Viral Infections With Significant Orofacial Manifestations

Oral Manifestations of SARS-CoV-2 Infection

SARS-CoV-2–infected individuals present a multitude of oral lesions, including ulcers, petechiae, vesiculobullous lesions, and dysgeusia or ageusia. However, there are considerable inconsistencies in the literature as to the time of oral manifestations with respect to the status of SARS-CoV-2 infection and the stage of COVID-19. Given the large population of SARS-CoV-2–infected individuals globally, some studies have speculated that the oral manifestations could be coincidental or could represent adverse drug-induced responses. Some of the erosive and ulcerative lesions on the oropharynx, palate, and posterior tongue have been suggested as lesions secondary to mechanical intubations. Thus it is not clear whether the oral lesions are true manifestations of the viral infection or a secondary phenomenon resulting from opportunistic infections or adverse effects of treatment.

The rationalr for oral manifestations as true effects of SARS-CoV-2 infection are listed in Box 8.1 . It is well recognized that are SARS-CoV-2 infection is transmitted by aerosols and the oral mucosa, much like the nasopharynx, could be the initial site of contact with the virus. The presence of entry factors for the SARS-CoV-2 in oral tissues suggests susceptibility to infection (discussed later). ^{, , ,} Further, much of the oral soft tissues are highly vascular and in a state of inflammation supporting increased vulnerability to SARS-CoV-2 infection, as the virus exhibited strong association with vascular inflammation in other organs. ^, Significantly, a few studies have reported the presence of oral pathogens in the bronchoalveolar lavage fluid from SARS-CoV-2–infected diseased lungs, suggesting coinfection or superinfection.

Clinical observations during the initial period of the pandemic may not have recorded oral manifestations, particularly in the context of the unexpected severity and mortality associated with COVID-19. As the testing for SARS-CoV-2 infection increased, the emphasis was on identifying early clinical manifestations to prevent and eliminate the rapid spread of infection. Several case reports and a few case series identified variable oral symptoms in SARS-CoV-2–positive individuals, and there was evidence that the oral manifestations could even constitute manifesting clinical features of COVID-19. ^{, ,}

In general, taste dysfunction, or dysgeusia, is the most reported oral symptom, with a prevalence rate ranging between 37% and 63% and occasional reports of loss of taste in more than 90% of the case series. ^{, ,} The initial symptom could be inflamed painful fungiform papillae of short duration of about a day, which then gives rise to an irregular asymptomatic ulcer that often heals completely without scar formation in about a week. ^, In addition, glossitis and plaque-like lesions on the dorsum of the tongue have been reported in COIVD-19 patients. ^{, ,} .

A broad classification of oral manifestations of SARS-CoV-2 infection is given in Box 8.2 . Chen et al. first reported xerostomia as a symptom in COVID-19 patients with an equal sex distribution and a prevalence of 46.3% in their study cohort. Subsequent studies also reported xerostomia as an early symptom in asymptomatic health care professionals or mildly symptomatic SARS-CoV-2–positive individuals. The hyposalivation not only results in decreased antimicrobial proteins and peptides but also reduces the efficacy of oral mucosal surface as a physical barrier. In addition, the reduction of saliva secretion may be linked to gustatory dysfunction. ^, Meta-analysis of available information identified additional oral symptoms such as, aphthous ulcers and vesiculobullous lesions in COVID-19 patients positive individuals. Pooled prevalence of oral manifestations derived from the strength of the observations in the number of infected individuals are listed in Table 8.1 . ( Box 8.3 and Box 8.4 )

SARS-CoV-2 Entry Into Host Cells: A Brief Review

To cause infection, the virus must enter the host cells and replicate. The entry of SARS-CoVs in target cells is facilitated by the interaction between the spike proteins protruding from the surface of the virus and the host cell surface receptors. In silico, molecular and functional assays have identified a metallopeptidase cell surface receptor named angiotensin-converting enzyme-2 (ACE2) on host cells as a common entry receptor for all coronaviruses. The spike (S) protein of SARS-CoV-2 is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor ACE2, whereas the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle by the two-heptad repeat domain. SARS-CoV-2 has been shown to bind ACE2 with higher affinity than SARS-CoV-1. Other host cell proteases that facilitate or promote the viral entry include furin and the transmembrane protease serine (TMPRSS). Furin, ACE2, desintegrin, and metalloproteinase domain 17 (ADAM17) or tumor necrosis factor-alpha (TNF-α)–converting enzyme (TACE) are proteases that cleave the viral spike protein between S1 and S2. Whereas the S1 domain potentially facilitates receptor binding, the S2 domain regulates the fusion of the virus with the host cell. ^, The TMPRSS belongs to a family of 17 members, divided into four subfamilies (HAT/DESC, epsin/TMPRSS, matriptase, and Corin). The TMPRSS2 of the epsin subfamily has been shown to participate in mediating SARS-CoV-2 entry. Much like furin, the TMPRSS2 also cleaves the spike protein between the S1 and the S2 subunits. The S2 subunit then undergoes conformational changes to complete the fusion of the viral envelope with the host cell membrane, mediating receptor internalization and facilitating viral entry. Replication within the target cells establishes the SARS-CoV-2 infection, leading to subsequent tissue damage. ^,

Pathogenesis of Oral Mucosal Lesions in COVID-19

In humans, ACE2 is predominantly observed in epithelial cells in contact with the environment, although expression also has been reported in internal organs, including the kidney and the heart. ^{, ,} The oral cavity in direct contact with the external environment is at an increased risk for viral invasion. Although one of the primary functions of the oral mucosa is to provide a barrier against microbial invasion, the surface epithelial cells often express receptors that would allow attachment and penetration of the cell membrane by the microbes. Based on the analyses of two public RNA sequence databases, Xu et al. first reported that ACE2 was differentially expressed in the oral mucosa in different sites, with the highest expression in the tongue and floor of the mouth. They confirmed the high expression of ACE2 in oral epithelial cells by single cell transcriptome analysis of normal oral mucosal biopsy samples. Subsequently, we and others also showed that ACE2 is abundantly expressed in the lining mucosa of the oral cavity and the dorsum of the tongue ( Fig. 8.1 ). In addition, the oral epithelial cells also express furin and TMPRSS2, supporting the potential for viral spike protein cleavage and SARS-CoV-2 internalization. The expression of TMPRSS2 is also observed in the acinar, myoepithelial and the epithelial cells lining the ducts in the salivary glands. ^{, ,} SARS-CoV-2 transcripts have been identified in oral mucosal tissue autopsies from COVID-19 patients.

Schematic Representation of the Mechanisms of Oral Manifestations of COVID-19.

Following SARS-CoV-2 exposure, the virus could infect the oral mucosa. (A) The epithelial cells lining the oral mucosa express cell surface angiotensin-converting enzyme-2 (ACE2). (B) Upon binding the ACE2 on the host cell surface, the spike protein of the SARS-CoV-2 activates the host proteases such as tumor necrosis-α converting enzyme (TACE) that cleaves both the spike protein and the ACE2 at the transmembrane region. The virus then enters the cell, and the ACE2 ectodomain is released as soluble ACE2 (sACE2). Toll-like receptor-4 (TLR-4) on oral epithelial cells potentially upregulated by the local dysbiosis secondary to viral trigger could facilitate viral entry by itself or assist the interaction of the viral spike protein with the ACE2. (C) Activation of TLR signal transduction induces inflammatory cell infiltration, macrophage activation, and facilitation of further viral invasion. (D) These changes lead to oral manifestations such as mucosal erosion and ulcer formation.

Emerging evidence suggests that in addition to ACE2, the SARS-CoV-2 also uses other pattern recognition receptors such as Toll-like receptors (TLRs) for host cell entry (see Fig. 8.1B ). In particular, the observations of TLR upregulation by damage-associated molecular patterns in clinical samples and the proposed models of direct binding of spike protein with TLRs 1, 4, and 6 suggest specific roles for these TLRs in facilitating the viral entry and/or in mediating the clinical symptoms of COVID-19. It has been suggested that the dysbiosis secondary to the invading SARS-CoV-2 increases the prevalence of pathogenic bacteria, which in turn modulates the innate host responses resulting in the release of cytokines and inflammation. ^, Such inflammatory reactions secondary to viral entry in mucosal and vascular cells has been used to explain the oral erosion, ulcers, and lingual pain in COVID-19. Collectively, these observations suggest that SARS-CoV-2 can infect a wide variety of oral tissues and cells and provide the scientific rationale for the oral symptoms in infected individuals.

Pathogenesis of Hyposalivation in COVID-19

Pathogenesis of Loss of Taste in COVID-19

As discussed earlier, systematic analyses showed that the gustatory dysfunction is one of the most common symptoms of COVID-19. ^{, , , ,} The epithelial cells of the dorsum of the tongue, including the taste bud cells, have been shown to coexpress the viral entry receptors ACE2 and TMPRSS2. ^{, ,} Indeed, the density of ACE2 receptor expression has been observed to be higher in tongue tissues than that in the buccal mucosa or gingiva. ^{, ,} Sakaguchi et al. showed by immunohistochemisry that ACE2 and TMPRSS2 are localized in human fungiform papillae taste cells. Significantly, Han et al. showed by single cell profile analysis of tongue tissues that the distribution of ACE2-positive cells correlated with typical the gene markers of taste buds, including TAS1R3, TAS2R4, TAS2R14, SNAP25, and NCAM1. Furthermore, taste bud cells have been shown to express TLRs more abundantly than the nongustatory lingual epithelium. Specifically, TLRs-2, -3, and -4 are highly observed in the gustducin-expressing type II taste bud cells. ^, Thus the expression of multiple viral entry receptors makes taste bud cells highly susceptible for SARS-CoV-2 infections. ^, Pertinently, human taste bud cells have also been shown to support SARS-CoV-2 replication. Biopsies of the dorsum of the tongue from COVID-19 patients showed transcripts of the SARS-CoV-2 by real-time polymerase chain reaction (PCR). Direct infection of the taste bud cells promotes inflammation and this could affect taste perception. ^{, ,} Consistently, gustatory dysfunctions have been correlated with high serum interleukin-6 (IL-6), a key cytokine upregulated in acute and persistent SARS-CoV-2 infection.

Taken together, a conceptual framework for the pathogenesis of dysgeusia in long-COVID could be proposed ( Fig. 8.2 ). SARS-COV-2 infection of the tongue epithelial cells, including the taste buds, modulates the host responses, and prolonged exposure will precipitate an exaggerated inflammatory reaction. Mucosal inflammation increases the epithelial cell exfoliation, a source of viral shedding in saliva and a potential cause for invasion of bystander epithelial cells. The lag in replenishment of the lost cells together with the reduced stem cell turnover could result in fewer taste buds. The reduced sensory perception precipitate dysgeusia. It will be interesting to investigate whether salivary epithelial cell analyses could reveal specific markers of dysgeusia in individuals with long-COVID.

Schematic Representation of Potential Mechanisms for Taste Dysfunction in Long-COVID.

(A) The lingual epithelium covered by a tongue film that includes extruded/exfoliated cells, microbiota, and residual saliva. The concentration of microbial metabolization products and the proportion of epithelial cells, including the taste cells, in the tongue film module taste sensitivity. The tastants diffuse the tongue film either unaltered or modulated by the metabolization products and reach taste receptor cells through the apical opening of the taste buds. Each taste bud includes tightly packed taste receptor cells, supporting (basal) cells and stem cells that replenish the continuously replacing taste receptor cells. (B) Dysbiosis secondary to viral invasion disrupts the commensal homeostasis (abundance of pathogenic or opportunistic oral microbes) and induce innate inflammatory responses. Persistent irritation induces host responses and increases epithelial proliferation, extrusion, and exfoliation. (C) Pressure on replenishment of taste receptor cells places increased demand on stem cells and thereby compromises taste bud homeostasis, affecting taste perception. ACE2, Angiotensin-converting enzyme-2; sACE2, soluble ACE2; TACE, tumor necrosis-α converting enzyme; TLR4, Toll-like receptor-4.

The Oral Flora and Lung Microbiome in Health

A healthy human inhales 12 to 15 times per minute at rest, on average, with approximately 20% of the air in the lungs being exchanged during each breath. The popular belief that the healthy lungs are sterile has been dismantled by a large body of evidence that supports the presence of a healthy lung microbiome, which when disturbed can contribute to many lung pathological conditions. Multiple theories have been proposed for the development of the lung microbiome. ^, The logical topological community theory proposes that the initial seeding of the lung microbiome occurs from the nearby anatomical sites based on the species similarity between the oropharyngeal and the nasopharyngeal microbiome with that of the lung microbiome. ^, The proximity and the anatomical continuity of the oral cavity and the lower respiratory tract suggests that the oropharyngeal microbiota could be a major contributor to the lung microbiome. Indeed, compositionally, bacterial communities from the lung are observed to be indistinguishable from the upper airways, albeit about 2 to 4 logs lower in biomass. The air passing through the oropharynx is admixed with saliva laden with inhaled microbes, oral microbes, and trapped particulates. The movement of the air not only assists in the development of the aerodigestive mucosal biofilm but also plays a role in the frequent modulation of the microbiome secondary to the flow and the composition of salivary microbiota. ^, Further movement of the epiglottis that diverts the solid contents to the esophagus and the air to the respiratory tract creates biologically significant number of aerosols. Microaspiration of these aerosols contributes to the vast majority of the constant microbial seeding of the lower airways from the oral cavity during health. ^{, ,} Thus, in general, the healthy lung does not contain a constant or distinct microbiome, but instead contains low levels of bacterial sequences largely similar to those of the upper respiratory tract flora. ^, Analysis of 16S rDNA and deep sequencing suggest that the lung-specific sequences are not shared among individuals. The biogeography theory posits that the spatiotemporal variability of the lung is influenced by the continual stream of immigrant bacterial species by microaspiration and selective replication of specific bacteria taxa. ^, Hence, this theory provides a rational explanation for the observations that despite the close resemblance of the lung microbiome to the oral microbiome, certain bacteria are represented in higher abundance in the lung microbiome than expected from the corresponding oral microbiomes. This is likely due to a selective advantage in replication among those bacteria taxa in the lung microenvironment as opposed to the oral microenvironment.

The Role of Oral Bacteria in Lung Microbiome Dysbiosis

As stated previously, the balance of three factors determines and shapes the lung microbiome: (1) microbial immigration into the airways, (2) elimination of microbes from the airways, and (3) the relative reproduction rates of the microbes found in the airways as influenced by the local environment for microbial growth. Acute and chronic lung diseases can dramatically change the ecological determinants of the lung microbiome, resulting in markedly different microbial communities. Inflammation alters the lung microbiome by affecting the regional growth conditions as a result of changes imposed in nutrient availability, temperature, pH, and oxygen tension. ^, A shift in the microbiome composition away from the Prevotella, Veillonella, and Streptococcus spp. that dominate the healthy lung microbiome toward Gammaproteobacteria, the class that contains many common gram-negative “pathogens” associated with lung diseases, has been observed in inflammatory pathological lung conditions.

Epidemiological studies support the notion that the oral flora is of relevance to acute and chronic lung disease. ^{, ,} An increase in bacterial immigration from the oropharynx occurs, and several oral anaerobes and facultative species have been cultured from infected lung fluids. These include Porphyromonas gingivalis, Bacteroides gracilis, Bacteroides oralis, Bacteroides buccae, Eikenella corrodens, Fusobacterium nucleatum, Fusobacterium necrophorum, Actinobacillus actinomycetemcomitans, peptostreptococci , Clostridium, and Actinomyces. ^{, ,} Although poor oral health has been associated with an increased risk for respiratory disease, improving oral health resulted in a reduction of respiratory events among patients in nursing homes and intensive care units (ICUs). ^,

Several mechanisms have been postulated for the role of oral bacteria in the pathogenesis of respiratory infection. Aspiration of oral pathogens into the lower respiratory tract can precipitate lung infection. Cytokines originating from periodontal tissues may alter respiratory epithelium promoting invasion and infection by bacterial pathogens. ^, Alternatively, periodontal disease–associated enzymes in saliva may modify the mucosal surfaces to promote adhesion and colonization by respiratory pathogens. Furthermore, backward mucus flow by the ciliary epithelium of the bronchial mucosa toward the oropharynx permit bidirectional movement of the microbiome during the coughing reflex. ^{, ,} The oral mucosa thus could act as a reservoir of respiratory pathogens, which are then aspirated into the lung with salivary droplets. ^{, ,}

Coronavirus Infections, Bacterial Coinfections, Pathological Lung Conditions, and the Role of the Oral Microbiome

Saliva for Diagnosis of SARS-CoV-2 Infection

The COVID-19 diagnosis is based on the detection of SARS-CoV-2 RNA by real-time PCR. Molecular diagnostic tests for quantitating the viral RNA include the traditional bench real-time qPCR system, a high-throughput real-time qPCR system (automated from RNA extraction to reporting of results), and direct rapid RNA extraction-free real-time qPCR kits have been widely used globally (3). Additional methods include reverse transcription–loop-mediated isothermal amplification and a rapid antigen test that combines immunochromatography with an enzyme immunoassay to detect the viral nucleocapsid (N) protein, for potential use as point-of-care tests.

Although SARS-CoV-2 RNA detection in the nasopharyngeal swab is considered the gold standard method for COVID-19 diagnosis, demand for swabs early in the pandemic drove a rapid collapse of supply chains, with shortages of personal protective equipment required by health care workers for sample collection. Further, the sample acquisition involved close contact of health care workers with the infected or suspected SARS-COV-2–positive individuals, increasing the risk for transmission. In addition, the specimen collection procedure was invasive and uncomfortable for patients. These shortcomings fostered search for use of alternative sampling methods for detecting the virus. More importantly, the rapid spread of the virus necessitated urgent development of methods for repeated sampling and mass testing.

Alternative samples assessed for SARS-CoV-2 detection include pooled nasal mid-turbinate swabs, throat swabs, oropharyngeal wash, and saliva. Each of the sample collection methods and the validity of the specimen with respect to SARS-CoV-2 detection has merits and drawbacks. Although all alternative methods were attempted as self-collected specimens with no contact with health care workers to minimize the risk for transmission, saliva collection was easier, less invasive, and more acceptable. Mishra et al. conducted a retrospective analysis of the validity of nonrespiratory samples for detecting the coronaviruses responsible for the previous three pandemics of the 21st century. Assessing data from a total of 3274 that included 802 SARS-CoV-1 samples and 2347 SARS-CoV-2 samples, they found that the sensitivity of nonrespiratory specimens for detection of SARS-CoV-2 was lower at 57.5% (95% CI, −1.2%–116.2%) than that for SARS-CoV-1 at 96.7% (95% CI, 87.6%–100.0%).

Previously, during the SARS-CoV-1 pandemic, a high concordance was observed between the saliva and the nasopharyngeal swabs as diagnostic specimens. Use of saliva for detection of SARS-CoV-2 was first reported by To et al., during the initial outbreak. They assessed the saliva of 12 nasopharyngeal swab–confirmed COVID-19 patients between 0 and 7 days of hospitalization. They reported a median viral load in saliva at 3.3 × 10 ⁶ copies/mL, with a range of 9.9 × 10 ² and 1.2 × 10 ⁸ copies/mL. ^, Subsequent studies testing saliva alone or testing both saliva and paired nasopharyngeal swab samples suggested that the SARS-CoV-2 titer in saliva was equivalent or even higher than that in the nasopharyngeal swab. The sensitivity of SARS-CoV-2 RNA detection in saliva ranged between 81.6% and 100%, and the specificity ranged between 88.4% and 100%. ^{, ,} Indeed, the virus was detected in the saliva of asymptomatic individuals, albeit at lower titers (10 ⁴ –10 ⁵ copies/mL) when the nasopharyngeal swabs were negative. Because the real-time PCR is based on well-characterized and validated primers, detection of SARS-CoV-2 RNA in saliva is not classified as false positive but rather as false negative or misclassification of nasopharyngeal samples. Further, in contrast to the inconsistent nasopharyngeal swab results, the viral titer in saliva decreased progressively in severely ill COVID-19 patients during recovery. In this context, the temporal analysis of SARS-CoV-2 viral load in saliva could serve a pivotal role for the translation of salivary tests in the clinic. Furthermore, glandular saliva from the parotid gland duct yielded high titers of the virus suggesting that SARS-CoV-2 targets the ductal and/or glandular epithelial cells. ^, Interestingly, fecal-oral transmission has been suggested as a source of the virus in saliva in COVID-19 patients presenting with GI symptoms with fecal shedding of SARS-CoV-2. ^,

Encouraged by the data from early studies, the use of saliva as a specimen for detecting SARS-CoV-2 increased globally. Several systematic reviews and metanalytic studies conducted comparative analyses of the sensitivity of saliva and that of the gold standard nasopharyngeal swabs as biospecimens for detecting SARS-CoV-2 ^{, , ,} ( Table 8.2 ). Collectively, there is evidence that the saliva as specimen exhibits high sensitivity and specificity for detecting SARS-CoV-2 ( Box 8.4 ). Further, the feasibility of frequent and self-collection of saliva are distinct advantages in infections with rapid spread and transmission such as SARS-CoV-2. Indeed, Eduardo evaluated 55 self-collected unstimulated saliva samples from hospitalized COVID-19 patients and demonstrated that the saliva samples were 87.3% in agreement with the nasopharyngeal swab for the detection of SARS-CoV-2 virus. In contrast, in studies comparing paired nasopharyngeal swabs and self-collected saliva obtained simultaneously, saliva samples exhibited lower sensitivity ranging from 16% to of 24.4%. Nagura-Ikeda et al. reported that the viral RNA was detected at significantly higher percentages (65.6%–93.4%) in saliva specimens self-collected within 9 days of symptom onset. However, the virus detection was lower as the time passed after at least 10 days of symptoms (22.2%–66.7%) and in specimens collected from asymptomatic patients (40.0%–66.7%). ¹³⁹ In asymptomatic individuals, random saliva samples (92.3%) were superior or equivalent to the pooled nasopharyngeal and oropharyngeal samples (73.2%) for detecting the SARS-CoV-2 virus by amplification of the open reading frame 1a (ORF1a) and nucleocapsid (N) genes. Reanalysis of SARS-CoV-2–positive frozen saliva samples by immunochromatographic assay and chemiluminescent enzyme immunoassay detected SARS-CoV-2 in 41% by the former method and in 91% of samples by the latter method.

Table 8.2

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