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.

Papular-purpuric gloves and socks syndrome due to parvovirus B19: a report of two simultaneous cases in cohabitant families.

The so-called papular-purpuric gloves and socks syndrome (PPGSS) is a condition characterized by acute onset of intense erythema, edema and petechiae with a typical localization on the hands and feet, besides mucosal lesions of the oral cavity. The syndrome has a favorable and self-limited course, requiring only a symptomatic therapy. In the 50% of the cases described in literature (ninety cases in 22 years), is documented an acute infection caused by parvovirus B19 and in only two cases the onset of PPGSS is reported among different members of the same family. The aim of the work is to describe two cases of PPGSS arisen during a short time period in two family members affected by an acute parvovirus B19 infection found by serum sampling. The peculiarity of the study was the infrequence of the syndrome and the rareness of the description of PPGSS in rheumatology. This syndrome is usually described in dermatology, but it is also interesting for the rheumatologist because it comes in differential diagnosis with various autoimmune diseases.

Clinical assessment of disease severity in recurrent aphthous stomatitis.

BACKGROUND: Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases in many parts of the world. However, there is very limited published clinical evidence for the therapies used in this condition. This could be partly due to the difficulty in evaluating the efficacy of oral ulcer treatment objectively. In this paper, we present a method for assessing and monitoring the severity of oral ulcers before and after treatment. METHODS: Six ulcer characteristics, number, size, duration, ulcer-free period, site and pain, were used to generate an ulcer severity score (USS). The scores for 223 RAS patients were determined, and 79 were scored again after 3-month therapy with topical betamethasone. RESULTS: The scores for the minor RAS group were between 18 and 43 (mean 29.2 ± 5.3). The mean score in the major ulcers group (range: 28-60, mean 39.9 ± 6.1) was significantly greater than in the minor group (P < 0.001). The herpetiform recurrent ulcers score range was wide (range: 18-57, mean 36.6 ± 8.4). The mean severity score decreased significantly after treatment (P < 0.001). CONCLUSIONS: The USS was indicative of the disease activity in recurrent oral ulceration. It helped in assessing the efficacy of therapy, as the change in the numerical score reflected the change in ulcer severity in response to treatment. This tool may well prove to be of value in clinical management, research and in clinical trials.

Comparative genome analysis provides insights into the evolution and adaptation of Pseudomonas syringae pv. aesculi on Aesculus hippocastanum.

A recently emerging bleeding canker disease, caused by Pseudomonas syringae pathovar aesculi (Pae), is threatening European horse chestnut in northwest Europe. Very little is known about the origin and biology of this new disease. We used the nucleotide sequences of seven commonly used marker genes to investigate the phylogeny of three strains isolated recently from bleeding stem cankers on European horse chestnut in Britain (E-Pae). On the basis of these sequences alone, the E-Pae strains were identical to the Pae type-strain (I-Pae), isolated from leaf spots on Indian horse chestnut in India in 1969. The phylogenetic analyses also showed that Pae belongs to a distinct clade of P. syringae pathovars adapted to woody hosts. We generated genome-wide Illumina sequence data from the three E-Pae strains and one strain of I-Pae. Comparative genomic analyses revealed pathovar-specific genomic regions in Pae potentially implicated in virulence on a tree host, including genes for the catabolism of plant-derived aromatic compounds and enterobactin synthesis. Several gene clusters displayed intra-pathovar variation, including those encoding type IV secretion, a novel fatty acid biosynthesis pathway and a sucrose uptake pathway. Rates of single nucleotide polymorphisms in the four Pae genomes indicate that the three E-Pae strains diverged from each other much more recently than they diverged from I-Pae. The very low genetic diversity among the three geographically distinct E-Pae strains suggests that they originate from a single, recent introduction into Britain, thus highlighting the serious environmental risks posed by the spread of an exotic plant pathogenic bacterium to a new geographic location. The genomic regions in Pae that are absent from other P. syringae pathovars that infect herbaceous hosts may represent candidate genetic adaptations to infection of the woody parts of the tree.

Aids e estomatite aftóide recidivante / AIDS and recurrent aphtous stomatitis

O estado de imunodeficiência em pacientes HIV positivos tem sido causa de episódios severos de Estomatite Aftóide Recidivante (EAR). OBJETIVO: Este estudo objetiva estabelecer evidências da relação entre o surgimento (ou agravamento) de EAR com o estado de imunossupressão causado pelo vírus HIV, por meio da contagem de células CD4+, CD8+ e da carga viral infectante. FORMA DE ESTUDO: estudo de série. MATERIAL E MÉTODO: Noventa e quatro pacientes HIV (1)-positivos (25 mulheres e 69 homens) com EAR foram acompanhados no ambulatório de Aids da Divisão de Clínica ORL do Hospital das Clínicas da FMUSP no período de janeiro de 1998 a dezembro de 2003. A idade dos pacientes variou de 19 a 63 anos (média = 35,3 anos). RESULTADO: Os pacientes com Aids e soropositivos apresentaram, respectivamente, oito aftas e duas aftas por surto. Da mesma maneira, os pacientes portadores de úlceras do tipo major apresentaram menor contagem de células CD8+, CD4+ e relação CD4+/CD8+ e maior valor médio da carga viral do que os pacientes portadores de aftas herpetiformes e minor. Entre os portadores de aftas minor e herpetiforme não houve diferença estatística. CONCLUSÕES O aparecimento das lesões, principalmente as do tipo major, está diretamente relacionado ao estado imunitário do paciente soropositivo, acarretando déficits nutricionais e piora na qualidade de vida. Desta forma, o diagnóstico e tratamento da EAR é um desafio que não deve ser desprezado.

AIDS and Recurrent Aphthous Stomatitis.

UNLABELLED: The immunodeficiency state in HIV infected patients has been the cause of severe episodes of Recurrent Aphthous Stomatitis (RAS). AIM: Our study aims to establish correlation between the manifestations of RAS and the immunosuppression state caused by HIV infection, through counting of CD4+ cells, CD8+ cells, CD4+:CD8+ cells ratio and viral load. STUDY DESIGN: Series study. MATERIAL AND METHOD: Ninety-four HIV infected patients (25 women and 69 men) with RAS were evaluated in the ENT Department of the University of Sao Paulo-Medical School from January 1998 to December 2003. The age ranged between 19 and 63 years (mean = 35.3 years). The patients were divided in two groups: AIDS group and HIV infected group. RESULTS: The patients with AIDS and HIV infection presented, respectively, eight ulcers and two ulcers by outbreaks. Similarly, patients with major RAS presented smaller counting of cells CD8+, CD4+ and CD4+/CD8+ cells, and higher mean value of viral load than the patients with herpetiform and minor RAS. Between patients with minor and herpetiform RAS there were no statistical differences. CONCLUSIONS: The emergence of the lesions, mainly in major RAS, is directly related to the immunological state of the HIV infected patient. These patients frequently present nutritional deficits and worsening in life style. Thus, diagnosis and treatment of RAS is a challenge that should not be neglected.

Fatal hepatic failure secondary to acute herpes simplex virus infection.

Acute hepatitis with severe hepatic failure is an uncommon manifestation of herpes simplex virus (HSV) infection. It has been described in both immunocompromised and immunocompetent patients and is usually fatal. Due to the better survival after acyclovir treatment in a few reported cases, physicians need to be aware of the characteristic clinical abnormalities so that early diagnosis and treatment can be implemented. The authors describe an adolescent diagnosed with Hodgkin disease who developed fatal hepatic failure secondary to acute HSV. Typical signs and symptoms in patients at risk, when there is no other obvious cause of fulminant hepatitis, should lead to early empirical treatment with acyclovir.

Mechanisms of expression of HHV8, EBV and HPV in selected HIV-associated oral lesions.

Opportunistic DNA viruses, particularly members of the herpesvirus family, are frequently the aetiological agents of HIV-associated oral lesions. Oral lesions common to the early phase of the AIDS epidemic, including Kaposi's sarcoma (KS), oral aphthous ulceration, AIDS-associated oral lymphoma, and oral hairy leukoplakia (OHL), have been tested for the prevalence of Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). While EBV DNA is detected by PCR in all of these lesions, abundant viral replication can only be detected in OHL. In OHL, a novel state of EBV infection has been discovered with concurrent expression of replicative and transforming proteins, with all of these proteins contributing to the development of the lesion. Activation of signalling pathways and up-regulation of the viral receptor, proliferative and antiapoptotic genes by these proteins induce several of the histological features common to OHL, such as acanthosis and hyperproliferation. In contrast to other permissive herpesvirus infections, expression of EBV transforming proteins within the permissively infected OHL tissue enables epithelial cell survival and may enhance viral replication. Detection of KSHV in these HIV-infected individuals has been localized only to their saliva. Replicative and latent KSHV gene products have been detected in association with the development of oral KS lesions. EBV, but not human cytomegalovirus (HCMV), has been detected by PCR in minor salivary gland biopsies of HIV-associated salivary gland disease. Human papillomaviruses (HPV) are associated with oral warts in HIV-positive individuals; a diagnosis that appears to be increasing in frequency in the era of highly active antiretroviral therapy. To date, there appears to be little increase in the incidence of HPV-associated oral cancer. The mechanisms of interaction between HIV and HPV are not fully understood. Expression of viral gene products is clearly important and necessary for the development of multiple AIDS-associated oral lesions.

HIV-related oral manifestations among adolescents in a multicenter cohort study.

PURPOSE: To describe baseline prevalence of oral mucosal diseases among HIV infected adolescents in relationship to biological and behavioral risk factors. METHODS: Participants in Reaching for Excellence in Adolescent Care and Health (REACH), a multicenter longitudinal observational study of HIV/AIDS in adolescents, received physical examinations, blood tests, and oral examinations at 3-month intervals. We evaluated participants for oral conditions commonly seen in relationship to HIV, and explored the association of the most common lesion with selected biological and behavioral variables at baseline using contingency tables and Fisher's Exact test. RESULTS: Among 294 HIV infected adolescents recruited between March 1996 and March 1999, the majority were female (75%), aged 17 to 18 years (69%), and African-American (73%). More than 90% had a CD4(+) T-lymphocyte count > 200 cells/mm(3) at baseline and 57% had a plasma HIV-1 RNA concentration

Examination of the oral mucosa and peripheral blood cells of patients with recurrent aphthous ulceration for human herpesvirus DNA.

OBJECTIVE: The purpose of this study was to exam the oral mucosa and peripheral blood cells of patients with recurrent aph-thous ulceration (RAU) for the presence of the following human herpesviruses: herpes simplex viruses 1 and 2, varicella zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus-6, and human herpesvirus-7. STUDY DESIGN: Fifty-eight subjects with RAU and 10 control subjects were recruited at an academic referral center and enrolled in this prospective, nonrandomized, case-controlled study. Each of the subjects with RAU was seen during an acute episode, and swab specimens from lesional (RAU-acute/lesion) and clinically normal (RAU-acute/normal) oral mucosa were obtained. Each of 2 subjects with RAU was evaluated during more than one acute episode. Three subjects with RAU were seen between active episodes, and swab specimens were taken from clinically normal (RAU-convalescent) oral mucosa. Swab specimens from clinically normal (control/normal) oral mucosa were obtained from the control subjects. Peripheral blood specimens were obtained from subjects with RAU and control subjects at the time the swab specimens were performed. Through use of polymerase chain reaction, all swab and peripheral blood specimens were examined for the presence of human herpesvirus DNA. Statistical significance was determined by means of chi(2) analysis. RESULTS: Herpes simplex virus and human herpesvirus-6 were found in a higher percentage of mucosal specimens from the control subjects (herpes simplex virus, 4/10; human herpesvirus-6, 5/9) than from the subjects with RAU (RAU-acute/lesion: 3/45 herpes simplex virus, 13/53 human herpesvirus-6; RAU-acute/normal: 7/48 herpes simplex virus, 9/53 human herpesvirus-6). No difference was demonstrated between RAU-acute/lesion, RAU-acute/normal, and RAU-convalescent mucosal specimens for any of the human herpesviruses. Different human herpesviruses were identified from individual subjects with RAU during subsequent episodes of disease. Epstein-Barr virus (6/35), human herpesvirus-6 (3/40), and human herpesvirus-7 (7/43) were detected in the peripheral blood mononuclear cells during acute RAU but not in RAU-convalescent or control peripheral blood mononuclear cells. CONCLUSIONS: The detection of human herpesvirus DNA from the oral mucosa and peripheral blood mononuclear cells of patients with RAU appears to represent normal viral shedding rather than a direct causal mechanism in this disorder.

[Cytomegalovirus infection and the changes of T-lymphocyte subsets in RAU patients].

OBJECTIVE: To study the quantitative changes of the T-lymphocyte subsets in RAU patients with different stages and to know the influences of cytomegalovirus(CMV) on cellular immunity in RAU patients. METHODS: CD4(helper/inducer) and CD8(suppressor/cytotoxic) cells in the peripheral blood were tested with monoclonally immunocytochemical technique (APAAP method) in 26 ulcerative stage patients and 10 inactive patients. RESULTS: The percentages of CD4 and CD8 cell were 36.19% and 29.38% respectively in ulcerative stage. The ratio of CD4/CD8 was 1.28 and it was inverted (< 1.0) in 26.92% of the patients. The percentages of CD4, CD8 cells was 39.90% and 34.21% in inactive stage respectively. The ratio of CD4/CD8 was 1.17. The number of CD4 and CD8 cells in ulcerative stage and CD4 cells in inactive stage was significantly lower than the normal values, P < 0.05. The number of CD8 cells in inactive stage was not significantly different compared with the normal value. However the numbers of CD3(total T cells), CD4 and CD8 cells increased to some extent in inactive stage. CD4 cells was significantly lower in 11 human cytomegalovirus (HCMV) DNA positive patients than that in 9 HCMV DNA negative patients (P < 0.05). CONCLUSIONS: A permanent disorder of cellular immunity was an important part of pathogenesis in RAU. CMV infection may be an important factor resulting in the disorder of cellular immunity because of the imbalance of T lymphocyte subsets.

Herpesvirus-induced diseases: oral manifestations and current treatment options.

The dentist is often the first health professional to be contracted by patients who develop acute orofacial symptoms of viral conditions such as shingles (varicella zoster) or herpetic gingivostomatitis. The diagnosis, treatment, and management of virally induced oral diseases is a challenge inasmuch as their presentation is atypical and may be complicated by immunosuppression. However, an increasing body of knowledge regarding the manifestations of viral infections in immunocompromised patients and the advances achieved in antiviral drug therapy during the past several years should make the task less daunting for the dentist. In this paper, the natural history, typical and atypical oral manifestations, diagnosis, current treatment options, and advances in the prevention of common herpesvirus-induced diseases are reviewed, with particular attention to primary and recurrent varicella zoster virus and herpes simplex type 1 infections.

Detection of serum antibodies against cytomegalovirus, varicella zoster virus and human herpesvirus 6 in patients with recurrent aphthous stomatitis.

There has recently been renewed interest in the possible role of viruses in recurrent aphthous stomatitis (RAS). In this study, sera from 22 patients with RAS, 24 patients with oral lichen planus (OLP) and 15 healthy controls were screened for IgG and IgM class antibodies to human cytomegalovirus (HCMV), varicella zoster virus (VZV) and human herpesvirus 6 (HHV-6). Commercially available ELISA and immunofluorescence kits were employed. There were no significant differences in the prevalence of IgG antibodies to HCMV, VZV or HHV-6 among the three patient groups. Similarly, there were no significant differences between the prevalence of HCMV and VZV IgM antibodies among RAS patients and controls. However, specific HHV-6 IgM was detected in 21 (95%) of the RAS patients and 17 (71%) of the lichen planus patients compared with 8 (53%) of the healthy controls. This difference between RAS patients and controls was statistically significant (P<0.01). These results do not support an aetiological role for HCMV or VZV in RAS but suggest possible involvement of HHV-6.