Covid-19 and oral diseases: Crosstalk, synergy or association?

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.

Sialadenitis: A Possible Early Manifestation of COVID-19.

Acute sialadenitis may be caused by viruses, including coronaviruses. Although there are anecdotal reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) salivary gland infections, there have been no well-documented cases of sialadenitis in patients with COVID-19 described in the literature. We report a case of parotitis and submandibular gland sialadenitis, as well as an isolated case of parotitis, in two patients with concurrent SARS-CoV-2 infections. Computed tomography imaging demonstrated parotid and submandibular gland enlargement with heterogenous enhancement and attenuation, consistent with sialadenitis. Medical management was sufficient for successful resolution of the acute sialadenitis. Laryngoscope, 130:2595-2597, 2020.

Oral saliva and COVID-19.

Outbreak pneumonia announced in Wuhan, China, in December 2019, had its causative factor classified as a new coronavirus (SARS-CoV-2). Since saliva can host several viruses including SARS-CoV-2, the transmission chance of viruses through saliva, particularly those causing respiratory infections, is unavoidable. COVID-19 can be detected through salivary diagnostic testing which has lots of advantages for medical care professionals and patients. It should be noted that not only does saliva offer an ecological niche for the colonization and development of oral microorganisms, but it also prevents the overgrowth of particular pathogens such as viral factors. The aim of this study is to gather all the information about saliva and its association with COVID-19 for the whole health care professionals across the world.

Acute sialadenitis associated with 2017-2018 influenza A infection: A case series.

The influenza A virus has accounted for the majority of influenza infections in the 2017 to 2018 flu season, with the typical clinical presentation including fever, myalgias, malaise, and nonproductive cough. Notably this season, we have recognized a cluster of influenza A cases presenting as severe neck and facial swelling, with the subsequent diagnosis of sialadenitis. Whereas previous authors have demonstrated isolated case reports of sialadenitis associated with influenza A infection, herein we describe the clinical history, laboratory values, and radiographic findings of four patients presenting to our institution in January 2018 with acute sialadenitis and influenza A infection. Laryngoscope, 2500-2502, 2018.

Postmortem diagnosis of cytomegalovirus and accompanying other infection agents by real-time PCR in cases of sudden unexpected death in infancy (SUDI).

As an opportunistic pathogen with high mortality rates, Cytomegalovirus (CMV) may lead to fatal disseminated CMV infection of the premature and newborn; thus necessitating the demonstration of CMV-DNA with clinical history and/or histopathological findings of CMV infection and defining other bacterial and viral infection agents with real-time polymerase chain reaction (RT-PCR) in udden unexpected death in infancy (SUDI) cases as we aimed in this study. 314 (144 female, 170 male) SUDI cases were prospectively investigated from January 2013 to January 2015 in Istanbul Forensic Medicine Institution. The study includes 87 tissue samples of 39 cases for post-mortem histopathological examination of interstitial pneumonia, myocarditis, meningitis, encephalitis, hepatitis, colitis or tubulointerstitial nephritis and/or accompanying chronic sialadenitis. CMV-DNA was found positive in 35 (40.2%) salivary gland, 19 (21.8%) lung, 1 (1.1%) tonsil, and 1 (1.1%) brain tissues. CMV sialadenitis and/or CMV pneumonia associated with other viral and/or bacterial agents were detected in 23 (60%) of 39 infant cases. The demonstration of CMV-DNA would significantly clarify the cause of death and collection of epidemiological data in SUDI cases with clinical history and histopathological findings of CMV infection accompanying chronic CMV sialadenitis. Furthermore, CMV suppresses the immune system, and may predispose to other bacterial and/or viral infections in these cases. Post-mortem molecular investigations are useful in explaining cause of death in SUDI with a suspicion of infection in forensic autopsies.

HCV Treatments and Their Integration Into Rheumatology.

Hepatitis C virus (HCV) has been associated with distinct rheumatic syndromes including arthritis, sialadenitis, and cryoglobulinemic vasculitis (CV). The therapy of these HCV-associated syndromes includes antiviral therapy with or without the addition of immunosuppressives while clinical response is mainly seen in patients who clear the virus after antiviral therapy. Despite significant therapeutic advances, existing antiviral therapies with interferon-a (IFNa)-based schemes achieve viral eradication only in approximately half the patients. Recently, oral antivirals that target specific HCV proteins referred as direct acting antivirals (DAAs) have been developed and approved. Short-term (12-24 weeks) combination schemes with or without IFN ("IFN-free" regimens) including these inhibitors clear the virus in more than 90 % of treated patients. Here, we review current therapeutic options in HCV-associated rheumatic syndromes and the potential role of the newly available antivirals in an integrated therapeutic approach.

Oral manifestations of hepatitis C virus infection.

Extrahepatic manifestations (EHMs) of hepatitis C virus (HCV) infection can affect a variety of organ systems with significant morbidity and mortality. Some of the most frequently reported EHM of HCV infection, involve the oral region predominantly or exclusively. Oral lichen planus (OLP) is a chronic inflammatory condition that is potentially malignant and represents cell-mediated reaction to a variety of extrinsic antigens, altered self-antigens, or super antigens. Robust epidemiological evidence support the link between OLP and HCV. As the virus may replicate in the oral mucosa and attract HCV-specific T lymphocytes, HCV may be implicated in OLP pathogenesis. Sjögren syndrome (SjS) is an autoimmune exocrinopathy, characterized by dryness of the mouth and eyes and a multitude of other systemic signs and symptoms. SjS patients have also an increased risk of non-Hodgkin lymphoma. Patients with chronic hepatitis C do frequently have histological signs of Sjögren-like sialadenitis with mild or even absent clinical symptoms. However, it is still unclear if HCV may cause a disease mimicking SjS or it is directly responsible for the development of SjS in a specific subset of patients. Oral squamous cell carcinoma is the most common oral malignant tumour and at least in some part of the world could be linked to HCV.

Implication of Epstein-Barr virus infection in disease-specific autoreactive B cell activation in ectopic lymphoid structures of Sjögren's syndrome.

OBJECTIVE: To examine whether the B cell tropic γ-herpesvirus Epstein-Barr virus (EBV) is aberrantly expressed in its latent and lytic forms within ectopic lymphoid structures (ELS) in the salivary glands of patients with Sjögren's syndrome (SS), and to investigate the relationship between EBV dysregulation, B cell activation, in situ differentiation of autoreactive plasma cells, disease-specific autoantibody production, and cytotoxicity. METHODS: Latent and lytic EBV infection in the salivary glands of 28 patients with SS and 38 patients with nonspecific chronic sialadenitis (NSCS), characterized for the presence or absence of ELS, was investigated by reverse transcription-polymerase chain reaction, in situ hybridization, and immunohistochemical/immunofluorescence staining. Glandular versus synovial production of anti-Ro 52, anti-citrullinated protein antibodies (ACPAs), and anti-EBV peptide antibodies was analyzed in situ or in vivo in human SS/SCID and human rheumatoid arthritis/SCID mouse chimeras. RESULTS: EBV dysregulation within inflammatory infiltrates was observed exclusively in ELS+ SS salivary gland tissue, as revealed by latent EBV infection and lytic EBV infection in B cells and plasma cells, respectively. Conversely, epithelial latent membrane protein 2A expression was observed in both patients with SS and patients with NSCS. Importantly, perifollicular plasma cells displaying Ro 52 immunoreactivity were frequently infected by EBV. Furthermore, ELS-containing SS salivary gland tissue that was transplanted into SCID mice supported the production of anti-Ro 52/anti-La 48 and anti-EBV antibodies but not ACPAs. Analysis of CD4+ and CD8+ T cell localization and granzyme B expression demonstrated that the persistence of EBV in ELS-containing SS salivary glands was associated with follicular exclusion of CD8+ T cells and impaired CD8-mediated cytotoxicity. CONCLUSION: Active EBV infection is selectively associated with ELS in the salivary glands of patients with SS and appears to contribute to local growth and differentiation of disease-specific autoreactive B cells.

Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease.

The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.

Experimental encephalomyocarditis virus infection in small laboratory rodents.

Encephalomyocarditis virus (EMCV) is a cardiovirus that belongs to the family Picornaviridae. EMCV is an important cause of acute myocarditis in piglets and of fetal death or abortion in pregnant sows. Small rodents, especially rats, have been suspected to be reservoir hosts or carriers. This virus also induces type 1 diabetes mellitus, encephalomyelitis, myocarditis, orchitis and/or sialodacryoadenitis in small laboratory rodents. This paper reviews the pathology and pathogenesis of experimental infection with EMCV in small laboratory rodents.

[Study of virus content of Herpes viridae family in parotid secretion of patients with inflammatory-dystrophic diseases of salivary glands].

The study is devoted to disclose the interrelation between Herpes viridae family carriage and inflammatory-dystrophic diseases of salivary glands (SG). It was shown that inflammatory and dystrophic diseases of SG in observed patients run on the background of latent and active chronic herpes-virus infection. In the case the frequency of disclosure and content of antibodies to nuclear protein of Epstein-Barr virus in the peripheral blood serum in patients with different inflammatory and dystrophic SG diseases were statistically significantly higher and antibodies to simple 1st type virus and cytomegalovirus lower than in patients with different types of maxillofacial region pathology without SG involvement. The immediate contamination of parotid secretion by virus of Herpes viridae family was detected with the help of polymerase chain reaction in 18% of patients with SG diseases.

Xerostomia, hyposalivation and sialadenitis in patients with chronic hepatitis C are not associated with the detection of HCV RNA in saliva or salivary glands.

OBJECTIVE: Salivary gland disorders in patients with chronic hepatitis C (CHC) have been considered oral extrahepatic manifestations, reinforcing the hepatitis C virus (HCV) as a sialotropic virus. Hence, the authors investigated the prevalence of HCV RNA in saliva and salivary glands and its possible association with xerostomia, hyposalivation and sialadenitis in patients with CHC. PATIENTS AND METHODS: In 65 patients with confirmed CHC, the HCV RNA was investigated by nested RT-PCR in saliva samples and minor salivary glands. Xerostomia, hyposalivation, clinical and histopathological evidence of sialadenitis were also evaluated. Univariate and multivariate analyses were employed to verify associations. RESULTS: HCV RNA was detected in the saliva of 26/65 (40.0%) patients and in 12/65 (18.5%) salivary glands. Xerostomia was reported by 23/65 (35.4%) patients, and hyposalivation was diagnosed in 13/65 (20.0%) patients. Sialadenitis was confirmed by histopathological features in 31/65 (47.7%) patients. Twelve (38.7%) of the 31 patients with sialadenitis presented HCV RNA in saliva and 2/31 (6.5%) in salivary glands. No associations were found between xerostomia, hyposalivation or sialadenitis and the detection of HCV RNA in saliva or in salivary glands. CONCLUSIONS: Although xerostomia, hyposalivation and sialadenitis are frequent findings in CHC patients, our study did not confirm the association between the detection of HCV RNA in saliva or salivary glands with these salivary gland disorders. However, an indirect role of HCV by immune-mediated virus mechanisms in the pathogenesis of salivary gland disorders in this group of patients cannot be ruled out.

[Viral sialadenitis]. / Virale Speicheldrüsenentzündungen.

Beside a secondary, clinically latent salivary virus secretion, differentiation can be made between concomitant sialadenitis induced by various viruses and viral sialadenitis showing characteristic and/or pathognomonic morphological and clinical features, whereby sialadenotropism must also be present. Viremia induces a viral inflammatory reaction via a local cytopathogenetic effect. Clinically important viral diseases include epidemic parotitis (mumps), cytomegaly and HIV infection presenting with large lymphoepithelial cystic lesions.

Non-HIV viral infections of the salivary glands.

Historically, the most significant non-HIV viral infection of salivary glands has been, and remains, mumps. Despite the widespread administration of mumps vaccines worldwide, sporadic outbreaks continue to be reported. Epidemiologic studies are invaluable in understanding the etiology of these outbreaks. Information gleaned from these studies, coupled with advances in immunology, virology, and DNA/RNA testing will hopefully result in the development of vaccination regimens to ensure eradication of the disease.

HIV-associated salivary gland disease.

The authors review the clinical presentation, diagnostic evaluation, and treatment modalities for salivary gland enlargement in an HIV-infected population. Because this can occasionally be the presenting clinical symptom of HIV infection, it is important for the oral/maxillofacial surgeon to diagnose and manage HIV salivary gland enlargement.

Oral diseases associated with hepatitis C virus infection. Part 1. sialadenitis and salivary glands lymphoma.

Morbidity associated with hepatitis C virus (HCV) infection is due not only to the sequelae of chronic liver disease, but also to a variety of extraheaptic manifestations (EHM). Some of the most frequently reported EHM of HCV infection involves the oral region predominantly or exclusively and they are the topics of this 2-part review. The current part 1 discusses the evidences on the association of salivary glands disorders with HCV. HCV- infected patients may frequently have histological signs of Sjögren-like sialadenitis with mild or even absent clinical symptoms. However, the pathogenetic role of HCV in Sjogren Syndrome (SS) development and the characteristics distinguishing classic SS from HCV-related sialadenitis are still an issue. It is unclear if the virus may cause a disease mimicking primary SS or if HCV is directly responsible for the development of SS in a specific subset of patients. Notably, some patients may present a triple association between HCV, SS-like sialadenitis and salivary gland lymphoma and the virus may be involved in the lymphomagenesis. The risk of having a salivary gland lymphoma is particularly high in patients with mixed cryoglobulinemia. Little attention has been paid to the effects of anti-HCV treatment on sialadenitis or lymphoma development.

Human cytomegalovirus-associated oral and maxillo-facial disease.

Human cytomegalovirus is a ubiquitous pathogen with protean clinical manifestations. After initial infection, the virus remains in a persistent state in the host. Immunity plays a pivotal role in counteracting its virulence, albeit intermittent virus shedding occurs in immunocompetent individuals. Should deficiencies in immunity occur, e.g., as a consequence of AIDS or iatrogenic immunosuppression, then virus replication and subsequent pathogenic manifestations ensue. In the oral and maxillo-facial region, the virus causes a wide variety of diseases, mainly atypical chronic ulcerations and sialadenitis. These morbidities are rarely reported and sometimes cause significant problems for clinicians.

Severe focal sialadenitis and dacryoadenitis in NZM2328 mice induced by MCMV: a novel model for human Sjögren's syndrome.

The genetic and environmental factors that control the development of Sjögren's syndrome, an autoimmune disease mainly involving the salivary and lacrimal glands, are poorly understood. Viruses which infect the glands may act as a trigger for disease. The ability of sialotropic murine CMV (MCMV) to induce acute and chronic glandular disease was characterized in an autoimmune-prone mouse strain, NZM2328. MCMV levels were detectable in the salivary and lacrimal glands 14-28 days after i.p. infection and correlated with acute inflammation in the submandibular gland. After latency, virus was undetectable in the glands by PCR. At this stage, NZM2328 female mice developed severe chronic periductal inflammation in both submandibular and lacrimal glands in contrast to the much milder infiltrates found in female B6-lpr and male NZM2328. The focal infiltrates consisted of CD4+ and B220+ cells as opposed to diffuse CD4+, CD8+, and B220+ cells during acute infection. Salivary gland functional studies revealed a gender-specific progressive loss of secretory function between days 90 and 125 postinfection. Latent MCMV infection did not significantly affect the low incidence of autoantibodies to Ro/SSA and La/SSB Ags in NZM2328 mice. However, reactivities to other salivary and lacrimal gland proteins were readily detected. MCMV infection did not significantly alter the spontaneous onset of kidney disease in NZM2328. Thus, chronic inflammation induced by MCMV with decreased secretory function in NZM2328 mice resembles the disease manifestations of human Sjögren's syndrome.

Non-neoplastic salivary gland diseases.

A wide range of non neoplastic disorders can affect the salivary glands, although the more common are: mumps, acute suppurative sialadenitis, Sjögren's syndrome and drug-induced xerostomia. Salivary dysfunction is not a normal consequence of old age, and can be due to systemic diseases, medications or head and neck radiotherapy. Diagnosis of salivary disorders begins with a careful medical history, followed by a cautious examination. While complaints of xerostomia may be indicative of a salivary gland disorder, salivary diseases can present without symptoms. Therefore, routine examination of salivary function must be part of any head, neck, and oral examination. Health-care professionals can play a vital role in identifying patients at risk for developing salivary dysfunction, and should provide appropriate preventive and interventive techniques that will help to preserving a person's health, function, and quality of life. The present work provides an overview of most of the non neoplastic disorders of the salivary glands, in which the general presentation, pathology, and treatments are discussed.

Extrahepatic immunological complications of hepatitis C virus infection.

Chronic hepatitis C virus (HCV) infection is frequently associated with a number of extrahepatic complications. In the majority of cases the underlying pathogenetic mechanisms are immune mediated, as evidenced by the presence of circulating autoantibodies (mixed cryoglobulinemia), whereas for others a localized host cellular immune response is implicated (e.g. sialadenitis, lichen planus). In this review, the latest data on the pathogenesis and clinical manifestations of the most common autoimmune extrahepatic manifestations of chronic HCV infection are presented.