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.

Clinical and immunological features of chronic ulcerative stomatitis: A systematic review.

Chronic ulcerative stomatitis (CUS) is a rare disease of the mucous membranes with characteristics similar to other autoimmune diseases. The aim of this study was to conduct a systematic review of the literature to recover all reported cases of CUS in order to summarize what are the clinical, demographic, microscopic, immunological features of CUS and its therapeutic response to different drugs. A systematic review of the literature was carried out following the statements of preferred reporting items for systematic reviews and meta-analyses (PRISMA). The searches were performed in the electronic databases PubMed, Scopus, EMBASE, LILACS, Opengrey, and Google scholar. Inclusion criteria were articles or abstracts reporting at least one case with a final diagnosis of CUS. A total of 696 records were identified through databases, and 25 studies were selected reporting 81 cases. CUS affects more females (92%), and a greater number of cases are reported in Caucasian patients (53%). The age of patients ranged from 20 to 86 years with a mean age of 60 years (±13.86), and 15% of cases reported concomitantly skin lesions. The clinical and histopathological characteristics of CUS are very similar to those of oral lichen planus. The direct immunofluorescence (DIF) remains the gold-standard diagnostic resource and was performed in 69 cases, revealing a dotted pattern of deposition of stratified epithelium-specific antibodies (SES-ANA). The serum of 38 patients was collected for the performance of the indirect immunofluorescence (IIF), and the use of epithelial substrates such as monkey and guinea pig esophagus often resulted in positive SES-ANA IgG. Most patients were treated with antimalarials, and the treatment of choice that proved to be effective is hydroxychloroquine (HCQ). This entity must be considered in the differential diagnosis of other autoimmune diseases, as it may be underreported.

Chronic Ulcerative Stomatitis (CUS) as an Interdisciplinary Diagnostic Challenge: A Literature Review.

Chronic ulcerative stomatitis (CUS) is a rarely reported disease affecting the oral cavity, most often affecting middle-aged Caucasian females. The aim of the present study is to present the diagnosis, differentiation, and interdisciplinary treatment of this rare disease. CUS is characterized by the presence of an oral erosive or ulcerative lesion. The autoimmune pathogenesis of CUS includes affecting the antigen's activity by DNA-breaking and protein-hydrolyzing enzymes. The stratified epithelium-specific antinuclear antibodies (SES-ANA) are associated with CUS development. Clinically, the lesions presented in oral mucosa might resemble an erosive form of oral lichen planus, whereas gingival lesions seem to be similar to desquamative gingivitis related to dermatological diseases manifested in the oral cavity. Patients often report subjective symptoms related to oral mucosa and general symptoms. Histopathological presentation of CUS is often non-specific and includes sub-epithelial separation from underlying connective tissue, atrophic epithelium, and inflammatory infiltrate with an increased number of plasma cells and lymphocytes. Direct immunofluorescence (DIF) might be used in CUS diagnostics. CUS generally remains nonsusceptible to corticosteroid treatments; however, antimalarial drugs and calcineurin inhibitors are more effective. Further research should be conducted in order to implement a diagnostic protocol and observe the long-term results of CUS management.

Chronic ulcerative stomatitis: A comprehensive review and proposal for diagnostic criteria.

Chronic ulcerative stomatitis (CUS) is an immune-mediated disorder characterized by oral erosions and ulcers usually refractory to conventional treatments. The disease often involves middle-aged and older women with painful lesions sometimes resembling those of erosive oral lichen planus (OLP). The most affected sites are the buccal mucosa, the gingiva and the tongue, but the skin is involved in 22.5% of cases. Histopathologic features in CUS are non-specific and indistinguishable from those of OLP, with the exception of the presence of a mixed infiltrate composed of lymphocytes and plasma cells. Direct immunofluorescence (DIF) analysis reveals the presence of stratified epithelium-specific antinuclear antibodies (SES-ANA) in the lower third of the epithelium. The IgG antibodies detected on DIF are directed against the ∆Np63α isoform of p63 expressed in the nuclei of the epithelial basal cells. A distinguishing feature of CUS is the low response to conventional corticosteroid therapy and the good outcome with hydroxychloroquine at the dosage of 200 mg/day or higher dosages. This paper presents a comprehensive review of CUS and is accompanied by a new case report (the 73rd case) and a proposal for updated diagnostic criteria.

Chronic ulcerative stomatitis: Case series of an under-recognized entity.

Chronic ulcerative stomatitis (CUS) is a mucocutaneous condition characterized by chronic relapsing and remitting oral ulcers and erosions. This condition remains under-recognized among dermatopathologists, possibly because of common misdiagnosis as oral erosive lichen planus (LP). We report five cases of CUS in order to raise awareness of this uncommon condition. All patients presented with desquamative gingivitis and/or oral erosions, with biopsies showing lichenoid mucositis and epithelial nuclear IgG deposition on direct immunofluorescence. Recognition of the characteristic direct immunofluorescence findings allows for distinction of chronic ulcerative stomatitis from oral LP and appropriate therapy.

Clinical and Histopathologic Characterization of Canine Chronic Ulcerative Stomatitis.

Canine chronic ulcerative stomatitis, also known as chronic ulcerative paradental stomatitis, is a painful condition of the oral cavity. The purpose of this study was to determine if there are commonalities in clinical and radiographic features among patients, whether the histopathologic evaluation might inform the pathogenesis, and whether the condition appears similar to human oral mucosal diseases. To do this, we prospectively collected clinical, radiographic, and histopathologic data from 20 dogs diagnosed with the disease. Clinical data were based on a clinical disease activity index, oral and periodontal examination parameters, and full-mouth dental radiographs. The histopathological and immunohistochemical data were based on oral mucosal samples obtained from erosive or ulcerated areas. Our findings revealed that canine chronic stomatitis is clinically characterized by painful oral mucosal ulcers of varying size, pattern, appearance, and distribution, most often associated with teeth with early periodontitis. Histologic examination revealed a subepithelial lichenoid band (interface mucositis) where B cells, T cells, and Forkhead-box protein 3 (FoxP3)- and interleukin-17-expressing cells were present. These cells might play a role in the underlying immune response and an immune-mediated pathogenesis is suspected. The clinical and histopathologic features of this chronic inflammatory mucosal disease in dogs resemble those of oral lichen planus in humans.

[Necrotizing ulcerative diseases in military population].

Necrotizing ulcerative diseases were prevalent in military personnel throughout history. Nowadays, its prevalence declined substantially in industrialized countries. Studies among immunocompromised patients suggest it is still a reason for concern among this population. We present two cases diagnosed and treated at our department. It seems that necrotizing ulcerative diseases are still a relevant entity in the Israeli Defense forces therefore it is of great importance to conduct proper diagnosis, treatment and follow up of the patients.

[NUG--necrotizing ulcerative gingivitis: a review].

Necrotizing Ulcerative Gingivitis (NUG) is an acute and rare (0.5-11% of the population) infectious disease of the gum tissue, which is characterized by ulceration and inflammation of the inter-dental gum tissue. NUG was documented by historians since the fourth century BC, most of the reports from the ancient world were in the context of illness among fighting troops, present studies of NUG in the modern world are still common among soldiers. NUG is associated with poor oral hygiene and weakening of the host, especially in immunocompromised patients, malnutrition and poor living conditions, as well as in the context of mental stress. NUG is more common in young adults, but reports of morbidity in young children with malnutrition in the background are not uncommon. NUG diagnosis is based on three essential symptoms: sore gums, bleeding gums and the most diagnostic characteristic, ulceration and necrosis of the interdental papillae. The disease is considered to have a clear initial infectious etiology, when the main bacteria, associated with the disease, include: Bacteroides intermedius and Fusobacterium sp. The infection involves anaerobic \ aerobic bacteria with a majority of Gram-negative bacteria. The treatment of NUG is based on combining mechanical removal of tartar with local and systemic delivery of antimicrobial agents. Adequate treatment usually prevent the progression of the disease and ulcer healing is expected in a few days. Nevertheless, lack of treatment can lead to deterioration in the form NUP to Noma.

Periodontal diseases in children and adolescents: a clinician's perspective part.

UNLABELLED: Contrasting forms of periodontal disease can affect children and adolescents with varying prevalence, severity and extent, leading to a diverse prognosis in these age groups. For an early diagnosis and treatment of periodontal conditions in young patients, it is essential for the dental practitioner to be able to identify and classify the disease correctly at the earliest opportunity, applying basic principles along with understanding of aetiology and risk factors. The first part of this article discusses the classification, plaque-induced and non-plaque-induced gingival diseases, localized and generalized forms of chronic, as well as aggressive, periodontitis. CLINICAL RELEVANCE: Knowledge of different forms of periodontal diseases affecting children and adolescents may help to distinguish between different forms of diseases and have value in screening and early diagnosis of the disease.

Chronic ulcerative stomatitis: a distinct clinical entity?

Chronic ulcerative stomatitis (CUS) is a mucocutaneous disorder which is characterised by persistent oral mucosal ulceration. The clinical appearance is often reminiscent of oral lichen planus (OLP) leading to erroneous diagnoses. The immune mediated inhibition of the CUS protein (CUSP) is implicated in the pathogenesis of CUS. CUSP acts as an anti-apoptotic protein and when its action is prevented it may result in significant epithelial injury. The objective or this article is to present the first documented case of CUS in South Africa, with relevant reference to current international literature. CUS should be considered in patients previously diagnosed with OLP but who are unresponsive to glucocorticosteroid therapy. The condition can be successfully managed using hydroxychloroquine.

[Differential diagnosis of unilateral necrotic tonsillitis]. / Differenzialdiagnostik der nekrotisierenden Tonsillitis.

BACKGROUND: The best known clinical picture of a one-sided necrotisising, infectious tonsillitis is the by Plaut and Vincent (1894) described angina Plaut-Vincent. In addition to this fusospirochetosis it is in case of necrotisising inflammations in the oropharynx differential-diagnostically important to consider also the anaerobic type Prevotella, especially Prevotella disiens as a potential trigger . MATERIAL AND METHODS: Because the clinical course forms of a necrotisising oropharyngeal inflammations can be very different and complicate so a suitable diagnosis, it is very important to get a complete and perfect cause proof. For getting this proof a correct test production, transport and cultivation are of extreme importance . RESULTS: The type Prevotella consists of different species gram-negative, obligate anaerobic strains. They are regarded as a cause of suppurating inflammations and abscesses of the genital tract and are components of the aerobic anaerobic mixed flora in case of gingival infections. The sole proof in the microbiological culture as a smear test result of a one-sided necrotisising tonsillitis has to be seen as a first description by reason of missing literature . IMPLICATION: As triggers for one-sided necrotisising tonsillitis are considered different causes. Next a carcinoma of the tonsil, Lues, Angina Plaut-Vincent have to be excluded. An infection with Prevotella disiens is an extremely rare variation in contrast. However, the transmission is possible by insufficient hygiene, lack phenomena and sexual intercourse and to consider therefore as an exclusion diagnosis.

Immunopathogenesis of canine chronic ulcerative stomatitis.

Canine Chronic Ulcerative Stomatitis is a spontaneously occurring inflammatory disease of the oral mucosa. An immune-mediated pathogenesis is suspected though not yet proven. We have recently reported on the clinical and histologic features, and identification of select leukocyte cell populations within the lesion. A clinical and histologic similarity to oral lichen planus of people was proposed. In the present study, these initial observations are extended by examining lesions from 24 dogs with clinical evidence of chronic ulcerative stomatitis. Because dogs with chronic ulcerative stomatitis often have concurrent periodontal disease, we wondered if dental plaque/biofilm may be a common instigator of inflammation in both lesions. We hypothesized that dogs with chronic ulcerative stomatitis would exhibit a spectrum of pathologic changes and phenotype of infiltrating leukocytes that would inform lesion pathogenesis and that these changes would differ from inflammatory phenotypes in periodontitis. Previously we identified chronic ulcerative stomatitis lesions to be rich in FoxP3+ and IL17+ cells. As such, we suspect that these leukocytes play an important role in lesion pathogenesis. The current study confirms the presence of moderate to large numbers of FoxP3+ T cells and IL17+ cells in all ulcerative stomatitis lesions using confocal immunofluorescence. Interestingly, the majority of IL17+ cells were determined to be non-T cells and IL17+ cell frequencies were negatively correlated with severity on the clinical scoring system. Three histologic subtypes of ulcerative stomatitis were determined; lichenoid, deep stomatitis and granulomatous. Periodontitis lesions, like stomatitis lesions, were B cell and plasma cell rich, but otherwise differed from the stomatitis lesions. Direct immunofluorescence results did not support an autoantibody-mediated autoimmune disease process. This investigation contributes to the body of literature regarding leukocyte involvement in canine idiopathic inflammatory disease pathogenesis.

Oral ulcers in HIV-positive Peruvian patients: an immunohistochemical and in situ hybridization study.

BACKGROUND: This study describes the histopathological, immunohistochemical (IHC) and in situ hybridization (ISH) data of 25 cases of oral ulcers in HIV-positive patients, with clinical and microscopical features similar to ulcers not otherwise specified (NOS)/necrotizing ulcerative stomatitis (NUS). METHODS: Sex, age and clinical history were obtained from the clinical records. Histological analysis for H&E, Gomori-Grocott and Ziehl-Neelsen stains, IHC analysis to detect infectious agents and to characterize inflammatory cellular infiltrate, and ISH for cytomegalovirus (CMV) and EBER1/2 were performed. RESULTS: Twenty-one patients were men and four were women (mean age of 34.6 years). The tongue was preferentially affected. Microscopically, the lesions showed extensive necrosis, leukocytoclasia, vasculitis with luminal fibrin clots and an intense inflammatory cellular infiltrate predominated by CD68(+) atypical large cells, normal-sized and crescent-shaped nuclei macrophages, interspersed by CD8(+) T lymphocytes. Mast cells were also observed in all samples studied. CD4(+) T lymphocytes, CD20(+) B lymphocytes and VS38c(+) plasma cells were practically absent. CMV and EBER1/2 were identified in scarce cells of 3 and 16 of 25 cases respectively. CONCLUSION: These results show that CD68(+) macrophages, followed by CD8(+) T lymphocytes, were the predominant inflammatory cells, indicating they are relevant to the pathogenesis of the ulcers, possibly reflecting an abnormal immune response in the oral mucosa. The clinicopathological and immunoprofile features of the present cases are similar to NOS ulcers/NUS in HIV-positive patients.

Seventeen New Cases of Chronic Ulcerative Stomatitis with Literature Review.

Chronic ulcerative stomatitis (CUS) is a poorly understood disease with clinical and histologic overlap with lichen planus (LP). Unlike classic LP, direct immunofluorescence (DIF) studies in cases of CUS exhibit a granular pattern of IgG in nuclei of basal and parabasal cells. This study assesses the demographic, clinical, histologic, and DIF features of CUS. It is important to differentiate CUS from LP and other vesiculobullous diseases (VBD) because lesions of CUS are resistant to steroid therapy, which is typically used to control LP and VBD. A literature review and IRB-approved retrospective search of CUS was performed within the archives of the University of Florida (UF) Oral Pathology Biopsy Service from 2007 to 2017. Fifty-two cases were identified from the literature and seventeen new cases were identified in our series. All UF patients were female and the median age was 64-years. The majority of patients were Caucasian and the most common location was buccal mucosa. Frequent clinical presentations were pain, erythema, leukoplakia, and ulcerations. Histologic features included epithelial separation, atrophic epithelium, and a chronic inflammatory infiltrate. All cases were confirmed with DIF testing that showed a speckled pattern of IgG staining in basal and parabasal cell nuclei. Fibrinogen was present in eleven cases and two cases were positive for C3. The results of our series are in accordance with the literature. Since CUS has overlapping features with LP and VBD, clinicians and pathologists should consider this entity and confirm diagnosis with DIF testing when recalcitrant oral ulcerative diseases are encountered.

Identification of bacteria present in ulcerative stomatitis lesions of captive sea turtles Chelonia mydas.

Anthropogenic activities, predation, and diseases have contributed to a decrease in the sea turtle population in recent years. Ulcerative stomatitis is a condition that occurs in both wild and captive populations. The etiology of this condition is associated with bacteria such as E. coli, Citrobacter diversus, Klebsiella spp., Pseudomonas spp., Flavobacter calcoaceticus, Staphylococcus spp., and Flavobacterium spp. Some of these microorganisms are part of the oral microbiota of turtles, but alterations in the immune response can disturb the homeostatic relationship and cause an increase in the population of microorganisms, which in turn can cause disease. This work presents results on the isolation and identification of bacteria present in ulcerative stomatitis lesions in captive C. mydas turtles. Oral mucosa samples from 20 clinically healthy turtles and ten animals with ulcerative stomatitis lesions were studied. The samples were cultivated in enriched and differential media, and the identification was made using an automated method. The results showed a great diversity of bacteria in animals with ulcerative stomatitis with a higher prevalence of S. lentus and C. braakii was higher (60 and 50%, respectively) than in healthy animals. E. faecium was identified in 40% of diseased animals and 55% healthy animals. Turtles in this study had a diverse oral microbiota, and S. lentus and C. braakii may be involved in the etiopathogenesis of ulcerative stomatitis.

Necrotizing gingivitis of Kaposi sarcoma affected gingivae.

Necrotizing gingivitis and oral Kaposi sarcoma are common concomitants of HIV infection and both are regarded as indicators of HIV infection. Their simultaneous appearance in an HIV seropositive subject therefore, should be relatively common; but other reports documenting such cases could not be found. This article documents an uncommon case of necrotizing gingivitis superimposed on Kaposi sarcoma-affected gingiva, occurring in a patient with chronic periodontitis. The nature of necrotizing gingivitis and Kaposi sarcoma and the possible differential diagnosis of the periodontal attachment loss are discussed.

Necrotizing ulcerative periodontal diseases in children and young adults in Medellín, Colombia, 1965--2000.

Previous findings that necrotizing ulcerative gingivitis (NUG) is a precursor to noma or cancrum oris were confirmed by the follow-up of these clinical conditions in a study of 45 Colombian patients: necrotizing ulcerative gingivitis (NUG, n = 29), necrotizing ulcerative periodontitis (NUP, n = 7) and noma (n = 9). Patients were diagnosed at the outpatient clinic of the School of Dentistry at the University of Antioquia, at the University Hospital Saint Vincent of Paul, at the Luz Castro de Gutierrez University Hospital, at the Red Cross Hospital and at the private office of one of the authors (Jiménez L., M) in Medellín, Colombia, from 1965 until 2000. Almost all the patients came from low socioeconomic groups and presented with predisposing and/or contributing factors, such as acute herpetic gingivostomatitis, measles, and leukemia (including acute lymphoblastic and chronic lymphoid leukemia). Malnutrition and poor oral hygiene were associated with the necrotizing process and favored progression from the gingiva to deeper periodontal tissues and other structures within the oral cavity or the facial tissues. No patients had human immunodeficiency virus (HIV) or AIDS, which makes these findings different from other reports. Noma can be prevented by vaccinating children against infectious diseases, by controlling malnutrition and by improving their oral hygiene. It is arrested by mechanical lesion debridement, improving oral hygiene and antibiotic therapy. Necrotizing ulcerative gingivitis may progress in some cases to ulcerative necrotizing stomatitis, necrotizing ulcerative periodontitis, and, finally, to noma. Microbial studies among new Colombian NUG, NUP and noma patients are necessary, using bacterial culturing and identification methods and molecular techniques such as PCR for viruses and bacteria, in order to establish the exact nature of these lesions.

The diagnostic challenges of separating chronic ulcerative stomatitis from oral lichen planus.

OBJECTIVE: To attempt to establish criteria to differentiate between chronic ulcerative stomatitis (CUS) and oral lichen planus (OLP) with hematoxylin and eosin (H&E) staining alone. STUDY DESIGN: Ten confirmed cases of CUS were reviewed from the Stomatology Clinic at the Texas A&M University Baylor College of Dentistry. RESULTS: The original diagnosis on H&E evaluation was OLP, chronic mucositis, or mucositis with lichenoid features, but subsequent direct immunofluorescence (DIF) revealed a positive speckled intranuclear deposition of immunoglobulin G (IgG) in the basal and parabasal layers of the epithelium, confirming a diagnosis of CUS. CONCLUSIONS: No consistent histopathologic features were present that would allow recognition of CUS from H&E analysis alone. DIF remains the gold standard for diagnosis.