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.

Prevalence of ulcerative stomatitis in arbovirus infections in a Brazilian Northeast population

BACKGROUND: Although there are no population-based studies that support an association, there are reports in the literature of mucocutaneous, vesiculobullous and ulcerated lesions in the oral mucosa in cases of arbovirus infection. The aim of this study is to analyze the prevalence of ulcerative stomatitis in individuals affected by arboviruses in a population of the municipality of Arcoverde, Pernambuco, Brazil. MATERIAL AND METHODS: 1,003 people living in an area assigned to a Primary Health Care Unit were interviewed. A structured questionnaire was used for data collection, with questions about sociodemographic variables, residence conditions, general health information, as well as information about the general signs and symptoms of arboviruses and specifically about oral lesions. RESULTS: Of the 1,003 individuals interviewed, 815 (81.25%) were infected by one or more arboviruses. Of these, 147 (18%) reported ulcerated oral lesions during arbovirus infections. The association between arbovirus infections and the presence of ulcerated oral lesions was statistically significant (p = 0.000). CONCLUSIONS: In these cases, the ulcerated lesions on the oral mucosa appear to be associated with arbovirus infection, especially Chikungunya, although the pathophysiological mechanisms are not defined, and the studies are not sufficient to confirm this association

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Oral ulcers and necrotizing gingivitis in relation to HIV-associated neutropenia: a review and an illustrative case.

An unusual case of necrotizing gingivitis and neutropenic oral ulcers in an HIV-seropositive patient is presented. In spite of a very low CD4(+) T cell count and severe neutropenia, the necrotizing gingivitis responded favorably to standard periodontal treatment, and the oral ulcers healed after administration of granulocyte colony-stimulating factor (G-CSF). Nonspecific oral ulcers in HIV-seropositive subjects with neutropenia should be regarded as neutropenic ulcers. The term nonspecific ulcers should be restricted to those ulcers with nonspecific histopathological features in patients without neutropenia or a nutritional deficiency such as iron, folic acid, and vitamin B.

Severe presentation of necrotizing ulcerative periodontitis in a Nigerian HIV-positive patient: a case report.

OBJECTIVE: To report a case of severe necrotizing ulcerative periodontitis (NUP) with a rarely associated sequestrum formation in a Nigerian HIV-positive patient. CLINICAL PRESENTATION AND INTERVENTION: A 47-year-old HIV-positive male patient with no history of previous dental visits presented with a severe toothache in his lower jaw of 4 weeks' duration, which had affected his ability to chew properly. Clinical examination revealed marked gingival inflammation, moderate gingival recession and mobility of some of his lower anterior teeth: 31, 32, and 33. There was also a sequestrum present associated with the affected teeth. His CD4 cell count was 226 cells/mm(3). His viral load was very high (360,082 copies/ml). The intervention included thorough debridement of the necrotic lesion and sequestrectomy. The patient responded well to treatment after 1 week of follow-up. Unfortunately, the CD4 count was not assessed further because the patient was lost to follow-up. CONCLUSION: This case showed that a high CD4 cell count does not necessarily prevent the occurrence of NUP in HIV-positive patients. Intervention might have enhanced a rapid positive response to the treatment within a short time.

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.

Predicting HIV in a public dental facility using group I oral lesions.

UNLABELLED: Group I oral lesions have been strongly associated with HIV and in resource-poor settings could be useful predictors of HIV. No study has evaluated the predictability of these lesions in diagnosing HIV/AIDS in patients who attend dental public facilities in South Africa. OBJECTIVES: To determine the HIV status, prevalence of Group I oral lesions and their predictive value amongst patients attending a dental clinic in Soweto, South Africa. METHODS: This cross sectional analytical study comprised of adult patients attending a dental facility over one week in 2006. All patients underwent a clinical examination by calibrated dentists. RESULTS: A total of 165 patients (100% response) were screened of which 87 (53%) were female. The HIV prevalence was 28% (n = 46) and of those who tested positive, 15% (7) manifested with Necrotizing Ulcerative Gingivitis (NUG). This proved to be highly predictive for HIV (positive predictive value = 93.8%, specificity = 99.6% and likelihood ratio = 40). CONCLUSION: The high prevalence rate of HIV in dental facilities confirms the heavy burden of the HIV epidemic. NUG proved to be a good predictor of HIV in this setting.

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.

Acute necrotizing ulcerative gingivitis and bacteremia caused by Stenotrophomonas maltophilia in an immunocompromised host.

An 8-year-old girl with leukemia developed acute necrotizing ulcerative gingivitis with Stenotrophomonas maltophilia and herpes simplex virus. Progression to bacteremia with pathologic evidence of osteomyelitis occurred despite appropriate antimicrobial therapy. This case highlights the importance of prompt recognition, debridement and appropriate therapy in immunocompromised patients with acute necrotizing ulcerative gingivitis.

Herpesviruses in human periodontal disease.

Recent studies have identified various herpesviruses in human periodontal disease. Epstein-Barr virus type 1 (EBV-1) infects periodontal B-lymphocytes and human cytomegalovirus (HCMV) infects periodontal monocytes/ macrophages and T-lymphocytes. EBV-1, HCMV and other herpesviruses are present more frequently in periodontitis lesions and acute necrotizing ulcerative gingivitis-lesions than in gingivitis or periodontally healthy sites. Reactivation of HCMV in periodontitis lesions tends to be associated with progressing periodontal disease. Herpesvirus-associated periodontitis lesions harbor elevated levels of periodontopathic bacteria, including Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Bacteriodes forsythus, Prevotella intermedia, Prevotella nigrescens and Treponema denticola. It may be that active periodontal herpesvirus infection impairs periodontal defenses, thereby permitting subgingival overgrowth of periodontopathic bacteria. Alteration between latent and active herpesvirus infection in the periodontium might lead to transient local immunosuppression and explain in part the episodic progressive nature of human periodontitis. Tissue tropism of herpesvirus infections might help explain the localized pattern of tissue destruction in periodontitis. Absence of herpesvirus infection or viral reactivation might explain why some individuals carry periodontopathic bacteria while still maintaining periodontal health. Further studies are warranted to delineate whether the proposed herpesvirus-periodontopathic bacteria model might account for some of the pathogenic features of human periodontal disease.

Necrotizing ulcerative stomatitis in human immunodeficiency virus-seropositive individuals: a review of the histopathologic, immunohistochemical, and virologic characteristics of 18 cases.

OBJECTIVE: The purpose of this retrospective study was to delineate the histopathologic, immunohistochemical, and virologic characteristics of 18 cases of necrotizing ulcerative stomatitis. STUDY DESIGN: Eighteen examples or oral ulcerations in human immunodeficiency virus-seropositive individuals were identified that displayed unique histopathologic features. Immunohistochemic staining for CD1a, CD3, CD23, CD68, HLA-DR, p24, cytomegalovirus, HSV-1, and HSV-2 was performed, along with in situ hybridization for Epstein-Barr virus RNA and special staining for bacteria and fungi. RESULTS: The lesions demonstrated ulceration, extensive necrosis, leukocytoclasia, histiocytic vasculitis with luminal fibrin clots, and a prominent infiltrate of large atypical cells with amphophilic cytoplasm, vesicular nuclei, and prominent nucleoli, interspersed with crescentic histiocytes, a histologic picture resembling extranodal Kikuchi's disease. Immunohistochemical findings suggested that the large atypical cells were histiocytes. Fifty-six percent (10/18) of the cases were immunoreactive for human immunodeficiency virus p24 within focal histiocytes, whereas Epstein-Barr virus RNA was identified in 1 (6%) of 17 cases. CONCLUSIONS: Necrotizing ulcerative stomatitis is an inflammatory disease characterized by specific, reproducible microscopic features. We postulate that the histopathologic resemblance of necrotizing ulcerative stomatitis to extranodal Kikuchi's disease reflects a similar immune response to differing pathogens.

Herpesviruses: a unifying causative factor in periodontitis?

Human cytomegalovirus and Epstein-Barr virus type 1 are discussed in this review as they relate to destructive periodontal disease in humans. Genomes of the two herpesviruses occur frequently in severe adult periodontitis, localized and generalized juvenile periodontitis, Papillon-Lefèvre syndrome periodontitis, Down's syndrome periodontitis, HIV-associated periodontitis and acute necrotizing ulcerative gingivitis. Herpesvirus infections generally involve a mild or asymptomatic primary phase followed by an asymptomatic latent phase interrupted sporadically by periods of activation, where viral replication and possibly clinical disease become manifest. Herpesvirus reactivation is triggered by a number of immunosuppressing factors, some of which have also been shown to be risk indicators of periodontal disease. Available evidence argues for the involvement of active cytomegalovirus infection in the initiation and progression of localized juvenile periodontitis and possibly other types of periodontal disease. In periodontal disease, herpesviruses may cause release of tissue-destructive cytokines, overgrowth of pathogenic periodontal bacteria, and initiation of cytotoxic or immunopathogenic events. Understanding the significance of herpesviruses in the causation and pathogenesis of destructive periodontal diseases may have important implications in future prevention and treatment of the diseases.

Microbiological understandings and mysteries of noma (cancrum oris).

The microbiologic history of noma was reviewed. Studies have associated the disease process with large numbers of fusiform bacilli and spirochetal organisms. In order to study the microbiology of the staging and infection periods of noma 62 Nigerian children, aged 3-14 years, 22 children had acute necrotizing ulcerative gingivitis (ANUG) and were also malnourished, 20 exhibited no acute necrotizing ulcerative gingivitis but were malnourished and 20 were free of acute necrotizing ulcerative gingivitis and in good nutritional state) were evaluated for the presence of viruses and oral microorganisms. The ANUG cases in the malnourished children had a higher incidence of Herpesviridae, the main virus being detected was cytomegalovirus. There were more anaerobic microorganisms recovered, with Prevotella intermedia as the predominant isolate, in the malnourished children as compared to the healthy children. A study of the predominant microflora in active sites of noma lesions was carried out in eight noma patients, 3-15 years of age, in Sokoto State, northwestern Nigeria. Fusobacterium necrophorum was recovered from 87.5% of the noma lesions. Oral microorganisms isolated included Prevotella intermedia, alpha-hemolytic streptococci and Actinomyces spp. which were isolated from 75.0, 50.0 and 37.5% of the patients, respectively. Peptostreptococcus micros, Veillonella parvula, Staphylococcus aureus and Pseudomonas spp. were each recovered from one lesion. All strains were observed to be sensitive to all of the antibiotics tested with the exception of one strain of P. intermedia which showed resistance to penicillin. The pathogenic mechanisms of F. necrophorum as a trigger organism were discussed. The isolation from human noma lesions of F. necrophorum, a pathogen primarily associated with animal diseases, may have important etiologic and animal transmission implications.

Human Herpesviridae in acute necrotizing ulcerative gingivitis in children in Nigeria.

Herpesviruses have been implicated in the pathogenesis of human periodontitis. The present study investigated whether herpesviruses are present in the lesions of acute necrotizing ulcerative gingivitis. Sixty-two Nigerian children, aged 3-14 years, were studied. Twenty-two children had acute necrotizing ulcerative gingivitis and were also malnourished, 20 exhibited no acute necrotizing ulcerative gingivitis but were malnourished and 20 were free of acute necrotizing ulcerative gingivitis and in a good nutritional state. Polymerase chain reaction methods were used to determine the presence of human cytomegalovirus (HCMV), Epstein-Barr virus type 1 and type 2 (EBV-1, EBV-2), herpes simplex virus (HSV), human herpes virus 6 (HHV-6), human papilloma virus and human immunodeficiency virus type 1 in crevicular fluid specimens collected by paper points. Of the 22 acute necrotizing ulcerative gingivitis patients, 15 (68%) revealed viral infection and 8 (36%) viral coinfection. Thirteen (59%) acute necrotizing ulcerative gingivitis patients demonstrated HCMV, 6 (27%) EBV-1, 5 (23%) HSV and 1 (5%) HHV-6. Only 2 (10%) subjects from each group not affected by acute necrotizing ulcerative gingivitis showed viral presence, and no control subject revealed viral coinfection. These findings suggest that HCMV and possibly other herpesviruses contribute to the onset and/or progression of acute necrotizing ulcerative gingivitis in malnourished Nigerian children.

PIP: Recent laboratory studies have implicated herpesviruses in the pathogenesis of human periodontitis. This present study examines whether herpesviruses are present in the lesions of acute necrotizing ulcerative gingivitis. A total of 62 Nigerian children, aged 3-14 years were studied: 22 had acute necrotizing ulcerative gingivitis and were also malnourished, 20 showed no acute necrotizing ulcerative gingivitis but were malnourished, and 20 were free of acute necrotizing ulcerative gingivitis and in a good nutritional state. A polymerase chain reaction assay was used to determine the presence of human cytomegalovirus (HCMV), Epstein-Barr virus type 1 and type 2 (EBV-1, EBV-2), herpes simplex virus (HSV), human herpes virus 6 (HHV-6), human papilloma virus, and HIV-1 in crevicular fluid samples obtained by paper points. Of the 22 patients with acute necrotizing ulcerative gingivitis, 15 (68%) showed viral infection and 8 (36%) showed a viral coinfection. In addition, 13 (59%) of these patients demonstrated HCMV, 6 (27%) EBV-1, 5 (23%) HSV, and 1 (5%) HHV-6. Only 2 (10%) subjects from each group not affected by acute necrotizing ulcerative gingivitis revealed viral presence, and none of the control group demonstrated viral coinfection. The findings suggest that HCMV and possibly other herpesviruses contribute to the onset and/or progression of acute necrotizing ulcerative gingivitis in malnourished children in Nigeria.