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Slipping endlessly through the crack between oral and respiratory medicine, the humble mouthwash has slowly won more respect among savvy practitioners and patients as a solution for a range of indications. In Japan many millions of people gargle three times a day with green tea extracts or other mouthwashes to ward off upper respiratory tract infections (URTIs), and Japanese clinical studies have confirmed the value of this approach (Furushima D et al. Molecules. 2018 Jul 20;23(7)). Worldwide, medical practitioners recommend gargling to patients; and many people on their own have decided that gargling makes sense, while millions swish with mouthwash to protect teeth and gums as well as to combat halitosis.

Still, for curious reasons, this formidable method of suppressing infections remains in medical limbo. Not because there is no need. The average American suffers 2.5 episodes of URTI per year, with high costs for treatment, lost days of work, and morbidity. URTIs also exacerbate asthma, and they can enter the lungs and prove fatal.

Meanwhile, the financial costs of ineffective care of teeth and gums are very high, and oral infections cause considerable pain, loss of teeth, and in some cases systemic disease. Thus a truly effective mouthwash that can be gargled, then €”swished around the teeth and oral cavity €”would be of exceptional value, especially if its use could be expanded from the limited numbers of people who use it now to a majority of people everywhere.

Many companies have developed proprietary or generic mouthwashes, with the leader being Johnson & Johnson’s Listerine, acquired from Pfizer in 2006. Pfizer had funded and largely staffed a series of clinical trials that supported claims of efficacy for Listerine in the treatment of gingivitis and other dental and periodontal disorders. But it did not push aggressively to obtain FDA approval of Listerine for specific indications, nor did it market Listerine as a treatment of URTIs. Meanwhile, the findings and practices of the Japanese regarding URTIs have not had any discernible impact on the American health system or, it appears, on those of other countries.

What is going on here?  Let us first examine the swishing (oral care) side of mouthwash, then the gargling (anti-URTI) side.

Swishing for Oral Care

First mentioned in ancient China, mouthwashes form a venerable component of oral care. Nonetheless, they generally stand third behind brushing and flossing in the recommendations of American dental groups, and they can be rated as optional whereas brushing and flossing are designated as mandatory.

But studies have repeatedly shown that adherence to flossing is poor. For instance, just 11% of Danes and 14% of Germans reported that they flossed daily (Zimmer S et al. Periodontol 2006;72(8):1380-5). Moreover, many people don’t floss correctly, and self-flossing of children has been shown not to have reduced caries risk (Hujoel PP et al. J Dent Res 2006;85(4):298-305). Flossing is inherently an exacting task, and most people evidently don’t want to be bothered or are not skillful enough to perform it correctly. So to tell them to floss is to give them a counsel of perfection, worthless in the great majority of cases.

Aware that flossing was a privileged competitor of Listerine, Pfizer funded a clinical trial of flossing vs the use of “an essential oil antiseptic mouthrinse” (Listerine Antiseptic) in controlling gingivitis (gum inflammation) (Bauroth K et al. JADA 2003;134:359-65). Over 6 months, the Listerine group, which rinsed with 20 mL twice daily for 30 seconds, scored a gingival index reduction of 11.1 percent vs. 4.3 percent for flossing, and a plaque index reduction of 20 percent vs. 3.4 percent for flossing. Both differences were statistically significant. The authors concluded that the essential oil mouthrinse was “at least as good as” dental floss for controlling gingivitis; but in fact we can conclude that it was significantly superior to flossing, even without taking into consideration the problem of adherence to flossing.

Metaanalyses of comparative trials of flossing vs mouthwash have confirmed this (Berchier CE et al. Int J Dent Hygiene 2008;6:265-79). Other studies support the view that mouthwashes with various ingredients—€”essential oils such as thymol and eucalyptol, hypertonic saline (the low-cost solution), methyl salicylate, menthol, chlorhexidine gluconate, cetylpyridinium chloride, hydrogen peroxide, tea catechins, zinc, and so on—€”can prove effective in oral care, including against caries, gingivitis, periodontal disease, and halitosis. However, more comparative studies are needed.

Many tests have shown chlorhexidine gluconate and cetylpyridinium chloride to be effective against dental plaque, but their taste represents a negative factor. They and other ingredients can stain teeth, though the addition of a whitener can counteract this tendency.

Three Concerns

One concern is the safety of ethanol. Johnson & Johnson and the generic manufacturers that follow its formula for Listerine Antiseptic include as an “inactive ingredient” 21.6% ethanol. While various rationales are offered for this high ethanol content, we should not believe for a minute that ethanol is an inactive ingredient. Ethanol at this concentration, especially in combination with other active ingredients, can destroy microbes, though exactly how effective it is against which microbes remains unclear. In its other antimicrobial applications, ethanol has been proven effective against viruses and bacteria at 50% concentration and is highly effective at 80% (Moorer WR Int J Dent Hyg 2003;1:138-42). Indeed, we might surmise that Listerine performs so well in clinical trials largely because it contains so much ethanol, which is why Pfizer and Johnson & Johnson have not been willing to reduce the ethanol content.

But in turn that creates a problem because studies implicate ethanol-containing mouthwashes in the etiology of oral cancer. Australian cancer researchers recently concluded that “alcohol-containing mouthwashes contribute to the increased risk of development of oral cancer” (McCullough MJ, Farah CS Aust Dent J 2008 Dec;53(4):302-5; see also Carretero-Pelaez MA et al. Med Oral 2004;9:116-23). While McCullough and Farah state that such mouthwashes may be safe in a specific short-term application, they strongly advise against long-term daily use of ethanol-containing mouthwashes. What constitutes long-term use and what percentage of ethanol begins to pose a risk require careful investigation, in view of the leading market position of Listerine and its generic equivalents.

A second concern is that chronic use of mouthwash could foster resistant pathogens and reduce the efficacy of antibiotics.  Dentists now recognize that the normal oral biota play useful roles, e.g., in preventing colonization by pathogens.  So interventions should aim at modest plaque control in order to maintain a balance of strains and to minimize drug resistance.  Thus, chronic use of antiseptic mouthwashes has lost favor among dentists, though the public seems little aware of this.

Meanwhile, a third concern has arisen.  Studies show that anti-bacterial ingredients in many gargles correlate with the risk of high blood pressure and diabetes (Joshipura KJ et al.  Nitric Oxide. 2017 Dec 1;71:14-20).  The impact on metabolism seems to come from suppression of bacteria that reduce nitrate to nitrite, essential to the production of nitric oxide, which in turn wards off high blood pressure and insulin resistance.  The above study found that gargling just once per day did not raise the risk.  

We must ask, therefore, which gargles can manage to be effective in chronic use without causing resistance or destroying excessive numbers of health-promoting bacteria.  Being natural seems a positive trait, but essential oils were implicated in the risk of anti-bacterial mouthwashes.

On balance, therefore, while gargling seems an alluring alternative to flossing, we will do better to use mechanical removal of plaque via frequent toothbrushing plus every six or twelve months teeth-cleaning by a dental technician.  Teeth-cleaning runs little risk of inducing drug resistance or upsetting the balance of oral biota.  Similarly, while strongly antiseptic (antimicrobial) mouthwashes appeal to our desire to destroy pathogens, we need to set them aside (with the exception of povidone-iodine) because they can breed drug resistance and disrupt the balance of the oral microbiota.  Instead, we should investigate gargles like green tea extracts and hyperonic saline because they do not appear to have unwanted side effects and rely in part on influencing the immune system.  Also, we should give more weight to gargles’ disrupting and dislodging effects on pathogens rather than to their antimicrobial power.

Gargling vs Respiratory Infections

Physicians and lay persons alike have long recommended gargling as an adjuvant remedy of respiratory infections and other ailments. In particular, the Japanese have elevated this simple practice to an important technique in healthcare. During the Spanish Flu pandemic of 1918-1919, Japan’s health authorities recommended face masks, gargling, and inoculations to the public; and they prepared a gargle formula and distributed it to the people (Rice G and Palmer E.  Journal of Japanese Studies 1993;19:2).  Japan’s mortality rate from the pandemic was much lower than the rates of other Asian countries and even lower than rates in some more economically advanced Western countries. Persuaded of the benefits, the Japanese people assiduously gargle.

The Japanese have concentrated on the prophylactic effect of gargling. In particular, they have tested it in schools (millions of Japanese students regularly gargle), hospitals, and nursing homes. For instance, gargling with tea catechin extracts led to an incidence of influenza of only 1.3% in a nursing home in contrast to a rate of 10% among controls, even though the level of catechins was only half of that in green tea sold in Tokyo (Yamada H et al. J Alt Comp Med 2006;12(7):669-72).  Gargling with green tea led to a 4.9% rate of laboratory-confirmed influenza versus 6.9% in controls who gargled with tap water in a trial of Japanese high school students, though the results did not reach the level of significance (Ide K et al.  PLOSOne, May 2014, Vol. 9, Issue 5, e96373).

In a trial with 387 healthy subjects aged 18-65, researchers compared a povidone-iodine gargle with gargling tap water at least thrice daily and a no-gargling control group for 60 days (Satamura K et al. Am J Prev Med 2005;29(4):302-7). The incidence rate of the first URTI was 0.26 episodes per 30 person days in the controls; 0.17 in the water gargling; and 0.24 in the povidone-iodine group. The researchers explained the comparatively strong showing of tap water as an effect of washing out the pathogens and suggested that the relatively high level of chlorine in the cities studied (0.5-0.8 mg/L) might also have had an effect.  It seems possible that a high level of microbicidal activity of a mouthwash is less important than it might appear; and it needs to be weighed against side effects, which can become particularly salient in extensive gargling.

Curiously, the mechanism by which gargling prevents respiratory infections remains unclear.  Gargling just three times a day would leave large stretches of time during which a microbe could invade the throat and spread.  Also, microbes often settle in the nasal passages, while gargling is in the throat (Furushima D et al. Molecules 2018;23(7):1795).  Perhaps the gargling destroys some microbes, freeing the immune system to concentrate on the rest.  Perhaps gargling activates immune cells, and they remain active for hours.  Or the action of the gargle signals to somatic cells to up their defenses.

While the Japanese clearly lead the world in the area of prophylactic gargling, one senses that the rigor of some of their practices might impede the spread of gargling to the rest of the world. For instance, many Japanese garglers prefer povidone-iodine because of its powerful in vitro microbicidal effect, even though it has been shown in vivo, at least in one case (Satamura K et al. Am J Prev Med 2005;29(4):302-7), to be less effective than tap water, which contains chlorine, a proven microbicide. And the protocols of the Japanese trials call for a demanding gargling schedule, €”e.g., 30 seconds at a time three times in a row, repeated three times a day. Ideally, one would like to devise a simple protocol of 15 seconds of gargling followed by 5 seconds of swishing, three to five times a day, to ensure better adherence.

Therapeutic Gargling

If gargling can prove so effective against URTIs in a prophylactic mode, one must ask how effective it might be in actually treating early-stage URTIs, in effect stopping them before they can spread. Such Therapeutic Gargling (TG) would be a precious added weapon in the struggle against respiratory infections.

Infections are most vulnerable in their initial stage before the microbes have had a chance to multiply and entrench themselves. In the case of a head cold, gargling frequently may prevent the virus from entering and establishing itself in the rear of the oral cavity, from which it could spread further.

But in many respiratory viral and bacterial infections, the first sign is a sore throat.  In these cases, the invading microbe appears to establish a beachhead in the throat where it can safely multiply before the immune system can develop a response sufficient to wipe it out. Once the numbers of microbes reach a high enough level, they can break out and spread the infection throughout the respiratory tract or even system-wide. At the moment when an individual first becomes aware of having a sore throat, the invading microbes are most vulnerable because they tend to be concentrated in one place—€”a small tract in the throat.  Because sore throat is reportedly infrequent in COVID-19, yet a similar multiplication of the virus in the throat appears to occur, the first symptom of infection such as fever or dry cough can be used as a trigger for Therapeutic Gargling, then testing can determine the correct diagnosis.  However, because these symptoms are less certain triggers than a sore throat, it makes sense also to increase prophylactic gargling to 5x/day for the duration of the pandemic.

For TG, after becoming aware of a soreness in the throat that is reminiscent of such soreness that heralded past infections, the individual should try to make sure that he/she actually has a sore throat and is not just imagining it. Then, using, for instance, a saline mouthwash, one should gargle for 15 seconds, repeating this every 30 minutes for several hours, then at greater intervals. Gargling 10 times the first 24 hours and 5 times the second 24 hours might give the best assurance of full destruction of the microbes. It is possible that other protocols could be devised that would even more swiftly and surely prove effective.

Of utmost importance is to start gargling as soon as possible.   Once a sore throat makes its presence known, one must not put off treatment but rather stop whatever one is doing, find something to gargle with, and, after making sure that the throat is sore, start gargling.  In 15 years of this writer’s personal experience, TG with hypertonic saline effectively suppresses infections 80-90% of the time (this assumes that the infections are not self-limiting); and when it doesn’t, the culprit is almost always delay in starting to gargle.

However, there is one hitch:  Gastroesophageal Reflux Disorder (GERD), relatively common over age 60, can cause soreness in the rear of the throat.  So one needs to be aware of one’s tendency towards reflux.  Gargling with hypertonic saline can’t do any harm and may even soothe the generally mild sore throat (pharyngitis) associated with GERD, but there is no need for the frequent gargling of TG.

Therapeutic Gargling has only been used informally, but the anecdotal results are very encouraging. TG would be most useful for those with weakened immunity who are subject to frequent respiratory infections. It may not be necessary for people whose immune system is robust enough to fend off infections on its own.

If indeed TG were shown in clinical studies to be effective, it could significantly or perhaps even dramatically reduce the incidence of respiratory infections and the resulting morbidity and mortality. It could also save many billions of dollars in medical costs.

Gargling vs COVID-19

In the COVID-19 pandemic, even though some inhaled virus initially penetrates directly into the lungs, a significant amount remains in the throat where it replicates to very high numbers–for instance, a peak at 711,000,000 RNA copies per throat swab day 4 (Wölfel R et al.  Nature 2020;Apr 1).  According to a Reinforcement Model of COVID-19, many of these replicates descend to the lungs and elsewhere, where they furnish a steady stream of reinforcements for the initial virus.  These replicates eventually outweigh the replication of the initial dose that penetrated into the lungs.  Hence treating the throat with gargling seems highly desirable.  This holds even if replicates are also descending from the nasal passages, because respiratory infections are a numbers game, and any reduction in virus numbers in the lungs is of utmost importance.  Meanwhile, much of the virus from hands touching the face after picking up virus from surfaces as well as from from the fecal-oral route presumably remains in the oral cavity and replicates before descending to the lungs.

The first trial of gargling vs COVID-19 was a pilot study at a Malaysian university (ClinicalTrials.gov).  5 gargled with povidone-iodine, 5 with essential oils, 5 with tap water, and 5 did no gargling.  At Day 6, early viral clearance was povidone-iodine 5, essential oils 4, tap water 1, no gargling 0.  At Day 12, negative PCR was 5, 4, 2, and 1 respectively.  In other words, in this tiny study, the two real gargles far outperformed tap water and no gargling.

While discussion of gargling in epidemics tends to focus on self-protection, two other dimensions deserve attention.  First, gargling can reduce transmission of virus via breathing, speaking, and coughing.  Although the nasal passages tend to contain more virus in COVID-19 infections, the oral cavity contains a lot and may play an even greater role in transmission.  Thus gargling pays double benefits, protecting oneself and protecting others.  This is particularly important with a pathogen as stealthy and contagious as COVID-19, one that leads to a large number of asymptomatic carriers who can unknowingly transmit the virus.  Thus everyone should be gargling except those who have recovered and have immunity to the virus.

Second, if all students in a classroom, for instance, are participating in a gargling trial against the flu, then individual students will be less susceptible to infection than they would be if they were the only ones gargling.  So each individual has a vested interest in encouraging others to gargle.

The Halitosis Dimension

Many people use mouthwash for a reason that is not strictly speaking a medical one but rather a social one: to combat halitosis. Bad breath results from many causes. For instance, users might wish simply to cover up temporary smells of smoke, alcohol, garlic, or an acid stomach after drinking coffee. Or they could suffer from permanently high level of volatile sulfur compounds generated by bacteria breaking down organic substrates in the oral cavity and throat. Recesses under the tongue, gums, or tonsils may hide the bacteria involved. Regardless, mouthwash can effectively treat such odors for several hours at a time.

This capability clearly lends mouthwash considerable social utility. In turn, the use of mouthwash against bad breath can convey other benefits in terms of oral health and prophylaxis against URTIs. So part of a strategy to deploy mouthwash more effectively would entail finding ways to take advantage of the social considerations that induce people to use mouthwash against halitosis to benefit their overall health.  In this regard, gargling with green tea extracts such as EGCG deserves special attention because they are effective against both pathogens and halitosis (Tahani B, Sabzian R.  Dent Res J (Isfahan).  Nov-Dec 2018;15(6):379-384).

Thinking in terms of defense against halitosis has the peculiar merit that the remedy of a mouthwash spans the otherwise fairly rigid boundary between oral care and gargling for protection against respiratory infections. It provides the dentist a reason to encourage gargling, and it opens the door to the consideration of oral care by the respiratory infection specialist. As a review of the management of halitosis (van den Broek AMWT et al. Oral Dis 2008;14:30-39) makes clear, there are many ways to treat halitosis. We need to explore these modalities for their potential medical benefits in addition to the social ones. And any effort to identify a single recommended category of mouthwash should take careful account of the powerful social need to cover up bad breath and treat perduring halitosis because that will win adherents and boost adherence.

Barriers to Full Implementation

There seems to be sufficient evidence regarding both oral care and anti-URTI effects that researchers, research funders, professional organizations, and public health authorities should put a high priority on optimizing the use of mouthwash and communicating its value to people around the world. The very modest cost of mouthwashes adds another rationale for such efforts. Indeed, this should all have been done decades ago.

However, deep-set attitudes and interests block the way. First, general research funders have been negligent in this area for many decades. Even though mouthwashes excel against oral and throat infections, funding overwhelmingly goes to more technical approaches in areas like molecular biology. Staffers concerned with oral care are not concerned about respiratory infections, and vice versa. Nobody is charged with ensuring that two-for-the-price-of-one solutions receive priority. These attitudes and institutional priorities are not going to change soon.

Second, even though some companies display interest in this lucrative market, it is not easy to assure proprietary rights over something as mundane as a mouthwash. So only a few companies have been willing to fund studies, while other pharmaceutical companies and individuals might actually lose money if the mouthwash approach became more popular.

Third, professional organizations such as the American Dental Association perhaps rightly refuse to move out of their field of oral care to investigate and communicate the virtues of mouthwash in the prophylaxis and treatment of respiratory infections. Dental and respiratory medicine organizations have little incentive to link up with each other across the boundaries of specialties. Also, some members of the ADA howled when the Pfizer-funded study suggested that mouthwash was as good as flossing, and Pfizer retreated.

In poor countries, respiratory diseases exact a heavy toll, and oral diseases add to this. So the opportunity to deploy a low-cost intervention such as regular use of mouthwash as a public health measure could prove very attractive to conscientious practitioners and officials as well as non-government organizations. An effort in this direction could work better than one aimed at changing the status quo in rich countries with their entrenched interests oblivious to or even hostile to the notion of relying on such a mundane and low-cost intervention as the mouthwash.

A Research Agenda

Clearly, more research on mouthwashes could lead toward an optimal deployment of this promising modality. Here is a research agenda:

  1. Find out which mouthwash works best against which indication.  We need to test above all povidone-iodine at 0.5% and 0.25%, green tea catechins, and hypertonic saline, both for prophylaxis and, in the case of URTIs, for Therapeutic Gargling.
  2. Investigate which mouthwash best protects the balance of the oral biota and causes the least drug resistance.
  3. Investigate the risk of oral cancer from ethanol and other ingredients.
  4. Investigate flossing vs mouthwash vs teeth cleaning by a dental technician.
  5. Determine how many lung infections start as throat infections and can in theory be stopped there with gargling before reaching the lungs. Specifically, investigate the use of prophylactic and therapeutic gargling vs coronaviruses, influenza, TB, pneumonia, and biowarfare agents.
  6. Study the role of mouthwash in the comparative epidemiology of oral and respiratory diseases in Japan and in other countries.
  7. Investigate the effects of mouthwash for swishing and gargling on halitosis, cough, smoking, asthma, damage from air pollution, and other oral and respiratory tract phenomena.
  8. Identify what features of mouthwashes lead to better adherence.
  9. Investigate the effects of swishing and gargling with tap water. What mechanisms and molecules contribute to the effects?
  10. Devote special attention to hypertonic saline and green tea. As the low-cost solution, hypertonic saline seems unusually attractive, yet drug companies have no incentive to investigate or promote it.   Gargling with salt water seems to have the fewest side effects of all, nor is there any sign that it disrupts the balance of healthy oral biota.  So in theory it can be used intensively and extensively.  In a Japanese clinical trial, gargling with saline came in second to gargling with green tea in preventing URTIs in children aged 2-6 (Noda T et al. J Epidemiol 2012;22(1):45-49).  The body concentrates salt in infected areas, and this salt activates macrophages and T-cells to attack pathogens (Minton K.  Nature Reviews Immunology 2015;15:202). Gargling with hypertonic saline may also activate immune cells, in addition to destroying pathogens directly with salt’s chloride ions.  However, in COVID-19 infections, where an excessive, untargeted immune response can cause damage, it might prove that the green tea extract EGCG, which downmodulates T-cells and macrophages, works better to target an effective immune response (BioMed Research International 2018.  Article 9105261).
  11. Determine the minimal effective regime for gargling and swishing.
  12. Identify ways to bridge the gap between the dental and respiratory disease professions. Find ways to communicate findings and recommendations to them and to the public.

Conclusion

Clinical trials have demonstrated that mouthwash can be effective against pathogens in both oral care and respiratory infections. A concerted research and communication effort can further define its optimal uses, including which gargles work best for which indications, and communicate the results to people worldwide. Allowing this low-cost, compelling solution to an array of health problems to languish as it has for decades would show a negligent disregard for the health of the public. Even just spreading the word about current findings would move us in the direction of better deploying the significant potential of this simple, practical approach to improving oral and respiratory health worldwide.

*****

Kenneth J. Dillon is an historian who writes on science, medicine, and history.   See the biosketch at About Us.  For detective work on ancient and modern history, see his The Knowable Past (2nd edition, Washington, D.C.:  Scientia Press, 2019).

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