key: cord-0802177-eoi4j1l3 authors: Brandini, Daniela A.; Takamiya, Aline S.; Thakkar, Pari; Schaller, Samantha; Rahat, Rani; Naqvi, Afsar R. title: Covid‐19 and oral diseases: Crosstalk, synergy or association? date: 2021-03-01 journal: Rev Med Virol DOI: 10.1002/rmv.2226 sha: 8f3b6a4281d557e6221eaab7d3745ff3949e9640 doc_id: 802177 cord_uid: eoi4j1l3 The coronavirus disease 2019 (Covid‐19) is a viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that clinically affects multiple organs of the human body. Cells in the oral cavity express viral entry receptor angiotensin‐converting enzyme 2 that allows viral replication and may cause tissue inflammation and destruction. Recent studies have reported that Covid‐19 patients present oral manifestations with multiple clinical aspects. In this review, we aim to summarise main signs and symptoms of Covid‐19 in the oral cavity, its possible association with oral diseases, and the plausible underlying mechanisms of hyperinflammation reflecting crosstalk between Covid‐19 and oral diseases. Ulcers, blisters, necrotising gingivitis, opportunistic coinfections, salivary gland alterations, white and erythematous plaques and gustatory dysfunction were the most reported clinical oral manifestations in patients with Covid‐19. In general, the lesions appear concomitant with the loss of smell and taste. Multiple reports show evidences of necrotic/ulcerative gingiva, oral blisters and hypergrowth of opportunistic oral pathogens. SARS‐CoV‐2 exhibits tropism for endothelial cells and Covid‐19‐mediated endotheliitis can not only promote inflammation in oral tissues but can also facilitate virus spread. In addition, elevated levels of proinflammatory mediators in patients with Covid‐19 and oral infectious disease can impair tissue homeostasis and cause delayed disease resolution. This suggests potential crosstalk of immune‐mediated pathways underlying pathogenesis. Interestingly, few reports suggest recurrent herpetic lesions and higher bacterial growth in Covid‐19 subjects, indicating SARS‐CoV‐2 and oral virus/bacteria interaction. Larger cohort studies comparing SARS‐CoV‐2 negative and positive subjects will reveal oral manifestation of the virus on oral health and its role in exacerbating oral infection. Viruses are molecular parasites that depend on host cells for reproduction. 1 Viral infection occurs when a virus releases its nucleic acid into a cell, followed by transcription and translation of proteins essential for viral replication, for which it relies on host protein machinery. Evidently, viruses require specific proteins to enter and replicate inside cells. Incessant evolution of viruses allows them to adapt with their host and also provides an opportunity to broaden their host(s) spectrum. Coronaviruses (CoVs) constitute a family of single-stranded RNA viruses, with the potential to infect different animal species. 2 Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recent zoonotic CoV, results in coronavirus disease 19 . SARS-CoV-2 transmission primarily occurs via small airborne droplets, larger respiratory droplets and direct contact with infected individuals or contaminated surfaces. 3 SARS-CoV-2 appears to have originated from bats, as SARS-CoV-2 shares 96% of its genome with a SARS-like bat COV. 4, 5 However, bat COVs cannot infect humans, which introduces the pangolin as the potential intermediate host where the virus may have acquired mutations to infect humans. SARS-CoV-2 is a positive-sense RNA virus with icosahedral morphology and spike-shaped angiotensin-converting enzyme 2 (ACE2) binding proteins. 6 The spike proteins are responsible for highaffinity binding of SARS-CoV-2 to human ACE2 receptors, expressed on the lungs but primarily on salivary glands in the oral cavity. 2, 7 In individuals with angiotensin-2-dominated expression (e.g., chronically ill or elderly), the binding of SARS-CoV-2 to intact ACE2 receptors possibly inactivates ACE2 proteins, therefore attenuating ACE2 receptor expression. 8 Ultimately, the inability to regulate the reninangiotensin system leads to vascular inflammation. 9 Patients diagnosed with Covid-19 often experience mild-to-severe fever, cough and fatigue. 6 In severe cases, SARS-CoV-2 can also lead to obstruction of lung airways, resulting in pneumonia, cytokine storm syndrome and/or acute respiratory distress syndrome. Recently, it has been found that Covid-19 can result in multisystem inflammatory syndrome in children (MIS-C). 10 The diagnosis of MIS-C has also been found to coincide with other inflammatory markers such as elevated levels of troponin, interleukin-6 (IL-6), and procalcitonin. With primary expression of ACE2 receptors occurring in the oral cavity, Covid-19 manifestations may be linked to oral cavity ACE2 expression as well and thus warrant further investigation. 7, 10, 11 The objective of this article is to conduct a review of a wide variety of oral manifestations observed in patients with Covid-19. We present evidences strongly suggesting adverse clinical presentations in patients and its impact on common oral diseases and their manifestations. Treatments prescribed to Covid-19 were largely aimed at bacterial or viral aetiological agents and improving oral hygiene. The favourable outcomes indicate presence of opportunistic pathogens or coinfection of SARS-CoV-2 and other infectious agents in oral cavity. Finally, we provide several plausible molecular and cellular mechanisms behind these occurrences. This article highlights clinical outcomes of an evolving microbiome interaction in Covid-19 patients and its impact on oral tissue homeostasis. Covid-19 is a viral infection caused by SARS-CoV-2 that has manifestations in multiple organs of the human body. [12] [13] [14] Patients infected with SARS-CoV-2 present a myriad of clinical signs and symptoms with variable severity. 15 In the oral cavity, the main manifestations are related to tongue depapillation, 16, 17 Candidaassociated lesions, 17 xerostomia, 18 aphthous like-lesions, 13,17 recurrent herpesvirus infection, 12,13,19 ulcers, 14,19-22 necrotising gingivitis, 23 erythema multiforme-like lesions 24 and salivary gland infections. 25 It has been reported that these oral manifestations, in general, appear concomitant with the loss of smell and/or taste a few days later (up to 14 days), and progress more rapidly and severely among older patients. 13 Interestingly, resolution of the oral lesions occurs in parallel with the resolution of Covid-19 13 indicating an association between virus infection, oral clinical manifestation and their recession. The oral cavity is the entry portal for several pathogens, including SARS-CoV-2, which can be detected in the saliva of patients with laboratory-confirmed Covid-19. High viral load in saliva is detected at the beginning of infection and the titres reduce with disease resolution, suggesting that salivary shedding of virus correlates with disease manifestation. 11 SARS-CoV-2 binds to the ACE2 receptor that is expressed in the oral cavity, with a strong interaction between the receptor and viral spike protein (S). 7,10,11 Figure 1 illustrates the presence of ACE2 and virus in different oral tissues. The interaction of transmembrane protein ACE2 with the S protein allows the virus to fuse with the host cell, use cellular machinery to replicate and lyse the cell to trigger oral signs and symptoms. 7, 16 Apart from this mechanism, that could explain the cause of some oral manifestations, oral lesions may also result from opportunistic infections facilitated by systemic damage, alterations in the immune system and adverse effects of treatment. In this section, we will present evidence that suggests an association of Covid-19 and oral disease as manifested by exacerbation of oral disease symptoms. Periodontal diseases (PDs) are a variety of inflammatory conditions of multifactorial aetiology that affect the supportive tissues around the tooth and are commonly associated with long-term biofilm accumulation. In Covid-19 infection, it has been reported that patients have a wide variety of oral manifestations, including acute periodontal lesions. The prevalence of patients who present periodontal manifestations associated with Covid-19 remains uncertain because of limited case reports with small cohort size. 23 with severe halitosis, generalised oedema and erythema, necrotic interdental papillae and spontaneous gingival bleeding. Table 1 lists the studies with reported clinical periodontal manifestations and prescribed treatment. ACE2 and transmembrane protease serine 2 (TMPRSS2) are expressed in the sulcular epithelium and periodontal pocket epithelium. 16 Recently, it was shown that TMPRSS2 inhibitor blocked SARS-CoV-2 invasion via ACE2, presuming that there is a possibility of SARS-CoV-2 infection via periodontal epithelium and that periodontal epithelium may exhibit tropism for the virus. 27, 28 Although SARS-CoV-2 has many pathways to invade the host cells, the receptor-protease-mediated pathway is valuable for increasing viral infectivity. 9,16 SARS-CoV-2 interaction with ACE2 might alter the function of oral epithelial cells and it is one of the mechanisms that could explain the appearance of ulcerated gingival lesions. 13 systemically. In addition, the signs and symptoms of Covid-19 have been associated with pathophysiological mechanisms related to "cytokine storm" derived from dysregulated immune reaction with overproduction of proinflammatory cytokines and chemokines such as IL-1β, IL-6, tumour necrosis factor-α (TNF-α), macrophage inflammatory protein 1a, IL-10 and interferon-γ (IFN-γ). 9, 29, [33] [34] [35] In this sense, it is reasonable to consider that PD influences Covid-19related outcomes as a predisposing factor for more severe forms of the disease mediated by widespread inflammation. 27, 29, 35 It has been reported that affected nonsurvivor patients with severe Covid-19 had higher levels of circulating IL-6 compared to patients affected by the mild form of the disease. 9 Moreover, a recent study suggested that proinflammatory cytokines such as IL-1β and TNF-α from the inflamed gingiva could infiltrate saliva and aspirate to the lungs, contributing to acute inflammation in this organ. 29, 34 F I G U R E 1 (a) The interaction between angiotensin-converting enzyme 2 (ACE2) and SARS-CoV-2 spike protein (S) will allow viral entry, replication and activation of innate antiviral response including proinflammatory cytokine production and infiltration of immune cells. This may result in manifestation of signs and symptoms in the oral cavity of Covid-19 patients. (b) Different sites of the oral cavity where virus and its receptors are reportedly detected including periodontal tissues, buccal mucosa, tongue and salivary glands. Covid-19, coronavirus disease 2019; SARS-COV-2, severe acute respiratory syndrome-coronavirus-2 BRANDINI ET AL. Inflammation of the dental pulp, or pulpitis, is a very painful disease and is the most predominant inflammatory oral infection in dentistry. 36 Multiple microbial infections in the root canal system caused by disruption of enamel integrity or periapical contamination may lead to inflammation of the pulp and periradicular tissues. 37 Severe odontogenic pain and necrosis of the tissue are the main signs and symptoms of the disease. In general, immediate procedures to access the pulp chamber and debride the root canal system are necessary to mitigate pain and control the inflammation response. 38 The role of Covid-19 in exacerbating endodontic infection is a matter of debate. Recently, Guo et al. 39 described an increase of more than 20% in dental pulp and periapical infections during the Covid-19 pandemic. Yu et al. 40 history or possible Covid-19 cases that were identified by the designed questionnaire. Irreversible pulpits was the most common pathology observed in this study and the therapy recommended involved reduction in the time of dentist visit to minimise possible exposure of professionals to the virus from asymptomatic patients. 40 Although elective dental treatments were suspended during the Covid-19 pandemic, pulp and periradicular diseases are the most common dental emergency and immediate face-to-face treatment is deemed necessary. A global transcriptomic analysis reported that the receptors for SARS-CoV-2, ACE2 and TMPRSS2 are detected in healthy and inflamed human dental pulp without significant differences between healthy control and diseased biopsies. 28, 41 In this regard, it has been inferred that healthy and inflamed pulp tissues have a similar tendency to be infected by SARS-CoV-2. 42,43 However, further studies are required to establish a direct correlation between exacerbation of pulpal disease among individuals positive or suspected positive for SARS-CoV-2 and pulpitis/periapical periodontitis. Covid-19 patients present with a broad variety of signs and symptoms, including a variety of oral lesions. 12 virus to the brain. Recent studies have also suggested that changes in taste may be secondary to olfactory problems or nasal obstruction. 70 Probable hypotheses that justify dysgeusia and ageusia in Covid-19 also include the possibility of damage caused by SARS-CoV-2 to the epithelial cells of the salivary glands that are considered a target of the virus because of ACE2 expression. 25 It has been acknowledged that changes in salivary flow and composition can cause changes in taste perception. Moreover, the increased use of oral chemicals and disinfectants to prevent secondary oral infections could also injure the epithelial cells, thus disturbing taste sensation. 71 In general, it is not yet known whether the olfactory and gustatory symptoms caused by Covid-19 are transient or can be permanent, 58 Galectins are a class of soluble-galactoside-binding proteins with proinflammatory or proresolution functions. 81 Recent studies indicate galectins as a potential connecting link between PD and Covid- 19 . Higher plasma levels of galectins (including Gal-1, Gal-3 and Gal-9) are reported in Covid-19 subjects. 82 In addition, macrophages, monocytes and dendritic cells in patients with severe symptoms BRANDINI ET AL. -11 compared with mild symptoms suggests their pathological role in the disease severity. 83, 84 Inhibition of Gal-3, a proinflammatory galectin, suppresses cytokine secretion in macrophages indicating its therapeutic potential as a target for Covid-19 treatment. 85 Interestingly, subjects with severe PD also exhibit increased expression of Gal-3. 35 Expression of Gal-9, another galectin isoform, was induced in periodontal ligament cells challenged with P. gingivalis-derived lipopolysaccharide, suggesting that higher Gal-9 expression further exacerbate periodontal inflammation. 86 Multiple reports have demonstrated that proinflammatory cytokines TNF-α induce Gal-9 expression, 87 while overexpression of Gal-9 in monocytes upregulate IL-1α, IL-1β and IFN-γ levels 88 suggesting a feedforward correlation between inflammatory cytokines and Gal-9 in maintaining inflammatory microenvironment. 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