Epstein-Barr virus oral shedding and viremia and their association with oral hairy leukoplakia in HIV+ individuals.

OBJECTIVE: To assess the oral shedding and viremia of Epstein-Barr virus (EBV) in HIV-positive patients and their relationship with oral hairy leukoplakia (OHL). METHODOLOGY: A total of 94 HIV-positive patients were included in the study, in which blood and saliva samples were collected for EBV quantification. Data on gender, age, time of HIV seropositivity, combined antiretroviral therapy (cART), CD4+ T-cell counts, and HIV viral load were collected. OHL diagnosis was based on histopathological examination and EBV in situ hybridization. RESULTS: The EBV load in the 94 HIV-positive patients was higher in saliva than in blood (2.4 and 1.6, respectively), and there was a positive correlation between EBV oral shedding and viremia (p = 0.001). Twenty (21.27%) patients had OHL and also a higher EBV load in saliva (mean log10  = 3.11) compared to those who had no OHL (p = 0.045). Presence of OHL was only associated with age (p = 0.030). CONCLUSION: In HIV-positive patients, the presence of OHL was associated with EBV oral shedding but not with viremia, regardless of the amount of circulating CD4+ T cells.

Racial differences in dermatologic conditions associated with HIV: A cross-sectional study of 4679 patients in an urban tertiary care center.

BACKGROUND: Because of reduced mortality, patients with HIV are living longer and presenting with chronic diseases. Little is known about racial differences in dermatologic conditions associated with HIV infection. OBJECTIVE: This study examines associated dermatologic conditions in a large population of patients with HIV at a tertiary care center with a diverse patient population. METHODS: Cross-sectional study of patients with HIV seen between July 14, 2013, and July 14, 2018, in a tertiary health care system. The burden of HIV-related dermatologic conditions was collected by using medical records. Patients with HIV were compared with control individuals of the same race, and significance was assessed using the chi-square test. A Bonferroni correction was performed to control for multiple hypothesis testing. RESULTS: The study population (N = 4679) was 64.7% male and 69% African American, with 88.7% of patients receiving antiretroviral therapy. African American patients with HIV had a greater risk of oral hairy leukoplakia (odds ratio [OR], 64.49), herpes zoster (OR, 9.27), prurigo nodularis (OR, 8.80), and squamous cell carcinoma (OR, 5.72). LIMITATIONS: Our data describe patients seen by 1 health care system. CONCLUSIONS: African American patients with HIV may be at increased risk for pruritic disorders compared with race-matched control individuals and white patients with HIV.

Detection of Epstein-Barr virus DNA in saliva of HIV-1-infected individuals with oral hairy leukoplakia.

We present three cases of oral hairy leukoplakia (OHL) in whom the diagnosis was established by EBV DNA detection in whole saliva. Three HIV-infected patients came to the Oral Medicine Clinic with similar chief complaints of asymptomatic white lesions on the tongue. All patients were diagnosed with suspected OHL and oral thrush also in the first patient. A multiplex PCR DNA microarray was performed to detect EBV DNA in saliva collected by spitting method. All saliva samples showed positive results for EBV DNA, and the definitive diagnosis of OHL was made. Resolution of lesions was found at 1- to 2-month follow-up after treatment with application of acyclovir 5% cream 5 times daily. Additionally, anti-fungal treatment was given to the first patient and anti-retroviral treatment to the first and second patients. EBV is mostly transmitted by asymptomatic shedding into saliva. Therefore, the detection of salivary EBV DNA is useful in establishing a definitive diagnosis of OHL allowing more effective treatment for both HIV-infected patients receiving ART and treatment-naïve patients at any CD4 + count.

The global changing pattern of the oral manifestations of HIV.

The significance of the oral manifestations of HIV has been widely recognised since the start of the epidemic. It is estimated that more than 38 million people are living with HIV currently, with more than a third presenting with oral manifestations. Access to optimum clinical management and effective treatment in resource-rich countries has led to a remarkable decrease in some of the oral manifestations in the HIV population but this is not mirrored in developing countries, where most HIV-positive patients reside. In this paper, a review of the literature since the start of the HIV infection in different parts of the world is presented to highlight the current significance of the oral conditions in this population. Oral candidiasis was repeatedly reported as the most encountered oral manifestation of HIV in different countries, including in studies on groups on anti-retroviral therapy. Over time salivary gland disease was reported less in developed countries but was encountered more in developing countries. There is evidence to show that the prevalence of oral warts increased with the establishment of anti-retroviral therapy. A review of the worldwide prevalence of HIV-related oral conditions indicates that except for oral hairy leucoplakia, the prevalence of all other nine commonly reported oral conditions remained the same or increased over time. Oral opportunistic infections in HIV-infected patients are an ongoing clinical burden mainly in developing countries. Maintaining research in the subject and improving access to HIV treatment will help address the oral health inequalities around the world.

Oral manifestations of HIV: Can they be an indicator of disease severity? (A systematic review).

OBJECTIVE: To review the existing research literature on the paradigm that the oral lesions could be an indicator of the disease severity with the objective of documenting the current status of research, highlighting its major findings. MATERIAL AND METHODS: Publications were identified through a careful search, of which a majority focused on oral lesions as an indicator for HIV progression. A PubMed journal search of 10 years OF period publication (2009-2019) for "oral lesion, oral manifestation, indicator, HIV and HIV-associated" was performed and analysed. Various research methods were included within the study criteria including clinical study, clinical trial, comparative study and randomised control trial. RESULTS: A total 33 studies were obtained and analysed, including cohort study, cross-sectional study, case-control study, clinical trial, retrospective observational analysis study, prospective observational study and randomised control trial. The most common oral lesions found in the studies were Kaposi sarcoma (KS), followed by oral candidiasis, periodontitis, necrotising ulcerative gingivitis (NUG), necrotising ulcerative periodontitis (NUP) and oral hairy leucoplakia (OHL). The early diagnosis and accurate treatment plan were very important to indicate the disease severity related to HIV infection. CONCLUSION: Oral lesions reported in 39% articles and could be an indicator of HIV disease severity due to its effects on decreased cluster-differentiated (CD4+) T-cell count and increased viral load.

Oral hairy leukoplakia in a child using a corticosteroid nasal spray.

We report a case of atypical oral hairy leukoplakia (OHL) in a 9-year-old immunocompetent girl treated with fluticasone propionate nasal spray for allergic rhinitis. The OHL in childhood is uncommon and should be included in a differential diagnosis of white lesions in the oral mucosa.

Epstein-Barr virus in the pathogenesis of oral cancers.

Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.

Oral Hairy Leukoplakia in Patients With No Evidence of Immunosuppression: A Case Series and Review of the Literature.

OBJECTIVES: Oral hairy leukoplakia (OHL) is caused by Epstein-Barr virus (EBV) and is often associated with HIV and other immunosuppressive conditions. It is rare in HIV-negative patients, but has been reported in patients who use immune-modulating medications (e.g., cyclosporine). The objectives of this study were to determine the occurrence of OHL in HIV-negative patients and report Langerhans cell counts in these lesions. STUDY DESIGN: A series of 7 new cases of OHL among HIV-negative patients is described. Langerhans cells were counted using an immunoperoxidase stain for CD1a and light microscopy. RESULTS: The 7 patients were male, ranging in age from 26 to 69 years. Clinically, all lesions were diagnosed as leukoplakia on the lateral border of the tongue. Microscopic examination revealed hyperparakeratosis and candidiasis in some cases, acanthosis and a band-like zone with clearing of cells in the upper spinous layer, which were EBV-positive by in-situ hybridization. There was a significant decrease in Langerhans cell counts in OHL patients. CONCLUSION: OHL can occur in HIV-negative patients.

Differentiation-Dependent KLF4 Expression Promotes Lytic Epstein-Barr Virus Infection in Epithelial Cells.

Epstein-Barr virus (EBV) is a human herpesvirus associated with B-cell and epithelial cell malignancies. EBV lytically infects normal differentiated oral epithelial cells, where it causes a tongue lesion known as oral hairy leukoplakia (OHL) in immunosuppressed patients. However, the cellular mechanism(s) that enable EBV to establish exclusively lytic infection in normal differentiated oral epithelial cells are not currently understood. Here we show that a cellular transcription factor known to promote epithelial cell differentiation, KLF4, induces differentiation-dependent lytic EBV infection by binding to and activating the two EBV immediate-early gene (BZLF1 and BRLF1) promoters. We demonstrate that latently EBV-infected, telomerase-immortalized normal oral keratinocyte (NOKs) cells undergo lytic viral reactivation confined to the more differentiated cell layers in organotypic raft culture. Furthermore, we show that endogenous KLF4 expression is required for efficient lytic viral reactivation in response to phorbol ester and sodium butyrate treatment in several different EBV-infected epithelial cell lines, and that the combination of KLF4 and another differentiation-dependent cellular transcription factor, BLIMP1, is highly synergistic for inducing lytic EBV infection. We confirm that both KLF4 and BLIMP1 are expressed in differentiated, but not undifferentiated, epithelial cells in normal tongue tissue, and show that KLF4 and BLIMP1 are both expressed in a patient-derived OHL lesion. In contrast, KLF4 protein is not detectably expressed in B cells, where EBV normally enters latent infection, although KLF4 over-expression is sufficient to induce lytic EBV reactivation in Burkitt lymphoma cells. Thus, KLF4, together with BLIMP1, plays a critical role in mediating lytic EBV reactivation in epithelial cells.

Oral lesions as an important marker for HIV progression.

BACKGROUND: Oral hairy leukoplakia (OHL) is a benign lesion caused by Epstein-Barr virus (EBV) replication in the oral epithelium affecting the borders of the tongue. It is strongly associated with immunosuppression, especially in HIV+ adults but is uncommon in pediatric population. The aim of the study is to show the importance of the correct diagnosis of OHL and its influence on HIV treatment.We report two cases of HIV+ adolescent patients that presented with leukoplakic lesions on the border of the tongue, suggestive of OHL. OHL diagnosis was confirmed in only one case through EBV in situ hybridization. After confirmation of the diagnosis, the patient with OHL was referred to an infectious disease specialist with the decision to start antiretroviral therapy. CONCLUSION: OHL definitive diagnosis can help clinical management of pediatric HIV+ patients.

Hairy leukoplakia; lessons learned: 30-plus years.

Well into the fourth decade of the HIV/AIDS pandemic, we can look back on the early years, the initial discoveries, and the broad sweep of the progress of our understanding of the nature, causes, and significance of the oral lesions seen in those infected with the virus. Prominent among these is oral hairy leukoplakia (HL), a previously unknown lesion of the mouth associated with Epstein-Barr virus (EBV) and initially seen only in people with AIDS, in the then-recognized risk groups, or those shown to be HIV positive. Subsequently, it became clear that the distribution of HL extends well beyond the HIV spectrum. In this brief review, we consider the clinical and histological features of HL, discuss how it was discovered, explore its cause, diagnosis, relationship with AIDS, pathogenesis, significance in EBV biology, options for management, and how it changes with HIV/AIDS therapy.

Oral Lesions in Kidney Transplant Recipients

Permanent immunosuppression is necessary to prevent rejection after kidney transplantation. However, it may predispose patients to different conditions and diseases including oral lesions. The most common benign oral lesions in kidney transplant recipients are gingival hyperplasia, oral candidiasis, hairy leukoplakia and saburral tongue. Oral form of Kaposi sarcoma, although rarely, can also be seen in kidney transplant patients. In this review, we present the incidence, etiology, clinical findings, diagnosis and treatment options for these lesions. For kidney transplant recipients,it is important to maintain good oral hygiene and care, as well as regular professional control by the dentist. This approach can reduce the number and severity of oral lesions.

Epstein-Barr virus: dermatologic associations and implications: part I. Mucocutaneous manifestations of Epstein-Barr virus and nonmalignant disorders.

Epstein-Barr virus (EBV) is a ubiquitous virus that has been implicated in a wide range of human diseases, many of which have mucocutaneous manifestations. As a member of the herpesviridae family, EBV causes lifelong infection by establishing latency in B lymphocytes. An intact immune response is critical in preventing progression of EBV disease, and the clinical manifestations of infection are dependent on the intricate relationship between virus and host immune system. This review provides a comprehensive overview of the epidemiology, pathophysiology, and diagnostic testing in EBV infection. In part I of this continuing medical education article, the mucocutaneous manifestations of EBV infection are reviewed with an emphasis on pathophysiology and management.

[Oral hairy leukoplakia induced by topical steroids]. / Leucoplasie orale chevelue induite par une corticothérapie locale.

BACKGROUND: Oral hairy leukoplakia (OHL) is an EBV-associated condition of the oral mucosa, which is often painless. It is found predominantly in HIV-positive patients and is considered a clinical indicator of immunosuppression. OHL has rarely been described in HIV-negative patients, being found most often in association with iatrogenic immunosuppression. OHL induced by topical steroids remains extremely rare. PATIENTS AND METHODS: An 81-year-old HIV-negative woman, treated for 3 months with topical steroids for oral lichen planus, developed an asymptomatic white, corrugated, non-removable plaque with vertical folds on the lateral edge of the tongue. Associated oral candidiasis was noted. Based upon histological findings and in situ hybridisation showing numerous EBV-infected epithelial cells, a diagnosis of oral hairy leucoplakia was made. DISCUSSION AND CONCLUSION: To our knowledge, we report herein only the second recorded case of OHL induced strictly by topical steroids. Self-medication and poor adherence to dosage recommendations were noted in the patient's medical history. Physicians must be aware of the rare but nevertheless possible adverse events associated with topical steroid use, particularly when such medication is prescribed over a long period for inflammatory diseases of the oral mucosa.

Oral hairy leukoplakia diagnosis by Epstein-Barr virus in situ hybridization in liquid-based cytology.

OBJECTIVE: To establish a definitive diagnosis of oral hairy leukoplakia (OHL) by in situ hybridization for Epstein-Barr virus (EBV) detection with liquid-based cytology (LBC), using the ThinPrep® Pap Test, and to compare its efficacy with the traditional method of performing biopsy. METHODS: Thirty-three individuals divided into three groups were included in this study. Group 1 consisted of 15 human immunodeficiency virus (HIV)-positive patients with a clinical and histopathological diagnosis of OHL on the lateral border of the tongue. Group 2 consisted of 10 HIV-positive individuals with neither OHL nor other oral lesions. Group 3 consisted of 10 immunocompetent HIV-negative individuals with neither OHL nor other oral lesions. For each patient from the three groups, exfoliative LBC was performed on the lateral border of the tongue using ThinPrep. For the patients from group 1, a 6-mm-diameter punch biopsy was obtained from the same anatomic site as the brush collection to confirm the diagnosis of OHL by histopathology with in situ hybridization. Slides were prepared for morphological cellular analysis using Papanicolaou (Pap) staining, and for EBV detection using in situ hybridization. RESULTS: Thirteen of the 15 patients from group 1 were confirmed on punch biopsy as OHL, providing the gold standard for the study. The sensitivity of LBC followed by a Pap-stained smear was 62% and the specificity was 90%. The sensitivity of LBC followed by in situ hybridization was 100% and the specificity was 100%. CONCLUSIONS: Exfoliative LBC associated with EBV in situ hybridization is a simple, effective and non-invasive diagnostic tool for OHL.

Oral hairy leukoplakia in healthy, immunocompetent individuals.

Oral hairy leukoplakia (OHL), while typically associated with HIV infection and immunosuppression, is rarely seen in HIV negative immunocompetent individuals. We report on two cases of OHL in immunocompetent patients.

Association between oral candidiasis and low CD4+ count among HIV positive patients in Hoima Regional Referral Hospital.

BACKGROUND: The aim of this study was to determine the prevalence of Human Immune Virus (HIV) related oral lesions and their association with Cluster of Differentiation 4 (CD4+) count among treatment naïve HIV positive patients. METHODS: This was a descriptive and analytical cross sectional study. Participants were 346 treatment naïve HIV positive adult patients. These were consecutively recruited from Hoima Regional Referral hospital between March and April 2012. Data collection involved interviews, oral examinations and laboratory analysis. RESULTS: A total of 168(48.6%) participants had oral lesions. The four commonest lesions were oral candidiasis (24.9%, CI = 20.6-29.7%), melanotic hyperpigmentation (17.3%, CI = 13.7-21.7%), kaposi sarcoma (9.3%, CI = 6.6-12.8%) and Oral Hairy Leukoplakia (OHL) (5.5%, CI = 3.5-8.4%). There was significant association between oral candidiasis and immunosuppression measured as CD4+ less than 350 cells/mm3 (OR = 2.69, CI = 1.608-4.502, p < 0.001). Oral candidiasis was the only oral lesion significantly predictive of immunosuppression (OR = 2.56, CI = 1.52-4.30, p < 0.001) with a Positive Predictive Value (PPV) of 48.2%, Negative Predictive Value (NPV) of 74.3%, 38.1% sensitivity and specificity of 81.4%. CONCLUSION: Oral candidiasis can be considered as a marker for immunesuppression, making routine oral examinations essential in the management of HIV positive patients.

Knowledge, attitudes and practices of oral health care workers in Lesotho regarding the management of patients with oral manifestations of HIV/AIDS.

Lesotho has the third highest prevalence of HIV in the world with an estimated 23% of the adult population infected. At least 70% of people living with HIV/AIDS (PLWHA) have presented with oral manifestation of HIV as the first sign of the disease. Oral health workers regularly encounter patients presenting with oral lesions associated with HIV disease and therefore need to have adequate knowledge of these conditions for diagnosis and management. The aim of the present study was to determine the knowledge, attitudes and practices of oral health care workers (OHCW) of Lesotho regarding the management of oral manifestations of HIV/AIDS. A descriptive cross-sectional survey was conducted on all 46 OHCW in 26 public and private care facilities in all ten districts of Lesotho. A self-administered questionnaire was used to gather information. The response rate was 100%. Nearly all (94.7%) agreed that oral lesions are common in people living with HIV and/or AIDS. The majority (91.3%) named oral candidiasis (OC) as the most common lesion found in PLWHA while Kaposi's Sarcoma (KS) (34.7%) and Oral Hairy Leukoplakia (OHL) (32.6%) were mentioned as the least common oral lesions of HIV. Most correctly identified the images of oral candidiasis (97.8%), angular cheilitis (86.9%) and herpes zoster (80.4%). Only 16.7% felt they had comprehensive knowledge of oral HIV lesions, although 84.8% reported having previously received training. Almost three quarters (71%) reported that there was no need to treat HIV positive patients differently from HIV negative patients. OHCW in Lesotho demonstrated high confidence levels in their competence in managing dental patients with oral lesions associated with HIV, however, they lacked an in-depth knowledge in this regard. Amongst this group there is a need for comprehensive training with regards to diagnosis and management of oral lesions of HIV including the training of other cadres of health care workers together with nurses and community health workers.