COVID 19-An Update on Oral Changes

The Severe Acute Respiratory Syndrome (SARS) coronavirus-2 is a novel coronavirus belonging to the family Coronaviridae originating in Wuhan, China has created a impact across the globe. The disease has been declared a pandemic by the WHO on March 11, 2020. In this review, an update on virology, pathophysiology, clinical presentation with detailed update on oral manifestations


INTRODUCTION
A series of acute atypical respiratory disease occurred in Wuhan, China in dec 2019 which rapidly spread from Wuhan to other areas. The pathogen responsible for such disease was found to be a novel coronavirus belonging to the family Coronaviridae. Hence the severe acute respiratory syndrome coronavirus-2 (SARS-CoV 2) was coined by WHO) due to its high similarity
World Health Organization (WHO) declared COVID 19 as a Pandemic on March 11, 2020 . The SARS-CoV-2, which started initially as severe pneumonia outbreak in China, has now quickly spread all throughout the globally, COVID-19 has affected large number of people being reported in approximately 200 countries and territories [2,3]. As of Dec 7th, 2020
The virus is transmitted via respiratory droplets andaerosols from person to person. Once inside thebody, the virus binds to host receptors and entershost cells through endocytosis or membrane fusion [6]. The virus follows series of steps after gaining entry into the host cells: attachment, penetration, biosynthesis, maturation and release. After getting attached to the host receptors, penetration happens through endocytosis or membrane fusion into the host cell. Once viralcontents are released inside the host cells, viral RNA enters the nucleusfor replication. viral proteins (biosynthesis) are synthesized by viral MRNA Then, new viral particles are made (maturation) and released. Coronaviruses has four structural proteins; Spike (S) glycoprotein protruding from the viral surface, which determines the diversity of coronaviruses and host tropism.Spike comprises two functional subunits; S1 subunit is responsible forbinding to the host cell receptor and S2 subunit is for the fusion of theviral and cellular membranes Membrane (M), envelop (E) and nucleocapsid (N) [7]. Angiotensin converting enzyme 2 (ACE2) was identified as a functional receptor for SARS-CoV [8]. ACE2 receptor is highly expressed in various body organs like nasal and oral mucosa, especially the tongue, salivary glands, lung, heart, ileum, kidney and bladder [9]. In lung, ACE2 was highly expressed onlung epithelial cells.
After getting attached to ACE-2, which is highly expressed in adult nasal epithelial cells, the virus undergoes local replication and propagation, along with the infection of ciliated cells in the conducting airways [10]. Then, there is migration of the virus from the nasal epithelium to the upper respiratory tract whichcauses symptoms of fever, malaise and dry cough. About one-fifth of all infected patients progress to next stage of disease and develop severesymptoms [10]. The virus invadesand enters the type 2 alveolar epithelial cells via the hostreceptor ACE-2, undergoes replication which releases multiple cytokines and inflammatory markers such as interleukins (IL-1, IL-6, IL-8, IL-120 and IL-12),tumour necrosis factor-α (TNF-α), IFN-λ and IFN-β, CXCL-10, monocyte chemoattractant protein-1 (MCP-1) and macrophageinflammatory protein-1α (MIP-1α) causing 'cytokinestorm' which further attracts neutrophils, CD4 helperT cells and CD8 cytotoxic T cells [11].
These cells fights against the virus also cause inflammation and diffusealveolar damage eventually culminating in an acute respiratorydistress syndrome [11].

CLINICAL FEATURES
The incubation period of COVID-19 is roughly 5-6 days, but canbe up to 14 days. During this period, the infected individuals may not show any symptoms but can be contagious and transmit the virus to healthy individuals in the population. The common symptoms are fever, body aches, breathlessness, malaise and dry cough, can be categorised as mild, moderate or severe disease based on the severity. Some patients may also present with gastrointestinal symptomssuch as abdominal pain, vomiting and loose stools [12].

NASAL SYMPTOMS
Hyposmia and Anosmia can happen with COVID infected patients which lasts for more than 7 days. The main suspected mechanism is invasion of the olfactory receptors centrally or damage of the olfactory epithelium which leads to post olfactory loss. Anosmia is usually associated with frontal headache. The frontal headache could be due to an acute rhinosinusitis with a mucosal inflammation due to SARS-CoV 2.Anosmia is seen in 68% to 85% of affected population [13]. Normal chest X-ray.

Moderate
Symptoms of pneumonia (persistent fever and cough) with normal oxygen saturation.
Significant lesions on high-resolution CT chest.
Severe Pneumonia with reduction in oxygen saturation level (SpO2<92%), neurological manifestations such as acute cerebrovascular diseases, skeletal muscle injury and impaired consciousness.
Lesions on high-resolution CT chest.

Critical
Acute respiratory distress syndrome, hypovolemic shock, coagulation defects, encephalopathy, heart failure and acute kidney injury.

EAR SYMPTOMS
Patients with COVID-19 may present ear symptoms such as tinnitus and hearing loss. Kilicet al.(2020) concluded that sudden sensorineural hearing loss (SSNHL) may be one of the symptoms of COVID19 and can also be considered to be a neurologic symptom [14]. The reasons could be neuritis caused by viral involvement in the cochlear nerves, cochleitis due to viral involvement in the cochlea and perilymphatic tissues [13].

Dysgeusia
Dysgeusia can be an early symptom of COVID-19 infection with prevalence of 71% to 88.8%. Angiotensin-converting enzyme 2 (ACE2) receptors have been found in the epithelium of taste buds and salivary glands, resulting in salivary gland dysfunction with subsequent salivary flow impairment, in both quality and quantity, and the resultant dysgeusia as an early symptom in asymptomatic patients with COVID-19 [15,16,17].
Adirect damage to nonneuronal cells in the olfactory epithelium where numerous ACE2 receptors are expressedcan also result in taste disturbance. There can be a direct damage of ACE2-expressing cells of the taste buds or direct damage of any of the cranial nerves responsible for gustation (CN VII, IX, or X) especially Chorda tympani .Also, the oral mucosa is lined with ACE2 receptors, can triggeran inflammatory response, which leads to cellular and genetic changes that could alter taste ultimately lead to the development of taste dysfunction. There could be tissue hypoxia in patients with COVID-19 which may also result in tissue injury leading to disturbance in taste sensation. Another possible mechanism may involve zinc, which has an important role in taste perception. Chelation of Zinc can happen through immune mechanisms result in acute hypozincemia leading to gustatory dysfunction. Finally, xerostomia can also causes alteration in taste preception [17].

Xerostomia
Xerostomia or dry mouth syndrome has been linked with COVID-19 as most of the patients have xerostomia. It is a sign of dehydration which could occur secondary to underlying illness such as COVID-19. Alsoneuroinvasive and neurotropism potential of SARS-CoV-2 can also leads to Xerostomia.Angiotensin-converting enzyme (ACE2) receptor 2 in epithelial cells of the salivary gland are the primary site for coronavirus which leads to viral induced infection and inflammation causing xerostomia [18].

Burning Mouth Syndrome
Burning mouth syndrome was also seen many COVID positive patients. Xerostomia along with gustatory dysfunction could have a strong association in causing Burning mouth syndrome. [19].

Opportunistic Infections
Also, COVID-19 acute infection, when treated with medications could potentially contribute to various oral lesions due secondary opportunistic fungal infections, recurrent oral herpes simplex virus (HSV-1) infection. There can be nonspecific oral ulcerations, mucosal bullous eruptions, fixed drug eruptions, gingivitis as a result of the impaired immune system and/or susceptible oral mucosa. Geographic tongue has also been reported [20].

Hyperpigmentation
There has also been hyperpigmentation in labial gingiva noted in asymptomatic covid positive patient. Immunoinflammatory processes leading to inflammatory mediators like prostaglandins, leukotrienes, cytokines (TNF alpha, IL-1) and inflammatory mediators, may play a role in this response and increased melanogenesis and cause hyperpigmentation [21].

CONCLUSION
There can be a wide array of oral manifestations in covid 19 patients, some may be an initial sign of COVID without showing symptoms. A thorough examination of the oral cavity is recommended and should be practised for better understanding of pathobiology of these oral alterations.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable.