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In late 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2)(2) emerged from Wuhan, China, causing a highly transmissible respiratory infection-coronavirus disease 19 (COVID-19)-that may result in acute respiratory distress syndrome or pneumonia in severe cases. COVID-19 quickly began to spread worldwide, achieving global pandemic status by March 2020. Since the 1960s, there have been seven beta-coronavirus strains. Of the seven, three may result in severe life-threatening respiratory symptoms: SARS-CoV, the Middle East respiratory syndrome coronavirus (MERS-CoV), and now, SARS-CoV-2.1
It has been challenging for healthcare professionals, including dental professionals, to manage the early diagnosis and prevention of COVID-19.1 The common initial symptoms are a dry cough, with or without fever, sore throat, fatigue, body ache, nasal congestion, conjunctivitis, diarrhea, hepatic and gastrointestinal disorders, lymphopathy, and neurologic symptoms. In severe cases, shortness of breath can develop, with acute respiratory distress syndrome potentially requiring subsequent mechanical ventilation.1-3 However, many patients with COVID-19 remain asymptomatic or exhibit only mild symptoms.4 Recent research has demonstrated that xerostomia, or dry mouth, may occur before or as a prodromal symptom of the disease.5,6
Transmission of COVID-19
COVID-19 is transmitted primarily via aerosolized infectious particles and droplets expelled during coughing, sneezing, speaking, and laughing by infected symptomatic and asymptomatic individuals in close contact with others.7,8 Saliva droplets vary in size, with size determining their travel distance. Droplets with a diameter of 60 μm or greater appear to settle quickly from the air, posing minimal risk of transmission, whereas droplets less than 60 μm can cause short-range transmission at distances of slightly more than 3 feet. The size of the droplets, their quantity, and their travel distance varies among individuals. Speaking for 5 minutes can produce the same amount of saliva droplet nuclei as a cough (approximately 3,000 saliva droplets nuclei).9
On a cellular level, SARS-CoV-2 enters the human body through target cells that express angiotension-converting enzyme 2 (ACE-2) and transmembrane protease serine 2 (TMPRSS2). These enzymes are attached to the membrane of cells in the intestines, kidney, testis, gallbladder, and heart. Transmission occurs through a two-step process, by which the virus spike protein first binds to the ACE-2 receptor, and then the TRPRSS2 activates or primes the viral spike protein, leading to its fusion on the cell surface.10 Once virus-host membrane fusion occurs, viral contents (eg, RNA) are released into the cytosol.1,3,11Therefore, the ACE-2 and TMPRSS2 need to be simultaneously expressed for SARS-CoV-2 infection to occur.12 This entry mechanism is the same as that for SARS-CoV-113; thus, organ cells with ACE-2 receptor distribution may become host cells for SARS-CoV-2 and cause further reactions in related organs.14
In research on these receptors, it has been discovered that ACE-2 and TMPRSS2 exist in various oral mucosal tissues, namely, the tongue, floor of the mouth, buccal mucosa, and gingival epithelium.15 Xu H et al reported that ACE-2 and TMPRSS2 were enriched in the dorsal surface of the tongue and localized in the fungiform papillae taste cells.16,17 In another study, Xu J et al found that these enzymes were expressed in the submandibular, parotid, and minor salivary glands, proposing that salivary glands could act as conceivable reservoirs for asymptomatic infection,18 thereby releasing viral particles through the salivary duct.19 They also reported that the ACE-2 expression in minor salivary glands was greater than that in the lungs, indicating that the salivary glands may be a possible target for COVID-19. Moreover, the SARS-CoV RNA has been found in the saliva before the appearance of lung lesions. This could possibly account for asymptomatic cases of COVID-19.18
Impaired Salivary Flow as a Symptom of COVID-19
Saliva is essential for digesting food, lubricating oral mucosa, cleaning and preserving the oral cavity, and influencing the homeostasis of the oral cavity. It consists mostly of water (94% to 99%) and also of organic (0.5%) and inorganic molecules (0.2%). An adult can produce about 600 mL of saliva each day. Saliva may serve as a gatekeeper and plays a role in the first-line prevention of and protection from viral infection, as it prevents pathogens from spreading to the gastrointestinal and respiratory tract.20 Changes to an individual's salivary flow can alter the effectiveness of the immune system in the oral cavity, allowing SARS-CoV-2 to induce oral mucosal ulceration and inflammation due to its mucotropic activity. Iwabuchi et al have proposed that a decrease in salivary flow (hyposalivation) results in the disruption of the oral and airway mucosal surfaces that act as physical barriers, allowing viral colonization and adhesion to be enhanced, and thus may be a risk factor for acute respiratory infection.21
Saliva contains proteins and peptides that have exhibited antiviral effects. Cathelicidin (LL‐37), lactoferrin, lysozyme, mucins, peroxidase, salivary agglutinin (gp340), secretory immunoglobulin (sIgA), secretory leucocyte protease inhibitor (SLPI), α, β defensins, and cystatins are the known proteins in the oral cavity that demonstrate antiviral activity for at least one virus. For example, salivary gp340 has demonstrated antiviral activity against HIV‐1 as well as influenza A.22-25 Farshidfar et al reported that salivary cystatins can inhibit viral replication and that salivary microvesicles containing at least 20 microRNAs can limit viral replication.25 These researchers concluded that hyposalivation could be a potential risk factor for acute respiratory infection by enabling exposure in patients at high risk for acquiring COVID-19.25
In the early stage of COVID-19 infection, SARS-CoV-2 has been consistently found in whole saliva,26 and the virus has been found in saliva collected from the salivary gland duct opening in the late stages of the disease.5 Because the salivary gland epithelial cells are ACE-2-positive, they are early targets for SARS-CoV-2 invasion and may affect the normal functioning of salivary glands in the early stage of the disease.27 Oral symptoms of impaired salivary flow may therefore appear in these patients. In a cross-sectional survey, Chen et al found 46% of 108 patients from Wuhan, China, with confirmed COVID-19 disease reported dry mouth as one of their symptoms.28
Freni et al summarized that empirical, biological, and clinical evidence supports that the initial entry site for SARS-CoV-2 is the oral mucosa. Oral symptoms, including loss of taste and dry mouth, may be early symptoms of COVID-19, appearing before symptoms of fever, dry cough, fatigue, or shortness of breath. These researchers found that early symptoms associated with dry mouth disorders were present in 32% of patients before other symptoms of COVID-19 were identified.5Accordingly, in the early diagnosis of COVID-19, one may look for salivary changes and their associated oral symptoms.26,28
Xerostomia Caused by "Mask Mouth"
The term "mask mouth" has been coined to describe the oral conditions that can develop from wearing a mask for extended periods of time. Wearing masks during healthcare procedures has long been a routine practice for medical and dental professionals. In the early phase of the COVID-19 pandemic (spring 2020), the supply chain for personal protective equipment (PPE) was greatly diminished owing to the tremendous surge in worldwide demand. Suppliers were forced to restrict their shipments to hospitals where patients with COVID-19 were treated. With this strain on supplies, many healthcare professionals who were not directly involved in the care of patients with COVID-19 found that they needed to reuse masks and increase the wear time in order to make the PPE supplies at their facilities last.29 Finally, in addition to the use of face masks in the healthcare setting, in April 2020, the Center for Disease Control and Prevention (CDC) recommended wearing of face masks in public if a person-to-person separation of at least 6 feet could not be maintained.30 Since there are now masks requirements in many locations to enter public buildings, to work in retail stores, to fly on an airplane, or to attend school, many people are prone to "mask mouth" and need to be educated on the potential problems associated with this phenomenon and on suggested treatments.
Xerostomia, or dry mouth syndrome, is one of the most common problems related to the extended use of face masks. Dry mouth syndrome resulting from using respiratory PPE for protracted periods is now a documented condition. Based on several recent studies, 53% of healthcare professionals have reported dry mouth and 66% have reported a sense of dehydration.31,32In a survey of 307 nurses on common problems associated with wearing surgical or N95 masks, Atay and Cura found that wearing a surgical mask for more than 4 hours significantly increased the risk of xerostomia.33
Wearing a mask for extended periods curtails the consumption of fluids, potentially leading to dehydration. Mask-wearing may also cause the individual to feel that they are not getting enough oxygen and therefore compensate through mouth breathing, which is a major cause of tissue surface dehydration and salivary flow reduction.
Numerous oral complications result from dry mouth syndrome, including a higher risk of tooth decay, fungal infections (such as thrush), halitosis, and periodontal disease.34Dry mouth may also lead to angular cheilitis, cracked lips, fissuring of the oral mucosa, taste impairment, painful tongue (glossodynia), sticky saliva, sore throat, speech problems, difficulty in swallowing or chewing dry and crumbly foods, and inflammation or ulcerations on the tongue. 34 Additionally, patients can develop salivary gland infections or denture sores caused by diminished denture retention. 34
CO2 Levels Associated With Mask-Wearing
For many people, breathing patterns can change while wearing a mask. Numerous side effects such as dyspnea, dizziness, reduced cognition, and headaches have been reported with mask use, particularly with the tight-fitting N95 masks and valved respirators.35After wearing a mask for more than 30 minutes, even healthy medical personnel have exhibited measurable physical effects that can lead to elevated transcutaneous carbon dioxide levels (CO2).36 Rhee et al studied the measured CO2 levels in healthy volunteers with no mask, a powered air-purifying respirator (PAPR), KN95 respirator, and valved-respirator.37 They found a significant increase in CO2 concentrations, but the levels were within the National Institute for Occupational Safety and Health (NIOSH) limits for short use. According to the Occupational Safety and Health Administration (OSHA), the Permissible Exposure Limit (PEL) for CO2 over an 8-hour work day (time-weighted average or TWA) is 5,000 parts per million (ppm) (0.5% CO2 in air).38Further studies are needed to evaluate the effects of long-term mask use with regard to CO2 levels.37
Treatment Options for "Mask Mouth" Xerostomia
Treatments for xerostomia include pharmaceuticals, behavioral modifications, and medical devices. 34 Cevimeline hydrochloride is generally used in patients with dry mouth caused by Sjögren's syndrome or who have undergone radiation therapy, and pilocarpine is used to increases natural saliva production. 39-42 However, side effects from both these medications may include sweating, nausea, and rhinitis. Salagen (a parasympathetic drug) should not be used in patients with acute glaucoma or cardiovascular or respiratory disorders.40
Chewing gum while wearing a mask can increase salivary flow and keep the mouth from becoming dry. Mouth rinses, mouth sprays, lozenges and discs specifically for the treatment of dry mouth are available, but many are acidic, and therefore the use of these agents should be investigated before they are recommended to patients.39
A low-voltage electrostimulation medical device for increasing saliva production may help reduce xerostomia symptoms.43 The device has two prongs that are placed under the tongue to send electrical pulses that stimulate the nerves associated with salivary gland secretion, and it is used for a few minutes every day. The electrical pulses are not felt by the patient, and the effect can last for hours. Patients can obtain this electrostimulation device only with a prescription.
Keeping nasal passage moist with the use of certain nasal sprays can help relieve dry mouth. Some nasal sprays that are useful for dry mouth are also effective in helping prevent COVID-19, such as a nasal spray containing xylitol and grapefruit seed extract, two components that have been found to have an antiviral effect on SARS-CoV-2; in studies from Northwestern University and Utah State University,44,45 the grapefruit seed extract has been shown to reduce viral loads, while xylitol prevented viral attachment to the ACE-2 receptor on the cell wall. The combination of grapefruit seed extract and xylitol may thus prevent the spread of viral respiratory infections.46 In addition, xylitol-based formulations may play a potential role in improving outcomes in patients with mild-to-moderate COVID-19.47
Preprocedural Mouth Rinse for COVID-19 Prevention
In addition to alleviating the symptoms of dry mouth, mouth rinses may also be used by patients before dental procedures, for the purpose of reducing the potential exposure of SARS-CoV-2 to the dental team.48Several mouth rinses have been studied that show the potential to reduce viral loads; these mouth rinses include 0.2% povidone iodine (PVP-I), 3% hydrogen peroxide, 0.2% chlorhexidine gluconate (Chx), and 0.01% (100 ppm) molecular iodine (I2).49
SARS-CoV-2 is an enveloped virus, and as such, it has an outer lipidic bilayer membrane that is highly sensitive to antiseptic agents such as iodine. The mode of action for iodine is through the degeneration of the nucleoproteins of viral particles. 50,51 In their study of the effectiveness of PVP-I antiseptic solutions for nasal and oral delivery, Pelletier et al found that all of the concentrations evaluated in the study were able to inactivate SARS-CoV-2 after 60-second exposure times.51
There is very limited clinical evidence for the effectiveness of mouth rinses against SARS-CoV-2 in vivo. Ferrer et al examined four mouth rinses (2% PVP-I, 1% hydrogen peroxide, 0.07% cetylpyridinium chloride, and 0.12% chlorhexidine) with regard to their virucidal effectiveness in reducing viral loads.52 Although these compounds have been previously evaluated in an in vitro study and found to have virucidal effects,53the Ferrer et al study, which evaluated the use of these mouth rinses in patients previously diagnosed with SARS-CoV-2 infection, showed that the salivary viral load in the study participants was not affected by the mouth rinses.52 These findings suggest that the in vitro results may not be extrapolated to the actual effects that those antiseptics have in the oral cavity. For example, salivary glycoproteins are likely to interfere with the antimicrobial activity of these mouth rinses. Dilution of the mouth rinse compounds by the saliva can be as high as 1:4, which can potentially reduce the effect. In the Ferrer et al study, the viral loads after the mouth rinses were used were measured using quantitative real-time polymerase chain reaction test, and a lack of viral load reduction was observed.52
For decades, PVP-I has been a gold standard antiseptic with proven efficacy against the previously identified beta coronaviruses.54 PVP-I was also one of the first compounds studied as prophylaxis for frontline healthcare workers at the start of the COVID-19 pandemic.55The virucidal effect of PVP-I is due to its I2content. If used at a concentration of 10%, which is the lowest concentration commercially available, PVP-I can deliver only 1 to 3 ppm of I2 in a compound of more than 31,600 ppm of total iodine atoms. The large percentage of bounded, nonactive iodine is responsible for all the unwanted toxicologic and staining effects of PVP-I.56
A newer patented iodine-containing mouth rinse has been introduced to offset the side effects of PVP-I.57 This "super iodine" contains 100 times more I2than PVP-I. This compound is also available in nasal spray and hand cleaner formulations.51With this mouth rinse, the percentage of nonactive iodine atoms was reduced from 31,600 ppm to several hundred, which accelerates the effects and reduces staining and potential irritancy.58
While the common symptoms of COVID-19 of dry cough and fever have garnered much attention over the course of the pandemic, oral manifestations of the disease are not infrequently seen and require prompt treatment. Xerostomia and hyposalivation, whether they develop as symptoms of COVID-19 or as a "side effect" of mask-wearing, can lead to numerous oral complications, including higher risk of tooth decay, fungal infections, salivary gland infections, and periodontal disease. In addition, dry mouth syndrome, which may be caused by extensive mask-wearing, has been identified as a risk factor for COVID-19 infection. It is therefore important the clinicians recognize and treat oral symptoms of COVID-19, and that they educate patients who are required to wear face masks for prolonged periods on the importance of remaining hydrated and using symptomatic treatment, such as medications that increase saliva production.
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