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BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1324 (Published 02 April 2020) Cite this as: BMJ 2020;369:m1324

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A simple, low-cost potential means of protecting healthcare staff is being overlooked

Dear Editor

The lack of personal protective equipment (PPE) against covid-19 for frontline healthcare staff is indeed scandalous. Remedies are urgently required, both for the UK and in countries with far fewer resources. Regrettably, a simple yet important potential means of protection has been overlooked through lack of familiarity with the evidence and mis-interpretation of its implications: the prophylactic use of oropharyngeal washing.

Over a decade ago randomised controlled trials (RCTs) found evidence for the effectiveness of gargling with both povidone-iodine (PVP-I) and (chlorinated) tap-water in preventing general upper respiratory tract infections (URTIs)[1] and influenza-like illnesses in particular[2]. Yet despite point estimates all indicating efficacy, their lack of statistical significance was taken to imply lack of effectiveness, a widespread inferential error [3]. A more sophisticated analysis [4] shows the findings of both studies are consistent with substantial efficacy concealed by inadequate statistical power.

Subsequent studies of other agents – notably tea-derived compounds – have led to similar outcomes: point estimates consistent with efficacy but lacking statistical significance. The role of inadequate statistical power rather than a lack of efficacy in these findings is supported by a meta-analysis of five studies[5] which pointed to a statistically significant risk reduction of around 30 per cent. The appropriate response to the evidence from human studies is thus not that gargling with active agents does not work, but that large-scale RCTs should be performed[5,6].

In relation to covid-19, the obvious rejoinder is that these trial findings are irrelevant as they concern prophylaxis against influenza and the common cold. Given that SARS-CoV-2 was only recently identified, the lack of directly-relevant studies is hardly surprising. However, there exists in vitro evidence for inhibitory effects of both PVP-I[7]and tea-derived compounds[8] against the closely-related coronavirus SARS-CoV-1. Biological plausibility of prophylactic gargling against covid-19 comes from the exploitation of ACE2 as the host cell receptor for infection by SARS-CoV-2. This receptor appears to be highly enriched in the oral cavity, which has accordingly been identified as a high-risk infectivity site[9]. The salivary glands may be an early target for SARS-CoV-2, with implications for community-wide spread of infection[10].

None of the above constitutes compelling evidence; that can only come from well-designed large-scale studies. It is regrettable that repeated calls for such studies in relation to familiar viral infections have gone unheeded. Given the urgency of the present situation and the low risk of adverse effects, large-scale studies of prophylactic naso- and oropharyngeal washing involving those virucidals already investigated and also novel agents (eg [11]) should be started as soon as practicable. A draft protocol for healthcare workers and patients has recently been formulated[12]. The use of similar forms of prophylaxis by the general population also merits urgent consideration, given its potential to reduce infection risk among both individuals and the community at large.

References
1. Satomura K, Kitamura T, Kawamura T, Shimbo T, Watanabe M, Kamei M, Takano Y, Tamakoshi A, Investigators GC. Prevention of upper respiratory tract infections by gargling: a randomized trial. American Journal of Preventive Medicine. 2005 29(4): 302-307.
2. Kitamura T, Satomura K, Kawamura T, Yamada S, Takashima K, Suganuma N, Namai H, Komura Y. Can we prevent influenza-like illnesses by gargling? Internal Medicine. 2007 46(18): 1623-1624.
3. Altman DG, Bland JM. Statistics notes: Absence of evidence is not evidence of absence. BMJ. 1995 311(7003): 485.
4. Matthews RAJ . Beyond ‘significance’: principles and practice of the Analysis of Credibility. Royal Society Open Science. 2018 5(1): 171047.
5. Ide K, Yamada H, Kawasaki Y. Effect of gargling with tea and ingredients of tea on the prevention of influenza infection: a meta-analysis. BMC Public Health. 2016 16(1): 396.
6. Furushima D, Ide K, Yamada H. Effect of tea catechins on influenza infection and the common cold with a focus on epidemiological/clinical studies. Molecules. 2018 23(7):1795.
7. Eggers M, Koburger-Janssen T, Eickmann M, Zorn J. In vitro bactericidal and virucidal efficacy of Povidone-Iodine gargle/mouthwash against respiratory and oral tract pathogens. Infectious diseases and therapy. 2018 7(2): 249-259.
8. Chen CN, Lin CP, Huang KK, Chen WC, Hsieh HP, Liang PH, Hsu JT. Inhibition of SARS-CoV 3C-like protease activity by theaflavin-3, 3'-digallate (TF3). Evidence-Based Complementary and Alternative Medicine. 2005; 2(2):209-215.
9. Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T, Chen Q. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. International Journal of Oral Science. 2020 12(1):1-5.
10. To KK, Tsang OT, Yip CC, Chan KH, Wu TC, Chan JM, Leung WS, Chik TS, Choi CY, Kandamby DH, Lung DC. Consistent detection of 2019 novel coronavirus in saliva. Clinical Infectious Diseases. 2020 Feb 12. Accessed 3 April 2020
11. Ramalingam S, Graham C, Dove J, Morrice L, Sheikh A. A pilot, open labelled, randomised controlled trial of hypertonic saline nasal irrigation and gargling for the common cold. Scientific reports. 2019 9 : 1015
12. Kirk-Bayley J, Challacombe S, Sunkaraneni S, Combes J. The use of povidone iodine nasal spray and mouthwash during the current covid-19 pandemic may protect healthcare workers and reduce cross infection. SSRN Preprint 3563092. Accessed 3 April 2020

Competing interests: No competing interests

04 April 2020
Robert A Matthews
Visiting Professor
Aston University
School of Engineering & Applied Sciences, Birmingham, B4 7ET, United Kingdom