**Temporomandibular Disorders and Bruxism Outbreak as a Possible Factor of Orofacial Pain Worsening during the COVID-19 Pandemic—Concomitant Research in Two Countries**

#### **Alona Emodi-Perlman 1,**†**, Ilana Eli 1,**†**, Joanna Smardz 2, Nir Uziel 1, Gniewko Wieckiewicz 3, Efrat Gilon 1, Natalia Grychowska <sup>4</sup> and Mieszko Wieckiewicz 2,\***


Received: 23 August 2020; Accepted: 27 September 2020; Published: 12 October 2020

**Abstract:** Background: In late December 2019, a new pandemic caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection began to spread around the world. The new situation gave rise to severe health threats, economic uncertainty, and social isolation, causing potential deleterious effects on people's physical and mental health. These effects are capable of influencing oral and maxillofacial conditions, such as temporomandibular disorders (TMD) and bruxism, which could further aggravate the orofacial pain. Two concomitant studies aimed to evaluate the effect of the current pandemic on the possible prevalence and worsening of TMD and bruxism symptoms among subjects selected from two culturally different countries: Israel and Poland. Materials and Methods: Studies were conducted as cross-sectional online surveys using similar anonymous questionnaires during the lockdown practiced in both countries. The authors obtained 700 complete responses from Israel and 1092 from Poland. In the first step, data concerning TMDs and bruxism were compared between the two countries. In the second step, univariate analyses (Chi2) were performed to investigate the effects of anxiety, depression, and personal concerns of the Coronavirus pandemic, on the symptoms of TMD, and bruxism symptoms and their possible aggravation. Finally, multivariate analyses (logistic regression models) were carried out to identify the study variables that had a predictive value on TMD, bruxism, and symptom aggravation in the two countries. Results: The results showed that the Coronavirus pandemic has caused significant adverse effects on the psychoemotional status of both Israeli and Polish populations, resulting in the intensification of their bruxism and TMD symptoms. Conclusions: The aggravation of the psychoemotional status caused by the Coronavirus pandemic can result in bruxism and TMD symptoms intensification and thus lead to increased orofacial pain.

**Keywords:** COVID-19; SARS-CoV-2; coronavirus pandemic; temporomandibular disorders; bruxism; orofacial pain

#### **1. Introduction**

Temporomandibular disorders (TMD) are a group of conditions that cause pain and dysfunction of the masticatory muscles, the temporomandibular joints (TMJs), and associated structures. The most common features of TMD are regional pain, limited jaw movements, and acoustic sounds from TMJs during motions [1]. The prevalence of TMD in the general population is estimated at about 10–15% [2–4], and these conditions affect women more frequently than men. Psychosocial factors, such as anxiety, stress, depression, coping strategies, and catastrophizing, may influence the onset of pain, as well as precipitate or prolong the TMD pain [5–8]. The International Association for the Study of Pain (IASP) reported that TMD-related facial pain occurs in 9–13% of the general population, while only 4–7% seek treatment. The TMD-related pain may also affect the daily activities, physical and psychosocial functioning, and quality of life of the affected individuals [9].

Bruxism is a repetitive jaw muscle activity characterized by clenching or grinding of the teeth, and/or bracing or thrusting of the mandible [10]. It can act as a potential risk factor for several negative consequences of health such as masticatory muscle pain, oral mucosa damage, mechanical tooth wear, and failures of prosthodontic constructions [11–13]. This condition is divided into sleep bruxism (SB) awake bruxism (AB). The prevalence of SB is estimated at about 16% among young adults and at 3–8% among adults, while the prevalence of AB in the general population is estimated at about 22–30%. Both forms of bruxism men and women equally [14].

Psychosocial factors, such as stress and anxiety, have been indicated as associated with both SB and AB [15–20]. However, the latest research showed that self-reported perceived stress was not correlated with the intensity of SB [21].

In late December 2019, a new unfamiliar and threatening pandemic called COVID-19 (Coronavirus 2019 disease), which is caused by the SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection, began to spread around the world. Due to almost complete uncertainty about the ways of virus spread [22] and the appropriate modes of treatment, insufficient availability of health services, and no existing vaccine or efficient drug for treatment, most countries adopted the policies of social distancing and partial to total lockdown.

The situation continued, and within weeks, routine life was drastically altered. This gave rise to severe health threats, economic uncertainty, and social isolation, causing potential deleterious effects on the physical and mental health of the people. The common psychological responses of individuals to the Coronavirus pandemic included stress, anxiety, and depression [22]. All these are capable of influencing the oral and maxillofacial syndromes, such as TMD and bruxism, which could further aggravate the orofacial pain [23].

Studies aimed to: (i) evaluate the effect of the current Coronavirus pandemic on the possible prevalence and worsening of TMD and bruxism symptoms, among subjects selected from two culturally different countries: Israel and Poland; and (ii) to define the predictors of TMD and bruxism during the lock down periods, in the above countries.

#### **2. Materials and Methods**

Studies were conducted as cross-sectional online surveys using anonymous questionnaires. The final questionnaire was compiled from tools commonly used with regard to TMD, bruxism, anxiety and depression (3Q/TMD, possible/probable bruxism, and Patient Health Questionnaie-4, as detailed below), and specific questions referring to demographics, concerns specific to the Coronavirus, media consumption, etc. The latter were agreed upon, and tested for content validity, by a group of subject matter experts (SMEs). The group consisted of four dentists (AE-P, IE, NU, and EG) who work at the Tel Aviv University School of Dental Medicine and have vast clinical and academic experience in working with patients suffering from TMD and bruxism. Each SME proposed questions for the study and, following discussions, the final questions were agreed upon. The questionnaire was compiled in Hebrew and translated to Polish by the Polish group. The surveys were carried out one month after the start of the total lockdown periods in each of the countries.

#### *2.1. Population*

The questionnaire was distributed through the internet (in Hebrew in Israel, in Polish in Poland).

In Israel, the study questionnaire was posted on SurveyGizmo (https:www.mysurveygizmo. com/s3) and distributed through mailing lists of dental clinics and social media (e.g., Facebook and WhatsApp).

In Poland, the questionnaire was posted on Reddit, an American social news aggregation platform that allows the users to interact on community-created discussion forums, and on r/Polska sub-reddit. In both countries, the responses were given anonymously by the participants.

Studies were conducted in full accordance with the World Medical Association Declaration of Helsinki. In Israel, all the study procedures were approved by the Ethics Committee of the Tel Aviv University in Israel (ID: 0001332-1). In Poland the Bioethical Committee of the Wroclaw Medical University approved the study protocol (ID: KB-302/2020). Informed consent was obtained from all the subjects as required.

#### *2.2. Instruments*

The following data were collected from the participants:


All questions were formulated in a first person voice (referring to self), and referred to the last 30 days, namely, to the period of the lock down.

The surveys were open to anyone who entered the SurveyGizmo (https:www.mysurveygizmo. com/s3) site and/or the Facebook and/or WhatsApp apps (in Israel) or the r/Polska sub-reddit in Poland.

In Israel, complete lock down was imposed on 19 March 2020. Data were collected from 16 April (namely, four weeks after the beginning of the complete lock down) to 20 May 2020. In Poland, complete lock down was imposed on 31 March 2020. Data were collected from 29 April (four weeks after the beginning of the lockdown) to 3 May 2020.

#### *2.3. Statistical Analysis of Data*

Data analysis was performed using STATISTICA PL Version 12 software (Tulsa, OK, USA), with the level of significance set at *p* < 0.05. In the first step, the data concerning TMDs, AB, and SB were compared between the two countries (descriptive analyses). In the second step, univariate analyses (Chi2) were performed to investigate the effects of anxiety, depression, and personal concerns of the Coronavirus pandemic (being contaminated, being influenced financially, experiencing negative effects on physical and/or mental health and on the relationship with relatives and friends) on the symptoms of TMDs, SB, and AB and their possible aggravation. Finally, multivariate analyses (logistic regression models—binomial logit models) were carried out to identify the study variables that had a predictive value on the symptoms of TMDs, AB, and SB and their aggravation.

#### **3. Results**

In Israel, a total of 867 subjects responded to the questionnaire, out of whom 80.74% (*N* = 700) fully completed it. In Poland, a total of 1096 subjects responded to the questionnaire, of which 99.63% (*N* = 1092) fully completed it.

The age groups of participants were defined according to "young adults" (age of 18–35 years) and "adults" (36–56 years old) as accepted in the literature [30]. Some significant differences existed between the two populations with regard to gender and age groups (Tables 1 and 2).



The Polish population had more females (*p* < 0.05), and the participants were significantly younger compared to their Israeli counterparts (*p* < 0.05).

Due to these significant differences in age and gender between the studied populations, comparisons were carried out separately for males and females, categorized into predefined age groups.


**Table 2.** Age of study populations.

#### *3.1. Descriptive Analyses—TMDs, Possible*/*Probable AB, and Possible*/*Probable SB*

1. TMD screening: The results showed that the odds of occurrence of TMDs among the Polish young adult and adult age groups (18–35 years and 36–55 years) were significantly higher for both males and females as compared to the Israeli groups (odds ratios ranged from 3.04 to 5.37). However, no such differences were observed for the elderly group (>56 years) between the populations (Table 3).


**Table 3.** Temporomandibular disorders (TMD) distribution.

\* Comparison of countries in regard to TMD positive/TMD negative in particular age and gender groups (Chi2). # OR comparing Poland versus Israel in regard to TMD positive in particular age and gender groups.

2. Possible/probable AB: Similar results were found for possible/probable AB. The odds of occurrence of these conditions among the Polish participants were significantly higher in general than among the Israeli participants (except the young and elder males), with the odds ratios ranging between 2.51 and 6.41 (Table 4).


**Table 4.** Awake bruxism (AB) distribution.

\* Comparison of countries in regard to Possible/Probable AB/AB negative in particular age and gender groups (Chi2). # OR comparing Poland versus Israel in regard to AB positive (Possible and Probable AB) in particular age and gender groups.

3. Possible/probable SB: The findings for possible/probable SB were also consistent. The odds of occurrence of these conditions among the Polish subjects (except for males in the two higher age groups) were similar to those of the Israeli subjects, with the odds ratios ranging from 1.4 to 3.99 (Table 5).


**Table 5.** Sleep bruxism (SB) distribution.

\* Comparison of countries in regard to Possible/Probable SB/SB negative in particular age and gender groups (Chi2). # OR comparing Poland versus Israel in regard to SB positive (Possible and Probable SB) in particular age and gender groups.

#### *3.2. Aggravation of AB, SB and TMD Symptoms*

Almost half (48.8%) of the Poles reported experiencing at least once a week pain in temple, face, jaw or jaw joint during the past 30 days, namely, since the beginning of the lockdown. A total of 247 individuals (22.6%) declared pain during mouth opening or chewing and 101 (9.2%) jaw locking or getting stuck at least once a week. Among the Israelis, the numbers were 166 (23.7%), 91 (13.0%), and 35 (5.0%), respectively.

Among the Polish responders, 372 (34%) reported TMD symptoms aggravation, 372 (34%) AB aggravation, and 311 (28%) SB aggravation. Among the Israeli responders, 107 (15%) reported TMD symptoms aggravation, 111 (16%) AB symptom aggravation, and 94 (13%) SB symptom aggravation.

Both in Israel and in Poland, females reported more symptoms of TMD, AB, SB and symptom aggravation, than males (Chi2, *p* < 0.05 for all). However, further logistic regression analyses, performed among Israeli population (see below), rejected gender as a predictor of SB. Distributions of TMD, AB, SB among males and females in Poland and in Israel are presented in Tables 3–5.

#### *3.3. The E*ff*ect of Conjugal Status*

Significant relationships were observed between subjects' conjugal status and TMD aggravation, AB aggravation and SB aggravation among the Polish responders (Chi2, *p* < 0.05, for all). Respondents living with a roommate or sharing apartment with a partner, reported more TMD and AB aggravation than those living with a spouse without children (Chi2, *p* < 0.001 for both). They also reported higher SB symptom aggravation than those with children but with no partner or spouse (*p* < 0.001).

In Israel, no differences in TMD, AB. and SB symptom aggravation were observed among subjects with different conjugal status.

#### *3.4. The E*ff*ect of Demographic Data on Anxiety and Depression*

In Poland, anxiety was more frequent among females than males (Chi2, *p* < 0.05). Additionally, a significant relationship was found between subjects' conjugal status and depression (*p* < 0.05). Depression was more often among respondents living with a roommate or sharing an apartment with a partner than among responders living with spouse and children (*p* < 0.001). There were no significant relationships between gender and depression or age and depression, between age and anxiety and between conjugal status and anxiety.

In the Israel, anxiety and depression were more frequent among females than males (Chi2, *p* < 0.05). No relationships between conjugal status and depression or anxiety, and between age and depression were detected. Anxiety was more frequent among young adults (18–35 years) than among the elderly group (>56 years) (Chi2, *p* < 0.001).

#### *3.5. E*ff*ect of Anxiety, Depression, and Personal Concerns on TMD, SB, and AB (Chi2)*

1. TMD: The presence of anxiety, depression, or personal concerns significantly increased the odds of occurrence of TMDs among both populations. The odds ratio ranged between 1.32 (concerns of being contaminated by the virus) and 2.75 (anxiety) for the Polish subjects, while it ranged between 1.46 (concerns about personal finances due to the pandemic) and 6.4 (anxiety) for the Israeli population.

2. Possible/probable AB: The presence of anxiety, depression, and personal concerns significantly increased the odds of occurrence of possible/probable AB among both populations. The odds ratios ranged from 1.45 (concerns of being affected financially, for Polish subjects) to 2.85 (anxiety, for Israeli subjects).

3. Possible/probable SB: Mixed results were observed for possible/probable SB. In Poland the odds ratios ranged from 1.34 (concerns of being affected mentally) to 1.84 (anxiety). No effect was observed for the concerns regarding personal finances or depression. Among the Israeli subjects, the odds ratios ranged from 1.38 (worries of being affected financially) to 2.27 (anxiety). No effect was observed for worries of being contaminated by the virus.

#### *3.6. E*ff*ect of Anxiety, Depression, and Personal Concerns on the Possible Aggravation of TMD, SB, and AB Symptoms (Chi2)*

1. Aggravation of TMD symptoms: Anxiety, depression, and personal concerns significantly increased the odds of aggravation of TMD symptoms in both populations. The odds ratios ranged from 1.58 (concerns regarding personal finances, for Polish subjects) to 3.03 (anxiety, for Polish subjects).

2. Aggravation of possible/probable AB symptoms: The obtained results were similar with regard to the aggravation of AB symptoms. The odds ratios ranged from 1.36 (concerns regarding personal finances, for Polish subjects) to 3.95 (anxiety, for Israeli subjects).

3. Aggravation of possible/probable SB symptoms: Similar results were observed for the aggravation of SB symptoms. The odds ratios ranged from 1.60 (concerns regarding personal finances, for Polish subjects) to 3.32 (anxiety, for Israeli subjects).

#### *3.7. Multivariate Analyses (Logistic Regression)*

1. TMD: The best predictors of TMD in Poland were female gender, anxiety, and personal concerns (worries of being contaminated by the virus and about the pandemic's effect on mental health) (Table 6). Aggravation of TMD was best predicted by female gender, worries of being contaminated, use of social media to look for information about the pandemic, and worries about the pandemic's effect on mental health (Table 7).


**Table 6.** Prediction of temporomandibular disorders (TMD) in Poland.

Link function: Logit. \* Feeling at high risk of being contaminated (yes/no). \*\* Worries about the effect of the Coronavirus on mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)).

On the other hand, the only significant predictor of TMDs in Israel was anxiety (Estimate: 0.917, S.E.: 0.107, Wald: 73.922, df: 1, odds ratio 6.25, 95% confidence interval 4.11–9.49).

The best predictors of TMD aggravation in Israel were female gender, concerns about the pandemic's effect on the relationship with family and friends, and anxiety (Table 8).


**Table 7.** Prediction of temporomandibular disorders (TMD) aggravation in Poland.

Link function: Logit. \* Feeling at high risk of being contaminated (yes/no). \*\* How often connecting to social media to check for news regarding the pandemic (not checking at all/checking once a day (I) versus checking several times a day/checking all the time (II)). \*\*\* Worries about the effect of the Coronavirus on mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)).

**Table 8.** Prediction of temporomandibular disorders (TMD) aggravation in Israel.


Link function: Logit. \* Worries regarding the effect of the Coronavirus pandemic on relations with relatives and friends (not at all/a little worried (I) versus somewhat worried/worried/very worried (II).

2. Possible/probable AB: In Poland, the best predictors of possible/probable AB were female gender, concerns of being contaminated by the virus, and concerns about the pandemic's effect on mental health (Table 9). The aggravation of AB was best predicted by concerns about being contaminated by the virus, anxiety, concerns of the pandemic's effect on physical and/or mental health, and use of social media for obtaining information about the pandemic (Table 10).

**Table 9.** Prediction of awake bruxism (AB) in Poland.


Link function: Logit. \* Feeling at high risk of being contaminated (yes/no). \*\* Worries about the effect of the Coronavirus on mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II).

**Table 10.** Prediction of awake bruxism (AB) aggravation in Poland.


Link function: Logit. \* Feeling at high risk of being contaminated (yes/no). \*\* Worries about the effect of the Coronavirus on one's physical health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)). \*\*\* Worries about the effect of the Coronavirus on one's mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)). \*\*\*\* How often connecting to social media to check for news regarding the pandemic (not checking at all/checking once a day (I) versus checking several times a day/checking all the time (II).

In Israel, the best predictors of possible/probable AB were female gender, depression, concerns regarding personal finances, and anxiety (Table 11). The aggravation of AB was best predicted by female gender, concerns about the pandemic's effect on the relationship with relatives and friends and on mental health, and anxiety (Table 12).


**Table 11.** Prediction of awake bruxism (AB) in Israel.

Link function: Logit. \* Worries about finances (not at al/a little worried (I) versus somewhat worried/worried/very worried (II)).


**Table 12.** Prediction of awake bruxism (AB) aggravation in Israel.

Link function: Logit. \* Worries regarding the effect of the Coronavirus pandemic on relations with relatives and friends (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)). \*\* Worries about the effect of the Coronavirus on one's mental health (not at all/a little worried versus somewhat worried/worried/very worried).

3. Possible/probable SB: In Poland, the best predictors of possible/probable SB were female gender, worries of being contaminated by the virus, and anxiety (Table 13). The aggravation of SB was best predicted by female gender, worries of being contaminated by the virus, anxiety, use of social media, and concerns of the pandemic's effect on mental health (Table 14).

**Table 13.** Prediction of sleep bruxism (SB) in Poland.


Link function: Logit. \* Feeling at high risk of being contaminated (yes/no).


**Table 14.** Prediction of sleep bruxism (SB) aggravation in Poland.

Link function: Logit. \* Feeling at high risk of being contaminated (yes/no)**.** \*\* How often connecting to social media to check for news regarding the pandemic (not checking at all/checking once a day (I) versus checking several times a day/checking all the time (II))**.** \*\*\* Worries about the effect of the Coronavirus on one's mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II).

In Israel, possible/probable SB was best predicted by anxiety and concerns regarding the pandemic's effect on the relationship with relatives and friends (Table 15). The aggravation of SB was best predicted by female gender, anxiety, and concerns about mental health (Table 16).


**Table 15.** Prediction of sleep bruxism (SB) in Israel.

Link function: Logit. \* Worries regarding the effect of the Coronavirus pandemic on relations with relatives and friends (not at all/a little worried (I) versus somewhat worried/worried/very worried (II)).


**Table 16.** Prediction of sleep bruxism (SB) aggravation in Israel.

Link function: Logit. \* Worries about the effect of the Coronavirus on one's mental health (not at all/a little worried (I) versus somewhat worried/worried/very worried (II))

#### **4. Discussion**

The two studies, carried out in two different countries, used similar tools and collected data at similar points in time, as far as the pandemic progression and lock down periods are concerned. In Israel, data collection started four weeks after the beginning of a total lockdown in the country. Schools, kindergartens, and universities were closed. Leaving home for a distance more than 100 m was prohibited, except for emergency, buying basic products, or work in vital posts (specifically defined by the government). All nonemergency medical and dental treatments were stopped. Shops, restaurants, and most public places were shut down. Personal contact with family members not cohabitating in the same home and/or with friends was forbidden. Similarly, in Poland, data collection started four weeks after the beginning of a total lockdown in the country, when the country was practicing an almost complete lockdown with similar regulations as mentioned above for Israel (with minor exceptions, e.g., there were no limitations on the distance of leaving home). Although the studied populations in Poland and in Israel were not similar, age- and/or gender-wise, the similarity in research tools and in the point in time allows us to evaluate some interesting differences between the two societies.

The first emerging finding of the two studies is that significant differences existed in the odds of occurrence of bruxism (AB and SB) and TMD between the Polish and Israeli populations during the lock down periods in the two countries. Except in a few cases (higher age group), the odds in Poland were found to be higher by several hundred percent than those in Israel.

In the general population, the prevalence of bruxism is estimated at 8–31% and tends to decrease with age [31]. SB prevalence is about 16% among young adults and 3–8% among adults, while the AB prevalence in the general population is 22–30% [14]. Even the reported prevalence of bruxing activities has a large range (2.7–57.3% for AB, 4.1–59.2% for SB) [26]. When considering TMD, it is believed that about 75% of the general population may experience at least one TMD-associated sign during their lifetime and about 33% have at least one TMD symptom at each time [32]. The differences origin mostly in different modes of measuring.

Regretfully, accurate data on possible differences in pre-pandemic occurrence of bruxism in the Polish versus Israeli populations are not available. However, some studies from Poland and from Israel suggest that the occurrence of TMD in the Polish population may differ from that in the Israeli population. Wieckiewicz et al. reported that 54% of Polish university students present TMD symptoms [33]. In another study, the same group of authors reported that 56% of participants were diagnosed with pain-related TMD after a clinical examination [34]. In Israel, Winocur et al. reported that 37% of individuals had at least one TMD symptom [35]. Thus, the differences between countries, observed in the present study, may be due to several reasons. First, the higher findings of TMD in the Polish populations may have been there before the pandemic [33–35]. Possibly, the increase in anxiety/depression in both countries affected TMD and bruxism in both countries in a proportional manner. Additionally, the differences in the demographic properties of populations were significant, a fact that might have affected the results.

As both bruxism and TMD can be caused and intensified by psychologic factors [8,31], the differences in their prevalence during the pandemic could have resulted from the psychological differences between the participants. These, in turn, may result from ethnic, socioeconomic, political, and cultural differences between the Polish and Israeli societies [36,37]. These factors could have potentially modulated the psychoemotional status of the participants, influenced their coping strategies

during the Coronavirus pandemic, and in turn increased the prevalence of both bruxism and TMD in Poland. However, this issue needs a further study focused on differentiating between the populations.

It should also be emphasized that TMDs are closely associated with orofacial pain. The IASP reported that TMD-related facial pain occurs in 9–13% of the general population. As TMD-related pain can affect the daily activities, physical and psychosocial functioning, and quality of life of the affected individuals, such a relationship could play an important role during the COVID-19 pandemic [9]. Increased psychosocial distress during the pandemic can exacerbate the TMD symptoms, including those associated with orofacial pain, which in turn may further negatively affect the patients' psychoemotional status.

When the effects of anxiety, depression, and personal concerns on TMD, SB, and AB, and the aggravation of their symptoms (pain in temple, face or jaw, pain when opening mouth, sticking of jaw, headache, difficulty in mouth upon awaking, and stiffness in jaw upon awaking, etc.) were analyzed, some similarities were observed between the countries. Although the odds of occurrence of TMD, SB, and AB in Poland were by far higher than in Israel, the effects of emotional factors and of personal concerns on the associated symptoms and their aggravation were found to be similar in both countries. Anxiety, depression, and worries regarding finances, health and relationships significantly increased the odds of occurrence of bruxism and TMD in both the Polish and Israeli societies (with some minor exceptions).

Apparently, anxiety, depression, and personal worries evoked by the Coronavirus pandemic increased the prevalence of TMD and bruxism. This is in line with the literature results, that anxiety, stress, depression, coping strategies, and catastrophizing may precipitate or prolong the TMD pain [2–8], and that psychosocial factors are associated with both forms of bruxism [13,14,16–20]. When the pandemic situation kept changing rapidly from day to day, uncertainty and worries about the present and future were common and unavoidable [38,39]. Moreover, subjects had to stay home and many were unemployed, with the media constantly broadcasting apocalyptic news. Under such conditions, a significant increase in the odds of occurrence of TMD, SB, and AB is not surprising.

The one prominent difference was observed between the studied populations. The studies show that unlike the Polish participants, the worry of being contaminated by the virus did not increase the odds of occurrence of AB and SB, or aggravate the symptoms of the conditions (TMD, SB, and AB) among the Israeli subjects. This may be explained by the advanced and generally good public health services available in Israel. All the Israeli citizens have governmental health insurance and are entitled to all the necessary health services with no extra costs (besides a mandatory monthly fee). Furthermore, hospitals are considered to meet high medical standards, and medical personnel are required to be well trained. In Poland, citizens' trust in national healthcare system is limited [40].

Logistic regression models used in this study for identifying the variables that can serve as significant predictors of TMD, SB, AB, and/or the aggravation of their symptoms, showed that female gender was significant in most of the calculations. In Poland, female gender played a significant role in predicting the presence of TMD, AB, and SB, as well as the symptom aggravation, while in Israel this factor played a significant role in predicting the presence of AB (but not TMD or SB) and the aggravation of TMD, SB, and AB symptoms.

The role of gender is expected because most of the TMD patients worldwide are women [1]. In spite of the differences between the two countries, results showed that women in both places are highly vulnerable to the effects of unexpected prolonged stress situations. Aggravation of chronic pain symptoms such as TMD and symptoms associated with bruxism may be only some of the negative consequences that affect women more severely than men [41,42].

Additional factors that were consistently identified as significantly predicting the TMD, AB, and SB (and/or the symptom aggravation) in the present studies were anxiety, worries of being contaminated by the virus, and concerns about the pandemic's effect on physical or mental health (to slightly different extents in the two countries). In some instances, two additional factors were identified in the regression analyses: worries that the pandemic will affect the relationship with relatives and friends (in Israel) and the use of social media (but not TV or internet) for checking news regarding the pandemic (in Poland).

In Israel, close family ties and long-term friendships are very common in the society [43]. Apparently, the social distancing period, which prevented face-to-face meetings, took its toll on Israeli society. The fact that the use of social media affected, in some cases, the Polish, but not the Israeli, participants, may be explained by the younger age of the former. Another explanation may be that the Israeli society is constantly exposed to security tension and alerts making it more resilient [44]. The Israeli public extensively check the news at all times, and the Coronavirus crisis is no different from many other emergencies experienced by these people.

In a recent study, Varshney et al. reported that during the initial stages of the Coronavirus pandemic in India, almost one-third of the respondents manifested a significant psychological impact [45]. The factors that predicted a higher psychological impact were young age, female gender, and the presence of a physical comorbidity. The authors of the study also showed that males faced a lesser psychological impact as compared to females [45]. Thus, in spite of the differences between countries and cultures, many of the basic factors affecting the public are similar.

Several limitations of the studies should be pointed out. No inclusion and/or exclusion criteria were specified and the study samples were not predetermined. The significant differences in demographic variables might have been a reason for some of the detected differences, especially in view of the fact that gender (but not age) came out as a predictive factor in most of the models calculated for TMD, bruxism, and symptom aggravation, in both countries. Moreover, the studies were performed during a specific point in time at the first phase of the pandemic and may be indicative of the immediate stress evoked by the sudden health risk and changes in life style. Additionally, possible confounders that could have influenced the results were not under control.

Further longitudinal studies are needed to evaluate the pandemic's possible long-term mental and physical consequences. Multifactorial and multicultural research should be performed to identify the risk groups and counteract the aggravation of emotional and physical effects in the case of future global crises.

#### **5. Conclusions**

The coronavirus pandemic has caused significant adverse effects on the psychoemotional status of both Israeli and Polish populations, resulting in the intensification of their bruxism and TMD symptoms and thus leading to increased orofacial pain.

**Author Contributions:** A.E.-P., I.E., and M.W. contributed to study conception and design. A.E.-P., I.E., G.W., N.U., and E.G. collected the data. A.E.-P., I.E., N.G., and J.S. were involved in data analysis and interpretation. A.E.-P., I.E., M.W., and J.S. drafted the article. A.E.-P., I.E. and M.W. critically revised the article. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

### *Article* **SARS-CoV-2 and Oral Manifestation: An Observational, Human Study**

**Bruna Sinjari 1,2,\*, Damiano D'Ardes 3,**†**, Manlio Santilli 1,2,**†**, Imena Rexhepi 1,2, Gianmaria D'Addazio 1,2, Piero Di Carlo 4,5, Piero Chiacchiaretta 6, Sergio Caputi 1,2,**‡ **and Francesco Cipollone 3,**‡


Received: 15 September 2020; Accepted: 3 October 2020; Published: 7 October 2020

**Abstract:** The correlation between SARS-CoV-2 and oral manifestations is still controversial. The aim of this observational study was to determine the oral manifestation of the hospitalized patients for COVID-19. A total of 20 patients met the inclusion criteria and gave their signed informed consent. A questionnaire of 32 questions regarding the oral and systemic health condition was administrated to these patients during the convalescence. A descriptive statistic was performed. Data were analysed through the use of χ<sup>2</sup> test, to assess the statistical significance. A statistically significant increase of about 30% of reporting xerostomia during hospitalization was observed (*p* = 0.02). Meanwhile, a decrease of oral hygiene was observed during the hospitalization, even if a non-statistically significant difference was shown between the two study time points (before and after hospitalization). During the hospitalization period, 25% of patients reported impaired taste, 15% burning sensation, and 20% difficulty in swallowing. An interesting result was that among the systemic conditions, hypertension was observed in 39% of patients and mostly in female patients (62.5%). Further studies are necessary to better understand the symptoms of this new virus in order to faster detect its presence in humans. Probably, a multidisciplinary team following the COVID-19 patients could be of key importance in treating this disease.

**Keywords:** SARS-CoV-2; COVID-19; oral manifestation; xerostomia; dysgeusia

#### **1. Introduction**

The SARS-CoV-2 (Severe Acute Respiratory Syndrome-CoronaVirus 2) is the seventh coronavirus known to infect humans [1,2]. Specifically, it belongs to the family of *Coronaviridae*, of the order *Nidovirales*, comprising large, single, plus-stranded RNA as their genome [3,4]. The new coronavirus SARS-CoV-2 has, like other coronaviruses, with high probability, a zoonotic origin [5]. Among these, α-CoV and β-CoV tend to infect the respiratory, gastrointestinal, and central nervous systems [6]. By studying nucleotide sequences thoroughly, SARS-CoV-2 has been seen to be part of β-CoV with a 79% similarity to the SARS-CoV virus already described in the past decades [7].

The main transmission routes described are direct, as caused by coughing, sneezing, droplets of saliva expelled during the phonation, or indirect by contact with the main body mucous membranes such as oral, ocular, and nasal [8–11]. Public awareness of the spread of microorganisms and infectious diseases in the dental office among the dentist, auxiliaries, and laboratory personnel has increased significantly [12]. Therefore, several scientific dental societies have produced recommendations on dental activity, specifically for the management of acute dental infections [13]. A recent paper demonstrated, through a survey, that during lockdown period endodontic urgency resulted predominant [14], thus increasing the probability of being infected if measures are not respected through the high aerosol generation during the dental procedures. All over the world, the evolution of the disease diffusion, which today counts high numbers, is being monitored. Specifically, to date, the numbers of infected people still result in a constant increase. The numbers registered by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University are 33,082,994 infected worldwide and 997,799 deaths (updated to 28 September 2020). On the other hand, cases of recovered patients are also increasing all over the world [7]. These high numbers justify the declared state of pandemic and are undoubtedly attributable to the ease of human infection of the virus itself.

The main symptoms of COVID-19 are fever, tiredness, and dry cough. Some patients may experience soreness and muscle pain, nasal congestion, runny nose, sore throat, or diarrhea, but in severe cases, the infection can cause pneumonia, severe acute respiratory syndrome, kidney failure, and even death [8]. Moreover, the possible asymptomaticity in infected patients is very important and should absolutely not be underestimated [9].

Although there are many studies in the literature on clinical signs in positive SARS-CoV-2 patients, the majority of them have not verified the oral health status of the patients [15].

Possible oral-related symptoms include: hypogeusia, xerostomia, and chemosensory alterations [16]. In fact, xerostomia has been found mainly among COVID-19 patients, due to the neuroinvasive and neurotropic potential of SARS-CoV-2. It was reported that angiotensin-converting enzyme 2 (ACE2)-positive epithelial cells of the salivary gland are an early target of SARS-CoV-2 in rhesus macaques, and these findings suggest that oral manifestations may appear due to impediment of salivary flow in COVID-19-affected patients [17]. In fact, a cross-sectional survey of 108 patients with confirmed SARS-CoV-2 in China observed that 46% of them reported dry mouth, among other symptoms [17,18].

In literature, several cases of oral manifestations apparently related to SARS-CoV-2 have been described [19–21]. The importance of good oral hygiene could be an interesting aspect to evaluate a hypothetical relationship between SARS-CoV-2 and oral manifestations. Badran et al. hypothesized that periodontal pocket could be a reservoir for this virus [22]. Periodontopathic bacteria, involved in several process like inflammation, bacteraemia, pneumonia, are also present in the metagenome of positive SARS-CoV-2 patients [23]. Several authors described case reports of SARS-CoV-2-positive patients with oral manifestations potentially compatible with this type of coronavirus [19–21]. Moreover, a key factor in the damage of the respiratory system and other organs could be related to the distribution of ACE2 receptors in the human system [24]. Therefore, cells with ACE2 receptor distribution may become host cells for the virus and further cause inflammatory reactions in related organs and tissues, such as the tongue mucosa and salivary glands [25]. It has also been demonstrated that COVID-19 acute infection, along with associated therapeutic measures, could probably contribute to adverse outcomes concerning oral health. In fact, Dziedzic and Wojtyczka, in 2020, showed that it can lead to various opportunistic fungal infections, unspecific oral ulcerations, recurrent oral herpes simplex virus (HSV-1) infection, dysgeusia, fixed drug eruptions, xerostomia linked to decreased salivary flow, ulcerations and gingivitis as a result of the impaired immune system and/or susceptible oral mucosa [26].

It is not clear if the abovementioned manifestations derive from the viral infection, or they could be caused by some systemic deteriorations, based on potential negative reactions to treatments or even possible opportunistic infections [27]. Furthermore, some reports affirm that the oral cavity represents the main channel for infection, considering also several consequences for the dental practice and the role of saliva in identifying COVID-19 [24,25]. One of the latest studies links a higher risk of getting COVID-19 to hyposalivation as well as to taste loss [28].

Although, despite the probable relationship between oral cavity and SARS-CoV-2, to date, there are also many variables that could influence the presence of the oral manifestations. In fact, most patients take a large number of drugs that may produce the oral manifestations, thus the need in evaluating in an observational study the oral manifestation of COVID-19 hospitalized patients.

Based on the hypothesis that oral manifestations could be an initial pattern typical of this virus, the aim of this study was to better understand the relationship between these manifestations and SARS-CoV-2.

#### **2. Experimental Section**

#### *2.1. Study Design and Sample Selection*

A total of 20 patients were enrolled in this observational study conducted in a period of one month (from May 2020 to June 2020). The survey was completed by 20 patients who met, during the described period, the inclusion and exclusion criteria. The average age of the participants was 69.2 years. Of these, 55% were male (aged between 44 and 91 years) and 45% female (aged between 35 and 85 years).

A specific anamnestic questionnaire of 32 questions (Appendix A) was submitted to these patients affected by SARS-CoV-2 and hospitalized in "Policlinico 'SS. Annunziata' - Chieti, Italy" with the aim to collect information related to health status, oral hygiene habits, and symptoms in the oral cavity before and during the disease manifestation. In addition, a series of questions were also addressed to the Unit of Internal Medicine of the hospital to better know the clinical condition of these patients. This observational study was administered through a printing questionnaire and, prior to completion, the patients gave their informed consent signed to the doctor working in the Unit of Internal Medicine at the "Policlinico 'SS. Annunziata'" hospital. The patients were free to participate or not (based in a volunteer way) in this observational study. The inclusion criteria were patients of both sex and of any age hospitalized for COVID-19 at the abovementioned hospital able to give their consent to participate in the study. The exclusion criteria were patients of both sex and any age hospitalized for COVID-19 at the Internal Medicine department of the SS Annunziata hospital in Chieti in need of intensive care and/or who were unable to give their consent to participate in the study or who were unable to intend or to want. The methodology adopted for the creation of the questionnaires allowed us to use both quantitative and qualitative variables, differently distributed. All the questionnaires were given to the patients during the doctor routine visits in that department. Then, all the papers were collected in a separate box with all the recommendations to reduce the contagion. The data were analysed after a period of rest from their collection.

#### *2.2. Ethical Consideration*

The study protocol was approved by the Ethical Committee of the "G. Annunzio University" of Chieti and Pescara: No. 1687 of 22 April 2020. Participants provided their informed consent in accordance with the EU General Data Protection Regulation GDPR (UE) n. 2016/679 and following the Declaration of Helsinki before beginning the completion of the questionnaire. Data collection took place in the time period from 8 May to 1 June 2020.

#### *2.3. Statistical Analysis*

Some of the answers were codified as dichotomous variables, namely as Yes/No responses, or in general as categorical variables, when a multiple-choice selection was requested. Given the nature of our survey we computed descriptive statistics for most of the questions. For each question, we computed the percentage of the respondents that gave a particular answer with respect to the number of total responses to the question. Answers obtained prior and during the disease manifestation were compared through the use of χ<sup>2</sup> test, to assess the statistical significance. All statistical comparisons were conducted with a significance level of *p* < 0.05. Statistical analyses were performed using the GraphPad version 8 (GraphPad Software 2365 Northsides, Dr. Suite 560 San Diego, CA, USA) statistical software.

#### **3. Results**

The results demonstrated that most of the patients (65%) had more than 20 teeth and used to go to the dentist routinely. Moreover, the majority of participants (90%) were nonsmokers. The 40% of them reported that they brushed their teeth three times a day, before hospitalization, but most of them (70%) did not use dental floss. The patients also reported that during the hospitalization period, the attention to oral hygiene decreased. In fact, the number of patients who did not brush their teeth at all increased during the hospitalization, and the number of those who regularly brush three times a day decreased, as shown in Figure 1. However, the difference between the groups was not statistically significant (*p* = 0.20). Regarding the presence of oral manifestations (i.e., xerostomia), none of the patients reported xerostomia before contracting the virus, whilst during hospitalization the percentage increased to 30%. The difference between the two study time points was statistically significant (*p* = 0.02), as shown in Figure 2. In addition, during the hospitalization period, 25% of patients reported impaired taste, 15% burning sensation, and 20% difficulty in swallowing. Finally, by comparing these data and the onset of some manifestations between sex and age, no statistically significant results emerged, although a trend in some of these was detectable (please see Appendix B). Among the latter's, the presence of hypertension was found in 40% of patients, mostly in female patients (62.5%), as shown in Figure 3. Furthermore, an interesting data aspect was that the burning sensation of the mouth was present only in female patients. In addition, 15% of patients were affected by diabetes, 15% by obesity, and 25% presented thyroid disorders such as hypothyroidism or hyperthyroidism. Of note, 95% of the patients were given the following drugs: lopinavir/ritonavir and/or hydroxychloroquine, in combination with other specific drugs for the various systemic pathologies they presented.

**Figure 1.** The graphic represents the times the patients used to brush their teeth before and after hospitalization. No statistical significance (*p* = 0.20) was shown between these two time points of the study.

**Figure 2.** The xerostomia manifestation before and after hospitalization of the patients. A statistical difference was shown between the study time points (*p* = 0.02).

**Figure 3.** The graph shows the presence of hypertension between males and females. No statistical significance (*p* = 0.34) was shown between the sexes on the presence of hypertension.

#### **4. Discussion**

The aim of this observational study was to better understand the relationship between SARS-CoV-2 and oral manifestations before and during the hospitalization. Several clinicians have observed many extrapulmonary manifestations of COVID-19. In fact, the recent literature suggests that the hematologic, cardiovascular, renal, gastrointestinal and hepatobiliary, endocrinologic, neurologic, ophthalmologic, and dermatologic systems can all be implicated [29,30]. On the other hand, numerous studies have drawn attention to the oral cavity as the main route of infection [28].

Although recent evidence suggests a relevant role of the oral cavity and its mucosae in the transmission and in the pathogenicity of SARS-CoV-2, as the entrance to the body of the virus, its protective or aggravating element for the infection and progression of the virus is still controversial [28]. It has been demonstrated that there is an association between periodontitis and a higher risk of increased gravity of COVID-19 in periodontopathic patients [31]. Most of the individuals (65%) in our sample had more than 20 teeth and they used to go to the dentist for control visits, demonstrating the importance given to the oral health condition. Moreover, about 14 out of 20 of the patients with COVID-19 diagnosis had performed extractions due to periodontitis.

In addition, regarding the presence of xerostomia, only 30% of the patients developed this symptom during the period of hospitalization. These data are relevant because xerostomia has also been found in a relatively high proportion of COVID-19 patients from Chinese researchers [32]. On the other hand, these results should be carefully discussed. In fact, it has been shown that xerostomia can also be induced by different drug therapies such as: antidepressants, antipsychotics, anticholinergics, antihypertensives, antihistamines, and sedatives [33]. Furthermore, there is strong evidence that xerostomia is very common in diabetic patients and may be present in >50% of cases, and recently it was reported that the use of artificial saliva spray was shown to be effective in the treatment of

xerostomia in type 1 and type 2 diabetes [34,35]. However, in our study, only 15% of patients were affected by diabetes (not specified if type 1 or type 2).

In fact, 56% of the patients enrolled in our study had these kinds of therapies, but only 5% of them manifested xerostomia during hospitalization. These data deserve attention, because the symptom of xerostomia was manifested by patients affected by COVID-19 and enrolled in our study in 30% of cases, regardless of the drug therapy followed prior to admission. Therefore, this oral manifestation can probably be linked to the disease itself. Indeed, it has been demonstrated that the salivary glands are a reservoir of the virus, thus the contagion of people by way of saliva droplets [36].

Interestingly, the SARS-CoV-2 infection has been shown to be more severe in individuals over 50 years old and with the presence of associated comorbidities such as diabetes, cardiovascular problems, and diseases involving the nervous system. These disorders have been associated with hyposalivation; in our case 15% of patients were affected by diabetes, 15% by obesity, 39% by hypertension, and 25% presented thyroid disorders such as hypothyroidism or hyperthyroidism, but none of them, before being hospitalized, reported having xerostomia. Therefore, the onset of this symptom can be associated with the drug therapy administered for the treatment of COVID-19 and also with the infectious and inflammatory processes activated by the virus itself. Regarding other symptoms such as altered taste, 25% of the participants said they had dysgeusia. This is a very important finding and in line with recent publications on this topic, which attest to 33% the frequency of COVID-19 patients who report having this symptom [37]. Indeed, dysgeusia can be described as one of the early symptoms of COVID-19 infection. Clinically, these data may allow easier identification of pre-symptomatic or asymptomatic patients. Moreover, the diagnosis of this oral manifestation may significantly reduce disease transmission, especially when diagnostic tests are not readily available and/or unpredictable [38].

Focusing on the patient's systemic conditions, it appears significant that most of the patients hospitalized for COVID-19 had previous systemic conditions such as hypertension, heart disease, oncological pathologies, pathologies affecting the thyroid gland, diabetes, and pathologies affecting the respiratory system. Furthermore, only one patient in his medical history did not report any previous pathology. In addition, it should be noted that, in a recent study on 5700 patients, the most common comorbidities were hypertension in 56.6% of cases, obesity in 41.7%, and diabetes in 33.8% of patients with diagnosis of COVID-19 [39]. Our results are in agreement with these data. In fact, about 39% of our patients had hypertension. It is almost known that such pathologies are aggravated by factors such as smoking. An interesting result that emerged from our study is that approximately 90% of the participants were nonsmokers. In the literature, there are several studies that analysed the relationship between COVID-19 and smoking. According to the World Health Organization (WHO), no studies examined tobacco use and the risk of infection or the risk of hospitalization with COVID-19 among smokers [40]. In fact, the majority of the studies in the literature are observational reports, and they reported the prevalence of smoking amongst hospitalized COVID-19 patients [40].

As for the presence of cardiovascular diseases, the results of our study show that 50% of the participants had cardiovascular diseases, specifically 78% of them suffer from hypertension. Currently, the literature is controversial, also in the management of patients with hypertension since the SARS-CoV-2 uses ACE2 as a cell entry receptor [41]. It is unclear whether uncontrolled blood pressure is a risk factor for acquiring COVID-19, or whether controlled blood pressure among patients with hypertension is or is not less of a risk factor [42].

Although this observational study reports interesting data of 20 COVID-19 hospitalized patients, it has different limitations. Firstly, the small sample size, only 20 patients enrolled. This was given from different limitations on performing the study during the pandemic; the difficulty in enrolling patients with the abovementioned criteria during that period and the difficulty in having personnel available to administrate the questionnaire.

After the results raised, the questionnaires probably should have been done in a more specific way to better understand on which day of the disease the symptoms appear and if they had prior to the first symptom the symptoms they reported.

#### **5. Conclusions**

This study demonstrates the importance of the close link between SARS-CoV-2 and oral manifestations. There is no scientific evidence in the literature that certifies which oral symptoms SARS-CoV-2 can actually cause. In fact, from the analysis of our data, it is hard to notice that clinical conditions that patients manifest are due to the SARS-CoV-2. The presence of xerostomia in our patients suggests a symptom given by the virus, but it must always be correlated with the patient's therapy. In addition, it may be essential to carry out the measurement of the salivary flow before and after the COVID-19 diagnosis to demonstrate a close correlation of it with the virus. Furthermore, the dysgeusia present in only 25% of our study suggests that this symptom may be a warning signal for the patients. Finally, the reduction of oral hygiene conditions in the hospitalized patient (even if it was not the focus of this study) suggests how important it is to have a team specialized in dentistry within hospitals.

Further studies are necessary to better understand the symptoms of this new virus in order to faster detect its presence in humans; probably, a multidisciplinary team following the COVID-19 patients could be of key importance.

**Author Contributions:** Conceptualization, B.S., F.C., and S.C.; methodology, B.S., D.D., and M.S.; software, G.D. and I.R.; validation, B.S., S.C., and F.C.; formal analysis, P.D.C. and P.C.; investigation, F.C.; resources, B.S.; data curation, G.D. and I.R.; writing—original draft preparation, B.S., D.D., and M.S.; writing—review and editing, F.C. and S.C.; visualization, I.R. and G.D.; supervision, S.C. and F.C.; project administration, F.C.; funding acquisition, S.C. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Acknowledgments:** The authors received no financial support and declare no potential conflicts of interest with respect to the authorship and/or publication of this article.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **Appendix A. Questionnaire**




#### **Appendix B. Statistical Results**

**Figure A1.** Use of dental floss before and after hospitalization of the patients. No statistical difference was shown between the study time points (*p* > 0.99).

**Figure A2.** Habit of tongue-brushing before and after hospitalization of the patients. No statistical difference was shown between the study time points (*p* = 0.333).

**Figure A3.** Bleeding of gums before and after hospitalization of the patients. No statistical difference was shown between the study time points (*p* > 0.99).

**Figure A4.** Tooth extraction (EX) carried out between males and females. No statistical significance (*p* = 0.15) was shown between the sexes on the tooth extraction performed.

**Figure A5.** Difference between fixed-prosthesis wearers between males and females. No statistical significance (*p* = 0.40) was shown between the sexes.

**Figure A6.** Difference between removable-prosthesis wearers between males and females. No statistical significance (*p* = 0.64) was shown between the sexes.

**Figure A7.** Difference between chewing problems between males and females. No statistical significance (*p* = 0.56) was shown between the sexes.

**Figure A8.** Difference between swallowing problems between males and females. No statistical significance (*p* > 0.99) was shown between the sexes.

**Figure A9.** Difference between oral burning sensation between males and females. No statistical significance (*p* = 0.56) was shown between the sexes.

**Figure A10.** Difference of halitosis perception between males and females. No statistical significance (*p* > 0.99) was shown between the sexes.

**Figure A11.** Difference of dysgeusia perception between males and females. No statistical significance (*p* = 0.31) was shown between the sexes.

#### **References**


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*Article*
