical trials. Her evidENT research team at UCL receives support from various funders, including NIHR, EU Horizon 2020 and Wellcome. Katie E Webster: none known. Helen V Worthington: none known.

Professors Martin Burton, Anne Schilder, Janet Clarkson and Anne‐Marie Glenny are Co‐ordinating Editors for Cochrane ENT and Cochrane Oral Health but had no role in the editorial sign‐off process for these reviews.

Figures

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Process for sifting search results and selecting studies for inclusion
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD013627

References

References to studies excluded from this review

Carrouel 2020 {published data only}
    1. Carrouel F, Conte MP, Fisher J, Goncalves LS, Dussart C, Llodra JC, et al. COVID-19: a recommendation to examine the effect of mouthrinses with beta-cyclodextrin combined with Citrox in preventing infection and progression. Journal of Clinical Medicine 2020;9(4):1126. [EMBASE: 2004172371] - PMC - PubMed
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    1. Hamid S, Mir MY, Rohela GK. Novel coronavirus disease (COVID-19): a pandemic (epidemiology, pathogenesis and potential therapeutics). New Microbes and New Infections 2020;35:100679. [EMBASE: 2005578249] [PMID: 10.1016/j.nmni.2020.100679] - DOI - PMC - PubMed
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    1. Henwood AF. Coronavirus disinfection in histopathology. Journal of Histotechnology 2020;43(2):102-4. [EMBASE: 2004386862] [PMID: 10.1080/01478885.2020.1734718] - DOI - PubMed
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NCT04408183 {published data only}
    1. NCT04408183. GLS-1200 topical nasal spray to prevent SARS-CoV-2 infection (COVID-19) in health care personnel. https://clinicaltrials.gov/show/NCT04408183 (first received 4 June 2020).
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PIIPPI (NCT04364802) {published data only}
    1. NCT04364802, Alexandra Kejner. COVID-19: povidone-iodine intranasal prophylaxis in front-line healthcare personnel and inpatients [Povidone-iodine intranasal for prophylaxis in front-line health-care personnel and inpatients during the Sars-CoV-2 pandemic]. https://clinicaltrials.gov/show/NCT04364802 2020 (first received 28 April 2020).
Ramalingam 2020 {published data only}
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References to ongoing studies

ACTRN12620000470998p {published data only}
    1. ACTRN12620000470998p, Firebrick Pharma Pty Ltd. Virucidal pilot study of Nasodine® antiseptic nasal spray (povidone-iodine 0.5%) in people with COVID-19 and confirmed nasal shedding of SARS-CoV-2 virus. https://anzctr.org.au/ACTRN12620000470998.aspx (first received 14 April 2020).
AMPoL (NCT04409873) {published data only}
    1. NCT04409873. Antiseptic mouthwash / pre-procedural rinse on SARS-CoV-2 load (COVID- 19) (AMPoL) [Effect of antiseptic mouthwash/gargling solutions and pre-procedural rinse on SARS-CoV-2 load (COVID-19)]. https://clinicaltrials.gov/ct2/show/NCT04409873 (first received 1 June 2020).
BBCovid (NCT04352959) {published data only}
    1. NCT04352959, Claude Bernard University. COVID-19: nasal and salivary detection of the SARS-CoV-2 virus after antiviral mouthrinses [COVID-19: nasal and salivary detection of the SARS-CoV-2 virus after antiviral mouthrinses: double-blind, randomized, placebo-controlled clinical study]. https://clinicaltrials.gov/show/NCT04352959 (first received 20 April 2020).
ChiCTR2000030539 {published data only}
    1. ChiCTR2000030539, Guangzhou EPH. Study for clinical oral characteristics of patients with novel coronavirus pneumonia (COVID-19) and effect of 3% hydrogen peroxide gargle on the intraoral novel coronavirus. http://apps.who.int/trialsearch/Trial2.aspx?TrialID=ChiCTR2000030539 (first received 6 March 2020).
ELVIS‐COVID‐19 (NCT04382131) {published data only}
    1. NCT04382131. Hypertonic saline nasal irrigation and gargling in suspected or confirmed COVID-19 (ELVIS COVID-19) [Hypertonic saline nasal irrigation and gargling with hypertonic saline for suspected or confirmed COVID-19: pragmatic web-based Bayesian adaptive randomised controlled trial]. https://clinicaltrials.gov/ct2/show/NCT04382131 (first received 11 May 2020).
GARGLESa (NCT04341688) {published data only}
    1. NCT04341688. A clinical trial of gargling agents in reducing intraoral viral load among COVID-19 patients [A quadruple blind, randomized controlled trial of gargling agents in reducing intraoral viral load among laboratory confirmed coronavirus (COVID-19) patients: GARGLES STUDY]. https://clinicaltrials.gov/show/NCT04341688 (first received 10 April 2020). [CENTRAL: CN-02091544] - PMC - PubMed
GARGLESb (NCT04410159) {published data only}
    1. NCT04410159. Povidone-iodine vs essential oil vs tap water gargling for COVID-19 patients (GARGLES) [A pilot, open-labelled, randomised controlled trial of povidone-iodine vs essential oil and tap water gargling for COVID-19 patients]. https://clinicaltrials.gov/ct2/show/NCT04410159 (first received 1 June 2020).
KILLER (NCT04371965) {published data only}
    1. NCT04371965, Poitiers University Hospital. Povidone iodine mouthwash, gargle, and nasal spray to reduce naso-pharyngeal viral load in patients with COVID-19. https://clinicaltrials.gov/show/NCT04371965 (first received 1 May 2020).
KONS‐COVID‐19 (NCT04357990) {published data only}
    1. NCT04357990, Kerecis Ltd. Kerecis oral and nasal spray for treating the symptoms of COVID-19 [Use of a medical device, kerecis oral and nasal spray, for treating the symptoms of COVID-19 via application to the naso- and oropharyngeal mucosa]. https://clinicaltrials.gov/show/NCT04357990 (first received 22 April 2020).
NCT04344236 {published data only}
    1. NCT04344236. Gargling and nasal rinses to reduce oro- and nasopharyngeal viral load in patients with COVID-19 [A phase II, randomized, open-label, single-institution study of the effects of povidone iodine oral gargles and nasal rinses on viral load in patients with COVID-19]. https://clinicaltrials.gov/show/NCT04344236 (first received 14 April 2020). [CENTRAL: CN-02091597]
NCT04347538 {published data only}
    1. NCT04347538. Impact of nasal saline irrigations on viral load in patients with COVID-19. https://clinicaltrials.gov/show/NCT04347538 (first received 15 April 2020).
NCT04347954 {published data only}
    1. NCT04347954. PVP-I nasal sprays and SARS-CoV-2 nasopharyngeal titers (for COVID-19) [Effect of PVP-I nasal sprays vs normal saline nasal sprays on SARS-CoV-2 nasopharyngeal titers]. https://clinicaltrials.gov/show/NCT04347954 (first received 15 April 2020). [CENTRAL: CN-02091692]
NCT04382040 {published data only}
    1. NCT04382040. A phase II, controlled clinical study designed to evaluate the effect of ArtemiC in patients diagnosed with COVID-19. https://clinicaltrials.gov/ct2/show/study/NCT04382040 (first received 11 May 2020).
NOCOVID (NCT04337918) {published data only}
    1. NCT04337918. Nitric oxide releasing solutions to prevent and treat mild/moderate COVID-19 infection [Multi-center, randomized, controlled, phase II clinical efficacy study evaluating nitric oxide releasing solution treatment for the prevention and treatment of COVID-19 in healthcare workers and individuals at risk of infection]. https://clinicaltrials.gov/show/NCT04337918 (first received 8 April 2020). [CENTRAL: CN-02091456]
PICO (ISRCTN13447477) {published data only}
    1. ISRCTN13447477. A pilot study of the ability of povidone-iodine (PVP-I) 0.5% aqueous solution oral/nasal spray and mouthwash to kill the SARS-CoV-2 virus in people with COVID-19. http://www.isrctn.com/ISRCTN13447477 (first received 22 May 2020). [DOI: ]
SINUS WASH (NCT04393792) {published data only}
    1. NCT04393792. SINUS WASH pilot study in adults testing positive for COVID-19 [Can a sinus rinse and mouth wash reduce viral load in COVID-19 positive individuals and their co-residents?]. https://clinicaltrials.gov/ct2/show/NCT04393792 (first received 19 May 2020).

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