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ISSN : 1226-7155(Print)
ISSN : 2287-6618(Online)
International Journal of Oral Biology Vol.49 No.3 pp.61-68
DOI : https://doi.org/10.11620/IJOB.2024.49.3.61

Oral symptom manifestations in patients with COVID-19: gustatory and saliva secretion dysfunctions and pathogenetic hypotheses

Joungmok Kim1, Jeong Hee Kim1,2*
1Department of Oral Biochemistry and Molecular Biology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
2Department of KHU-KIST Converging Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Republic of
Korea
*Correspondence to: Jeong Hee Kim, E-mail: jhkimh@khu.ac.krhttps://orcid.org/0000-0002-3884-4503
August 29, 2024 September 10, 2024 September 10, 2024

Abstract


Coronavirus disease 2019 (COVID-19) is a highly contagious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This disease is characterized by a wide spectrum of symptoms, ranging from mild to severe, including fatal outcomes. This study aims to review gustatory and salivary secretion dysfunctions and determine their potential pathogenic mechanisms. Gustatory impairment and salivary dysfunction are prevalent among patients with acute COVID-19 and those recovering from the disease. The mouth serves as a critical entry route for SARS-CoV-2. The cells within the oral epithelium, taste buds, and minor and major salivary glands express key entry factors for SARS-CoV-2, including angiotensin-converting enzyme 2, transmembrane serine protease 2, and furin. The co-occurrence of gustatory and salivary secretion dysfunctions possibly has pathogenetic association with the following factors: the expression of SARS-CoV-2 cellular entry receptors in the taste buds and salivary glands and SARS-CoV-2–induced zinc deficiency, which is crucial for normal taste perception and saliva secretion. Furthermore, the cytokine storm triggered by COVID-19 contributes to secondary damage affecting gustatory and salivary functions.


COVID-19 , Taste disorders , Salivary gland diseases , Pathogenesis

초록

    © The Korean Academy of Oral Biology. All rights reserved.

    This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Introduction

    The coronavirus disease 2019 (COVID-19) pandemic triggered by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread worldwide. And the pandemic resulted in unprecedented socio-economic and health impacts [1]. SARS-CoV-2 has resulted in ＞ 775 million COVID-19 patients worldwide [2]. In Korea, Korea Disease Control and Prevention Agency (KDCA) [3] data indicate that ＞ 34 million COVID-19 patients with ＞ 35,000 deaths were reported from January 20th, 2020 to August 31st, 2023.

    It has become clear that SARS-CoV-2 infection can present with a broad spectrum of manifestations, ranging from asymptomatic cases to severe respiratory distress syndrome and, in critical situations, death. It was observed that the risk of SARS-CoV-2 transmission increases with the length of exposure and the proximity of social interactions [4]. At the onset of illness, COVID-19 symptoms can vary widely and often include fever or chills, cough, shortness of breath or difficulty breathing, sore throat, congestion or runny nose, new loss of taste or smell, fatigue, muscle or body ache, headache, nausea or vomiting, and diarrhea [5]. In addition to these clinical manifestations, COVID-19 is also associated with several symptoms specific to oral tissues and functions. These include taste impairments such as ageusia and dysgeusia, which can be classified into severe, moderate, and mild hypogeusia. Also reported are impairments in saliva secretion, including dry mouth, xerostomia, and hyposalivation [6-8].

    Initially, COVID-19 oral symptoms were thought to be transient and expected to disappear without treatment. However, growing evidence suggests that taste and saliva secretion disorders may persist in individuals who have recovered from COVID- 19. The persisting symptoms following COVID-19 are difficult to determine as various health-related factors influence them [9]. Several studies have identified that COVID-19 has a wide range of long-term effects on nearly all body systems, including the respiratory, cardiovascular, muscular, neurological, gastrointestinal, psychiatric, and dermatological systems [10-15]. The most common syndromes are persistent fatigue, respiratory complaints, taste and smell disorders, and cognitive impairments [15-21]. Many COVID-19 survivors who were monitored after their recovery have reported persistent gustatory and salivary secretion dysfunctions [22,23].

    While gustatory and salivary secretion dysfunctions are not life-threatening, their persistence can significantly impact the oral health-related quality of life for COVID-19 patients and survivors [24]. These disorders can diminish appetite, negatively affect nutrition, and potentially increase the risk of other health issues [25,26].

    It is well-documented that the oral cavity functions as an entry portal for SARS-CoV-2, with the virus frequently being identified in saliva [27]. Hence, there has been more attention on the impact of SARS-CoV-2 infection on oral disease and the effect of post-COVID-19 on oral health care [28,29]. Therefore, addressing oral-related symptoms associated with COVID-19 has become a critical issue. The purpose of this study is to summarize oral symptoms, specifically gustatory disorders and salivary secretion disorders during the early stages of SARS-CoV-2 infection and after recovery. Furthermore, it aims to investigate the underlying pathogenic mechanisms of these conditions.

    Oral Cavity as an Entry Route and a Direct Infection Site for SARS-CoV-2

    SARS-CoV-2, a zoonotic virus that causes COVID-19 belongs to the coronavirus family. It is a positive-sense, singlestranded RNA virus [30]. At the onset of the COVID-19 pandemic, the oral cavity was regarded as a passive route for transmitting SARS-CoV-2 from other respiratory tract regions, despite evidence of the virus’s presence in saliva. However, recent reports indicate that all major oral mucosal sites and salivary glands are vulnerable to direct infection by SARSCoV- 2 [7,31,32]. It is critical to recognize that these initial infection sites may play a significant role in facilitating the spread of the virus to other areas of the body.

    It was demonstrated that saliva and nasopharyngeal specimens exhibit comparable sensitivity in detecting SARS-CoV-2 [33]. Given the hypothesis that the oral cavity might be a site of direct infection in COVID-19 [34], periodontal disease has been identified as a risk factor for COVID-19 [35]. Additionally, less common oral symptoms, such as salivary gland inflammation and oral mucosal lesions, are increasingly reported in COVID-19 patients [36,37].

    Following the identification of angiotensin-converting enzyme 2 (ACE2) as the cellular receptor for SARS-CoV-2 [38,39], its expression in the human tongue, gingiva, buccal mucosal cells, and salivary glands has indicated that the oral cavity is vulnerable to direct SARS-CoV-2 infection [40,41]. Furthermore, it has been reported that viral entry factors, including ACE2, furin, and the transmembrane serine protease (TMPRSS) protease family, are present in the epithelial cells of the glands and oral mucosae, as demonstrated by single-cell RNA sequencing of human minor salivary glands and gingiva. An ultrasound-guided postmortem biopsy was performed in cases of fatal COVID-19 and it was found through immunohistochemical analysis that ACE2 and TMPRSS2 are expressed in the ductal epithelium and serous acinar cells of the parotid, submandibular, and minor salivary glands [27]. Additionally, asymptomatic individuals can harbor infectious viruses, and the levels of SARS-CoV-2 in saliva have been found to correlate with the severity of taste alterations [7,42]. Epithelial cells exposed to the external environment, such as those in the gingiva, are particularly at high risk for viral infection [32]. Saliva from patients with asymptomatic or mild COVID-19 has been found to contain substantial amounts of virus and infected cells, indicating that the oral cavity may serve as a source of viral transmission both within and between individuals [32]. These findings suggest that the oral cavity functions not only as an entry route for SARS-CoV-2 but also as a site for direct viral infection and transmission.

    Gustatory Dysfunction

    The sense of taste is detected by taste buds, which convert taste stimuli into gustatory signals that are transmitted to the primary taste cortex. Taste buds, located in the stratified epithelium and distributed across the tongue, palate, and epiglottis, are specialized gustatory organs. Each taste bud is composed of clusters of columnar taste receptor cells (TRCs) with microvilli on their apical surface, housing various receptors that detect taste molecules [43]. TRCs can be categorized into three types—type I, type II, and type III—based on their ultrastructural features and gene expression patterns. These cells are continuously regenerated from stem cells within the taste buds and work together to transduce the five primary taste qualities: sweet, sour, bitter, salty, and umami [44-46].

    Most reports are based on self-reported smell and taste disorders, with many indicating that long-lasting taste deficiencies may occur following SARS-CoV-2 infection. Such deficiencies can influence nutrition, safety, and quality of life. However, self-reports are often inaccurate and typically reflect olfactory disorders [47], with fewer reports addressing taste system disorders. It has been reported that approximately 40% of COVID-19 patients experience taste disorders, encompassing various forms such as hypogeusia, ageusia, and dysgeusia [48,49].

    Saliva Secretory Dysfunction

    Saliva secretion abnormalities have been described using various terms. The terms, such as xerostomia, dry mouth, and hyposalivation are collectively designated as saliva secretory disorders for simplification. Dry mouth can arise from various causes, including autoimmune, endocrine, and neurological conditions, as well as the use of certain medications. Additionally, it is evident that intensive medical treatments, particularly in intensive care units, can significantly contribute to complaints of dry mouth.

    It has been reported that 42.5% of patients in the acute phase of COVID-19 experienced complaints of xerostomia and dry mouth [22]. A similar prevalence of dry mouth, at 44.2%, was also documented [50]. Additionally, saliva secretory sequelae were observed in 18.5% of COVID-19 survivors who were followed up for 28–230 days [22]. Other studies reported similar dry mouth symptoms with and without Sicca syndrome in COVID-19 patients [51-53]. Although the prevalence of xerostomia and dry mouth decreases after recovery from COVID- 19 compared to the acute phase, it is evident that saliva secretory dysfunctions can persist for an extended period.

    Possible Pathogenic Mechanisms

    From article search, it was found the association between gustatory dysfunction and saliva secretory dysfunctions. Tsuchiya [11] reported that a study on oral symptoms across various ethnic backgrounds, including Italian, Colombian, Chinese, Indian, Israeli, Egyptian, Turkish, and Saudi Arabian cohorts, concluded that persistent saliva secretory dysfunctions can occur concurrently with persistent gustatory dysfunctions, regardless of geographical or ethnic differences.

    The detailed mechanism behind COVID-19-related gustatory and salivary secretion dysfunctions remains unclear. COVID-19 patients exhibit gustatory and saliva secretory dysfunctions, both of which can persist for an extended period in survivors. This provides insights into the pathogenic mechanisms underlying the concurrent oral symptoms.

    1. Direct damage of oral symptoms-related cells

    The pathological hypotheses for COVID-19-related oral symptoms are as follows. First, there is the possibility that SARS-CoV-2 directly damages the taste-related and salivary gland cells. It has been observed that SARS-CoV-2 induces cellular damage through mechanisms involving both autophagy and apoptosis [54,55].

    SARS-CoV-2 binds to the cellular receptor ACE2 via its spike protein. This interaction is followed by the fusion of the viral and cellular membranes, facilitated by the cellular proteins convertase furin and TMPRSS2. Once the viral envelope merges with the host cell membrane, SARS-CoV-2 enters the host cells [42]. Considering the presence of viral entry-related biofactors and the virus detection in oral tissues, SARS-CoV-2 can target the oral cavity. The cytopathic effects of SARSCoV- 2 lead to functional disruptions in the affected cells [56- 58]. Specifically, SARS-CoV-2 targets taste buds and salivary glands that express the viral receptor ACE2, causing collateral damage that negatively impacts taste perception and salivary secretion. These direct cell damages may cause malfunction of the gustatory system and salivary secretion.

    2. Host zinc deficiency and SARS-CoV-2 infection

    Secondly, zinc deficiency and the disruption of local zinc homeostasis can be considered factors. Hypozincemia is frequently observed in COVID-19 patients, and the extent of zinc deficiency is associated with the extent of disease severity [59]. Zinc and zinc-binding proteins are important for the physiological processes of taste bud development, regulation, ion transport, and resistance to oxidative stress [22]. Zinc deficiency negatively impacts the vallate papillae, resulting in a reduction in both the number and size of taste buds [60]. Additionally, it leads to decreased taste sensitivity and impaired saliva secretion [61]. Although the exact mechanism is not yet known, clinical observations have shown that zinc supplementation improves taste function in patients [22,62].

    3. Cytokine storm plays a role in cell death induction

    The cytokine storm is critical to the pathogenesis of COVID- 19 [63]. Elevated levels of proinflammatory cytokines and immune cell infiltration in the oral mucosa of COVID-19 patients indicate the involvement of inflammation and immune responses in the pathogenic process [58].

    4. Other supporting hypothesis

    One of the hypotheses involved in the pathogenetic process of taste disorder and xerostomia is the disruption of reninangiotensin system (RAS) homeostasis. The host cell receptor ACE2, which is crucial for SARS-CoV-2 entry into the cell, plays a key role in maintaining the balance of the RAS - including renin, angiotensinogen, and ACE [48,64]. When the virus’ s S protein blocks ACE2, it damages the RAS [65]. This local imbalance in the RAS may contribute to the formation of an inflammatory microenvironment in taste buds and salivary gland cells [53].

    Additionally, it has been demonstrated that SARS-CoV-2 affects olfactory neurons, leading to impairment of chemosensory function [66]. Dysgeusia frequently arises as a consequence of impaired olfaction, owing to the complex integration and interaction between the gustatory and olfactory regions of the brain [67].

    Conclusion

    Gustatory and salivary secretion dysfunctions are highly prevalent symptoms in COVID-19 patients. Although these oral symptoms are not life-threatening, they significantly affect the overall quality of life. To resolve these problems, it is essential to elucidate the pathogenesis of the disease. The concurrent presence of gustatory and salivary secretion dysfunctions is pathogenetically related to several factors: the expression of SARS-CoV-2 entry receptors in taste buds and salivary glands, and zinc deficiency induced by SARS-CoV-2 infection, which is essential for maintaining normal taste perception and saliva secretion. The cytokine storm caused by SARS-CoV-2 infection also induces an inflammatory microenvironment within the affected cells.

    Funding

    No funding to declare.

    Conflicts of Interest

    No potential conflict of interest relevant to this article was reported.

    Figure

    Table

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