Oral Cavity and COVID-19: Clinical Manifestations, Pathology, and Dental Profession

The Oral Cavity and Viral Infections

The oral cavity is home to a vast microbial flora that also include a robust community of viruses. Although the viruses that infect bacteria or bacteriophages constitute the majority, viruses that infect human cells form a significant component of the oral microbiome. ^, Much like bacteria, viral communities are also site-specific alterations that can lead to disease. Indeed, one of the earliest associations of biofilm virome with human disease is the increased membership of lytic bacteriophages in subgingival plaque in periodontal disease. Although the evidence for oral virome and the contributions to oral health and disease is still emerging, the proclivity for specific viruses to affect the oral cavity is well recognized. ^, Furthermore, direct communication between the oropharynx and the nasopharynx makes the highly vascularized oral tissues more vulnerable to viruses harboring the respiratory or gastrointestinal (GI) tract. Consequently, many of these viruses have been implicated in the cause of chronic oral mucosal lesions. ^, In the sections that follow, we briefly review the oral manifestations of major DNA and RNA viruses, discuss the SARS-CoV-2 infection with particular focus on the pathology of oral symptoms, debate the scope of salivary diagnostics for SARS-CoV-2 infections, and, finally, the potential of SARS-CoV-2 transmission through saliva, including the spread in dental offices.

Viral Infections With Significant Orofacial Manifestations

DNA Viruses

The human herpesvirus (HHV) family constitute the most common viral infections of the oral cavity. They are relatively large, enveloped, double-stranded DNA viruses with icosahedral symmetry. Of the eight members in the family, the herpes simplex virus-1 (HSV-1) infection is the most common and is characterized by painful mucosal ulcers affecting the attached gingiva, such as the hard palate and the gum tissues surrounding the teeth and the portions of the jawbones encasing them. Following primary infection, the HSV typically remains latent in sensory nerve ganglia, and a recurrence occurs when the virus is reactivated, often seen clinically as herpes labialis characterized by periodic appearance of cold sores or ulcers in the lip. Infections by varicella zoster virus (VZV) and Epstein Barr virus (EBV) viruses are the next common HHV infections. VZ causes chickenpox that could manifest with blue Koplik spots in the oral mucosa, and the EB virus causes infectious mononucleosis (the kissing disease). Human papillomavirus (HPV) is a small, nonenveloped, double-stranded DNA virus with icosahedral symmetry and more than 70 genotypes. HPV 16 and 18 are often associated with benign papillomatous lesions of the oral mucosa. In addition, focal epithelial hyperplasia, or Heck disease, and condyloma constitute oral HPV infections. ^, ^, A significant finding is that HHVs are established risk factors for oral cancers and precancerous lesions. This role has been variably attributed to the virus-induced dysbiosis, increased inflammation, and production of carcinogenic metabolites.

RNA Viruses

Among the retroviruses, the human immunodeficiency virus (HIV) is the most common to cause infection of the oral cavity. Other RNA viruses causing oral infections include Ebola; enteroviruses causing hand, foot, and mouth disease (HFMD); influenza B and C viruses; and coronaviruses. HIV is an enveloped retrovirus transmitted through sexual contact or by infected body fluids. This virus primarily infects the lymphocytes, resulting in immunodeficiency with consequent clinical manifestations of increased opportunistic infections affecting the lungs and other organs, including the oral mucosa. Interestingly, infectious HIV virions have been shown to be internalized by oral epithelial cells and retained in vesicular compartments for several days. Subsequent contact with lymphocytes or dendritic cells is thought to direct the clinical presentation and potentially promote the viral spread. ^, Ebola virus is a nonsegmented, negative-stranded RNA virus surrounded by an outer viral envelope studded with viral glycoprotein spikes. The virus primarily causes hemorrhagic fever, and gingival bleeding that is typically associated with other forms of hemorrhage such as epistaxis and bleeding at injection sites. Oral mucosal ulcers, inflammation, and painful red and white patches are other symptoms reported in Ebola virus infections. HFMD is caused by the Picornaviridae family of viruses in the genus enterovirus. Outbreaks of HFMD have more often been caused by two types of enterovirus A species, coxsackievirus A16 (CVA16), or enterovirus 71 (EV71). Oral manifestations are vesicular lesions much like those observed on the skin of hand and feet. ^,

Zoonotic Viruses

Influenza and severe acute respiratory syndrome (SARS) heralded the surge of zoonotic virus outbreaks. Globally, influenza epidemics cause major health and economic concerns. These viruses cause self-limiting upper respiratory tract infections in immunocompetent individuals and cause lower respiratory tract infections in immunocompromised subjects and the elderly. Although the primary symptoms are due to respiratory tract infection, the oral cavity could be a major site for the initiation, progression, and pathological processes of the influenza virus–induced infections. Dry mouth, vesiculobullous lesions, aphthous‐like lesions, dysgeusia, and anosmia are common oral manifestations. Coinfection with oral bacteria is thought to aggravate the severity of the lung pathological conditions with increasing morbidity and mortality. ^,

Coronaviruses are enveloped, positive-sense, single-stranded RNA (+ssRNA) viruses with a size varying between 26 and 32 kilobases (kb), the largest genome of known RNA viruses. The four subgroups of this family are alpha (α), beta (β), gamma (γ), and delta (δ) coronaviruses. All coronaviruses are zoonotic pathogens, although the mechanisms and routes of transmission from animal to human remain unknown. The primary transmission is thought to be mediated by direct contact with the intermediary host animals, and consumption of milk or uncooked meat have been suggested as potential sources of infection.

This century has seen the emergence of three novel β coronaviruses; namely the SARS-CoV (SARS-CoV-1), the Middle Eastern respiratory syndrome (MERS-CoV), and most recently the novel SARS-CoV-2 that cause severe human diseases and death. The first SARS-CoV-1 outbreak was reported in 2002 in Guangdong, China. The outbreak resulted in more than 8000 infections, with a devastating effect on local and regional economies. The second coronavirus outbreak occurred in 2012 when a few Saudi Arabian nationals were diagnosed with the MERS-CoV infection, which later spread to 27 countries with an approximately 20% to 35% mortality rate.

The third and the most recent outbreak is the infection by the SARS-CoV-2 virus that caused COVID-19. This virus, first reported in the city of Wuhan in China, spread rapidly constituting a global pandemic affecting individuals in all continents. ^, ^, As of June 2021, globally over 163 million individuals were infected with SARS-CoV-2 and nearly 3.4 million individuals had died. A critical feature of COVID-19 was the wide variance in clinical severity among infected people and high mortality. In this chapter, we focus on oral manifestations, mechanisms, and significance of oral fluids in SARS-CoV-2 infection.

SARS-CoV-2 and the Oral Cavity

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.

Box 8.1

Rationale That Supports Oral Manifestations as Truly Representing SARS-CoV-2 Infection

Much like the nasopharynx, the oral mucosa being exposed to the environment could be the site of first encounter with SARS-CoV-2, and hence oral symptoms could be the first sign of COVID-19.
Inflammatory reactions, in particular vascular inflammation, have been associated with the multiorgan involvement of COVID-19. The highly vascularized oral mucosa is likely to be vulnerable, and the reports of oral ulcers, loss of taste, and petechiae in COVID-19 could be attributed to such inflammatory reactions.
Histopathological similarities were observed between the thrombotic vessels in oral lesions and in the pulmonary diffuse thrombotic disease in COVID-19. ^,
Specific entry receptors for SARS-CoV-2 are expressed in oral mucosa.
Oral lesions have been observed in other viral lesions such as the herpes simplex virus, herpes zoster virus, and Epstein-Barr virus infections.
Concurrent or coinfection of SARS-CoV-2 infected lung with oral pathogens have been frequently observed.

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 )

Box 8.2

Classification of Oral Manifestations of COVID-19

1.
Chemosensory perception
- a.
  Dysgeusia
- b.
  Ageusia
2.
Oral mucosal lesions
- a.
  Apthous ulcer
- b.
  Herpertiform ulcer
- c.
  Vesiculobullous lesions
- d.
  White lesions, plaques
- e.
  Mucositis, mucosal erosions
3.
Salivary gland symptoms
- a.
  Xerostomia
- b.
  Sialadenitis
4.
Periodontal and bone symptoms
- a.
  Bleeding gums, Swelling
- b.
  Bone pain
5.
Other:
- a.
  Lesions due to trauma associated with intubation
- b.
  Drug induced ulcers.
- c.
  Secondary opportunistic infections such as oral candidiasis

Table 8.1

Pooled Prevalence of Oral Manifestations in COVID-19

Symptom	Number of Studies (Total No. Patients)	Number of Patients (%)
Dysgeusia	40 (10,228)	10,220 (99%)
	59 (29,349)	13,615 (46%)
	140	67 (47.9%)
	111	66 (59.5%)
	1 (573)	318 (55.5%)
	3	2 (66.6%)
Oral mucosal lesions	7 (case reports)	8
	140	29 (tongue plaque) (20.7%) 6 (lesions on other oral mucosal sites) (4.3%)
	? (304 nonhospitalized)	75 (tongue) (24.7%) 3 (other oral mucosal sites) (<1%)
	74	23 (tongue) (31%) 35 (other oral mucosal lesions) (47.3%)
	1 (573)	117 (oral ulcers) (20.4%)
	1 (1237)	21 (<1%) 3 (tongue) (<1%) 18 (other mucosal regions) (<1%)
Salivary gland: Xerostomia	1 (573)	273 (47.6%)
	140	72 (51.4%)
	111	51 (45.9%)

Box 8.3

Potential Mechanisms by Which Poor Oral Health Contribute to COVID-19 Susceptibility

1.
Chronic periodontitis is associated with elevated salivary cytokines and harmful enzymes. Aspiration of salivary cytokines injures the alveolar epithelium, making it more susceptible for viral infection. ^,
2.
The SARS-CoV-2 spike protein has been shown to interact with the lipid A component of lipopolysaccharide, the cell wall structure of gram-negative bacteria. Because poor oral hygiene is often associated with higher gram-negative content of oral microbiome, preexisting gram-negative bacterial infection, and the associated presence of lipopolysaccharide might exacerbate local lung inflammation. This is a consequence of SARS-CoV-2 spike protein binding by enhanced nuclear factor-κB activation. ^, This shows that poor oral hygiene is contributing to the increased susceptibility of individuals in nursing care facilities to SARS-CoV-2 infection.

Potential mechanisms by which oral bacteria contribute to the COVID-19 pathogenesis:

1.
Oral bacterial migration or transport causing ventilator-associated pneumonia.
2.
Oral bacterial infection or superinfection of the lower respiratory tract. ^,
3.
Oral soft and hard tissue surfaces as reservoirs of respiratory pathogens and as sources of lung reinfection through microaspiration. ^,

Box 8.4

Advantages and Limitations of Saliva for Diagnosis of SARS-CoV-2

Advantages

Easy access and feasibility for frequent collection.
Higher compliance to test for SARS-CoV-2 under reduced direct contact.
Positive salivary detection of SARS-CoV-2 in patients with a negative nasopharyngeal swab consistent with true infection.

Limitations

Many studies evaluated saliva admixed with oropharyngeal fluid.
A potential limitation is detection of RNA in levels near the sensitivity limits.
A negative result is not a guarantee of the absence of SARS-CoV-2 infection.

Mechanisms of Oral Manifestations of SARS-CoV-2

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