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.

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.

Iatrogenic oral hairy leukoplakia: report of two cases.

Oral hairy leukoplakia (OHL) presents as a white, plaque-like lesion typically occurring on the lateral border of the tongue. This condition is caused by the Epstein-Barr virus, a human herpesvirus that often establishes lifelong, asymptomatic latent infection. OHL, initially described in immunocompromised men infected with the human immunodeficiency virus (HIV), has also been described in other severely immunocompromised patients. Only rarely has OHL been reported in less profoundly immunocompromised patients primarily in the setting of corticosteroid therapy. Here we report on two additional cases of OHL attributable to immunosuppressive medications.

Oral manifestations as predictors of immune suppression in a HIV-/AIDS-infected population in south India.

The objectives of the study are to evaluate the relationship between common HIV-related oral lesions and absolute CD4+ count, age, gender, and medication used and to assess the sensitivity, specificity, positive and negative predictive value of oral manifestations for low absolute CD4+ counts. HIV-positive patients, 200, from south India were selected, whose absolute CD4+ counts were determined within 2 weeks of oral examination. Sociodemographic data was obtained using a structured questionnaire. Oral manifestations were diagnosed according to presumptive criteria of EEC-clearinghouse classification (1993). Four or more concurrent oral lesions were statistically significant with low CD4+ counts <200 cells/mm3 (P = 0.005). The highest and lowest mean CD4+ cell counts were seen in individuals with linear gingival erythema (LGE; 172.5 cells/mm(3)) and pseudomembranous candidiasis (PC; 87 cells/mm(3)), respectively. Smoking, age (<35 years), and males had a positive association with oral hairy leukoplakia (OHL; P < 0.05). Patients with CD4+ counts < 200 cells/mm(3) were associated with 15 times greater risk of PC and four times at greater risk for occurrence of any oral manifestation. Concurrent oral manifestations (>or=4) were good predictors (80-100%) of severe immune suppression. In most resource poor countries where facilities for undertaking CD4+ counts are not available, the presence of concurrent oral manifestations may be used as an indicator of deteriorating immune status.

Synchronous kinetics of CD4+ lymphocytes and viral load before the onset of oral candidosis and hairy leukoplakia in a cohort of Mexican HIV-infected patients.

An observational, prospective, longitudinal cohort study was performed at the AIDS Clinic of a tertiary care institution in Mexico City to determine the association of viral load (VL) and CD4+ lymphocyte kinetics with the development of oral candidosis (OC) and hairy leukoplakia (HL). Participants were HIV-infected adult subjects, without a history of or current OC or HL, not receiving HAART. Oral examinations were performed at baseline and every month for evidence of OC or HL; CD4+ and VL determinations were done at baseline, at 6-month intervals, when oral lesions were detected, and 2 months later. Affected subjects (OL group) by OC or HL had clinical intervals defined before (antecedent), during (concurrent), and after their development. In the nonaffected individuals (NA group), 6-month intervals were determined. Differences (changes) along the clinical and study intervals were calculated for CD4+ and VL. The median study time was 178 (range: 31-924) days; 99 patients were included. The 2-year cumulative incidence of either oral lesion was 54% (49.5% for OC and 33.2% for HL). In the OL group (31 patients) a progressive and continuous decrease of CD4+ was found in the antecedent interval followed by a significant increase in VL in the concurrent period. The NA group showed a significant fall in CD4+ by semester 3, without a significant rise of VL in the following semester. The effect of CD4+ remained significant in a multivariate analysis. This study has shown that the onset of OC and/or HL is heralded by the sequence of a sustained reduction of CD4+, followed by a sharp increase of VL. In the multivariate analysis, the decrease in CD4+ lymphocytes appeared to be the predominant factor predicting the appearance of these oral lesions. Their potential use as markers of a recent change in the immunologic and virologic status of HIV-infected individuals is emphasized.

Low-dose prednisolone has a CD4-stabilizing effect in pre-treated HIV-patients during structured therapy interruptions (STI).

BACKGROUND: A favorable development of CD4+ T cells was firstly noticed in therapy-naive HIV-patients without antiretroviral therapy (ART) taking 5 mg prednisolone daily. This observation led to the prescription of prednisolone during structured therapy interruptions (STI). OBJECTIVE: To evaluate the effect of low dose prednisolone on pre-treated patients during STI. METHODS: A retrospective analysis including all pre-treated patients with prednisolone therapy for > or =6 months during STI has been conducted. The patients with prednisolone onset right at the beginning of STI (n = 95) were compared with all patients without prednisolone therapy during their first 6 months of STI (n = 49). Patients with prednisolone were divided into two subgroups: the ongoing STI-group and the patients with ART-restart. Additionally, the development of all 33 patients from the control group having started prednisolone later during STI was documented. Irrespective of the time of initiation of prednisolone therapy during STI, the development of CD4+ T cells in all patients with prednisolone for >12 months during STI was analyzed (n = 108). RESULTS: The mean daily CD4+ T cell decrease during STI was significantly less pronounced in the prednisolone-group (-0.50 vs. -0.74 cells/day; p = 0.0361). The daily CD4+ T cell decline of the 33 patients from the control subgroup including patients with a later onset of prednisolone therapy was only -0.11 during a mean time of 715 days under prednisolone. The CD4+ T cell count of the STI-patients treated with prednisolone for >12 months (n = 108; mean: 837 days +/- 64.6 (366-1,756 days)) decreased from 677/microl to 504/microl. - 51 of 81 patients (63%) included in 2-year-analysis showed stable CD4+ T cell counts (mean daily CD4+ T cell decrease: 0.08) and continued ART interruption. CONCLUSION: This retrospective evaluation provides evidence that low dose corticosteroids are associated with less decrease of CD4+ T cell count in pre-treated HIV patients resulting in prolongation of the potential time of structured treatment interruptions for many HIV patients.

Twenty-first-century oral hairy leukoplakia--a non-HIV-associated entity.

OBJECTIVE: This study presents the clinicopathologic features of a series (N = 35) of patients with non-human immunodeficiency virus (HIV)-associated oral hairy leukoplakia (OHL). METHODS: Patients with non-HIV-associated OHL were identified from three centers. Epstein-Barr virus infection was demonstrated by using EBV early ribonucleic acid in situ hybridization. The presence of Candida co-infection was evaluated by diastase periodic acid-Schiff staining. The clinical features were determined by review of the medical records. RESULTS: Twenty-eight patients had intercurrent respiratory problems requiring long-term steroid inhaler use, four suffered from autoimmune diseases requiring immunosuppressant therapy, and four had diabetes. The majority of lesions were located on the tongue, and 24 showed evidence of Candida co-infection. CONCLUSIONS: In the twenty-first century, the presence of OHL should not be regarded as pathognomic for HIV infection or significant systemic immunosuppression. Local and systemic immunosuppression, in the form of steroid inhaler use, is a risk factor for the development of OHL.

Oral opportunistic infections in HIV-positive individuals: review and role of mucosal immunity.

Oral opportunistic infections in the HIV-positive individual have been documented since the first reports of the epidemic, with many lesions associated with reduced CD4(+) T lymphocyte cell count. The most common oral lesions seen in HIV disease prior to the advent of highly active antiretroviral therapy (HAART) were oropharyngeal candidiasis and oral hairy leukoplakia. However, since the advent of HAART while many oral lesions have decreased significantly the incidence of oral warts has surprisingly increased. Despite the correlation of diminished CD4(+) T lymphocyte count to the occurrence of these lesions, it is rare for the lesions to occur concurrently suggesting that each pathologic lesion type is associated with distinct host immune dysfunctions. To date, the oral opportunistic infection most frequently investigated is oropharyngeal candidiasis, where data suggests that both systemic and local immunity is important for protection against infection. In contrast, recent investigations into the host responses associated with oral hairy leukoplakia and oral warts show little to no evidence of systemic or mucosal immune responsiveness despite the presumed competence of several types of leukocytes other than CD4(+) T cells. Together these data are suggesting that susceptibility to oropharyngeal candidasis in HIV-positive persons is predominantly immune-based, whereas protection or susceptibility to oral hairy leukoplakia and oral warts may be more associated with factors other than mucosal immune function.

Sensitivity, specificity, and positive predictive value of oral opportunistic infections in adults with HIV/AIDS as markers of immune suppression and viral burden.

OBJECTIVES: The purpose of this study was to assess the use of human immunodeficiency virus (HIV)-related oral opportunistic infections as markers of immune suppression and viral burden in adults with HIV/acquired immunodeficiency syndrome (AIDS). METHODS: The population consisted of a single institution observational cohort involving 606 patients with HIV/AIDS with CD4 count data and 277 with plasma viral load measurements examined between 1995 and 1999 for the presence of oral manifestations of HIV. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value is reported for the association of specific oral lesions and lesion sets with CD4 counts <200 cells/mm(3) and with plasma HIV RNA >/=20,000 copies/mL. RESULTS: Lesions with moderate-to-high PPVs for CD4 <200 cells/mm(3) were as follows: Kaposi's sarcoma (100%; P =.035), pseudomembranous candidiasis (82. 2%; P <.001), linear gingival erythema (70.0%; P =.015), hairy leukoplakia (66.3%; P <.001), angular cheilitis (60.0%; P =.128), and erythematous candidiasis (58.3%; P =.061). Necrotizing ulcerative periodontal diseases, HIV salivary gland disease, oral ulcers, and oral warts had PPVs below 50%. Concurrent infection with candidiasis and hairy leukoplakia had the highest PPV of 89.3%; P <. 001. PPVs for HIV RNA >/=20,000 copies/mL ranged from 27.3% to 100%, with significant association only for pseudomembranous candidiasis. CONCLUSIONS: Specific common oral lesions are strongly associated with immune suppression, as measured by CD4 cell counts, and are modestly associated with high viral burden, thus serving as potential clinical markers of HIV viremia and the consequent destruction of the immune system with progressive HIV disease.

Oral hairy leukoplakia in an HIV-negative patient with systemic lupus erythematosus.

Oral hairy leukoplakia (OHL) has been reported primarily in association with HIV infection. Recently, cases have been reported in HIV-negative immunosuppressed and in immunocompetent patients. This article reports the case of an occurrence of OHL in an HIV-negative immunosuppressed patient with systemic lupus erythematosus. The case presented illustrates the importance of a thorough examination of the oral tissues in patients who are undergoing immunosuppressive therapy.

Oral manifestations related to immunosuppression degree in HIV-positive children.

Oral manifestations often found in HIV-infected children are frequently the first clinical sign of the infection. This article aims to report the prevalence of oral manifestations in soft tissues and their relationship with the degree of immunosuppression in 80 HIV-infected patients (average age 6.30 +/- 3.32 years old) at the IPPMG-UFRJ. Thirty children (38%) presented some type of oral lesion and the percentage of CD4 was lower than that found in lesion-free children (p < 0.05); 22.5% presented candidiasis, 17.5% gingivitis, 8.8% enlargement of parotids, 1.3% herpes simplex and 1.3% hairy leukoplakia. Of the 30 children with lesions, 70% showed severe immunosuppression, 23.3% moderate immunosuppression and in only 6.7% was immunosuppression absent. Oral manifestations were directly related to the degree of immunosuppression and such lesions can be considered as indicators of the progression of the HIV infection in children.

Oral hairy leukoplakia in patients without HIV: presentation of 2 new cases.

OBJECTIVE: We report 2 cases of oral hairy leukoplakia (OHL) in patients without HIV and present a comprehensive review of OHL in HIV-negative individuals. STUDY DESIGN: Two cases of non-HIV-associated OHL are described. A PubMed search identified previously reported cases. The attributes of those cases were ascertained. RESULTS: OHL was confirmed in both of our cases. Both patients used inhaled steroids for pulmonary disorders, and were found to have depressed levels of immunoglobulin M. Additionally, 76 cases were identified in the literature. The condition occurred in association with various medical conditions, with the majority of patients on immunosuppressant medications (67 of 76). Systemic drugs were implicated most frequently. The condition has also been reported in healthy individuals (6 of 76). CONCLUSIONS: Although thought of as an HIV/AIDS-associated condition, OHL can develop in patients without HIV, including healthy individuals. There is a strong correlation between the use of immunosuppressants and development of OHL in these patients.

Correlation between oral lesions and opportunistic infections among human immunodeficiency virus - infected individuals in Indian population.

BACKGROUND: Human immunodeficiency virus (HIV) infection is a major global health problem. Tuberculosis and cryptococcal meningitis are the leading cause of death among people living with HIV. AIM: The purpose of this study was to determine whether any relationship exists between the occurrence of oral lesions and opportunistic infections among HIV-infected patients in Indian population. MATERIALS AND METHODS: A cross-sectional analytical study was performed in 232 HIV-infected persons (148 males and 84 females, aged 20-60 years, mean 33.6 ± 2.3 years). c2 test and logistic regression were used for statistical analysis. RESULTS: Oral candidiasis was the most common oral lesion seen in 28.4% males and 22.6% females of HIV-infected persons, followed by hairy leukoplakia in 27% males and 20.2% females which was statistically significant. Tuberculosis (21.6%) followed by cryptococcosis (9.9%) and pneumocystis carinii pneumonia (4.7%) were the most commonly found opportunistic infections. Logistic regression analysis revealed a significant association, between the occurrence of tuberculosis and candidiasis (OR 2.3; 95% CI 1.4-2.9), cryptococcosis and candidiasis (OR 1.4; 95% CI 1.0-1.9), and pneumocystis carinii pneumonia with hairy leukoplakia (OR 1.6; 95% CI 1.0-2.9). Mean CD4 count was also less. CONCLUSIONS: The results suggest a definite relationship in occurrence of oral lesions and opportunistic infections among HIV-infected patients.

Comparison of oral manifestations with CD4 count in HIV-infected patients.

AIM AND OBJECTIVE: This study was carried out with the primary aim of correlating oral changes and general changes of HIV-infected patients with their CD4 count. MATERIALS AND METHODS: 124 patients were selected, and after taking their informed consent, they were subjected to detailed history taking and thorough clinical examination. Specific oral lesions and general physical changes were recorded. Every patient was subjected to laboratory investigation for CD4 count. All these findings were tabulated. The clinical observation and laboratory findings were subjected to critical analysis and correlated. Statistical test, i.e. Student's " t" test, was applied and objective conclusions were drawn. RESULT: Out of 124 patients, 40 had oral candidiasis, 6 had oral hairy leukoplakia, 12 had periodontal disease, 20 had xerostomia, 30 had melanin pigmentation, while 4 had HSV2, and atypical ulceration. Out of 40 patients with oral candidiasis, 28 patients had CD4 count <200 (group A), 10 patients were in group, B (CD4 count 200-500 cell/mm 3 ) and 2 patients in group C(CD4 >500 cell/mm 3 ). Oral hairy leukoplakia occurred in equal proportions in group A and B. These periodontal diseases were more commonly in group B; xerostomia and melanin pigmentation was equally seen in group A and B. CONCLUSION: Oral candidiasis, oral hairy leukoplakia, linear gingival erythema, necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis are specific oral indicators which will definitely suggest to the dental surgeon that the disease is running a rapid downhill course and due to this the oral physician is in a position to raise a suspicion and alert the general physician regarding the declining immune status of patient.

Oral hairy leukoplakia in HIV-negative patients: report of 10 cases.

Ten cases of oral hairy leukoplakia (OHL) in HIV- negative patients are presented. Eight of the 10 patients were on steroid treatment for chronic obstructive pulmonary disease, 1 patient was on prednisone as part of a therapeutic regimen for gastrointestinal stromal tumor, and 1 patient did not have any history of immunosuppression. There were 5 men and 5 women, ages 32-79, with mean age being 61.8 years. Nine out of 10 lesions were located unilaterally on the tongue, whereas 1 lesion was located at the junction of the hard and soft palate. All lesions were described as painless, corrugated, nonremovable white plaques (leukoplakias). Histologic features were consistent with Epstein-Barr virus-associated hyperkeratosis suggestive of OHL, and confirmatory in situ hybridization was performed in all cases. Candida hyphae and spores were present in 8 cases. Pathologists should be aware of OHL presenting not only in HIV-positive and HIV-negative organ transplant recipients but also in patients receiving steroid treatment, and more important, certain histologic features should raise suspicion for such diagnosis without prior knowledge of immunosuppression.

Lack of evidence for local immune activity in oral hairy leukoplakia and oral wart lesions.

BACKGROUND: Oral warts, caused by human papillomavirus (HPV), and oral hairy leukoplakia (OHL) caused by Epstein-Barr virus (EBV), are common oral manifestations in HIV-infected persons. Although both conditions occur most often with reduced blood CD4+ T-cell numbers, oral warts and OHL rarely occur simultaneously, suggesting that dysfunctions in other secondary local immune parameters are also involved. The present study evaluated tissue-associated proinflammatory and T-helper cytokine and chemokine mRNA expression and the presence of T cells in each lesion. METHODS: Biopsies were taken from lesion-positive and adjacent lesion-negative sites of HIV+ persons with oral warts or OHL and lesion-negative sites from HIV+ persons who were oral HPV or EBV DNA-positive (matched controls). Cytokine/chemokine mRNA expression was quantified by real-time polymerase chain reaction. CD3, CD4, and CD8 cells were identified by immunohistochemistry. RESULTS: No differences were detected in tissue-associated cytokine/chemokine mRNA expression in warts or OHL when compared to lesion-negative sites. Immunohistochemical analysis of T cells showed CD8+ cells exclusively, but few cells were present in either lesion. No differences were detected between lesion-positive and -negative control sites of each pathologic condition. CONCLUSION: Little evidence was found for local immune reactivity to either oral warts and OHL, suggesting that CD4+ T cells are a primary host defense against both oral warts and OHL, but with nonimmune factors potentially responsible for the divergent prevalence of each.

Opportunistic oral infections in the immunosuppressed patient: oral hairy leukoplakia and oral candidiasis.

Several opportunistic infections associated with immunosuppression are noted to occur secondary to an altered relationship between host and organism. In relation to diminished host immunologic defenses, associated commensal organisms may evolve to a pathogen state. Candidiasis, a common oral marker disease reflective of immunosuppression, results from dysfunction of complex cellular interactions keyed by depressed T-cell activity or function. Certain viral infections may also serve as probable markers of immunosuppression. One such infection is typified by the development of oral hairy leukoplakia, a condition highly correlated to HIV infection in most, but not all, patients. Detection of Epstein-Barr virus particles and subsequent molecular analytic verification of such and the absence of other potential viral candidates, such as papilloma and human immunodeficiency viruses, have led to a general acceptance of this virus as the cause of this condition.

Oral hairy leukoplakia--10 years on.

Oral hairy leukoplakia (OHL) was first observed in 1981 and reported in 1984. Initially, this entity was restricted to HIV-seropositive male homosexual patients, but the risk group has been expanded since 1986 to all patients infected with HIV. It has been recognized that OHL is caused by Epstein-Barr virus (EBV). In 1988 we reported the first HIV-negative immunosuppressed patient with documented EBV-positive OHL. In patients with OHL, continuous shedding of EBV from saliva is necessary to maintain the lesion. EBV shedding leads to repeated infection of the intraoral epithelium. This may explain the highly variable course of OHL. The lesions may spontaneously disappear within few days. No latent EBV can be found in basal or suprabasal cells. In OHL coinfection with multiple strains of replicating EBV was documented recently. The clinical diagnosis of OHL may be confirmed by ultrastructural examination or in situ hybridization of exfoliative cytologic specimens. OHL is highly predictive for the development of AIDS. However, in HIV-seropositive patients, detection of EBV-DNA in the oral epithelium by the scraping method may be an earlier and more powerful predictor of progression to AIDS than is OHL.

Decreased blood TcR gamma delta+ lymphocytes in AIDS and p24-antigenemic HIV-1-infected patients.

The significance of blood TcR gamma delta+ lymphocyte level was evaluated in the context of immunodeficiency and infections in 209 HIV-1-infected patients. Blood TcR gamma delta+ lymphocyte values were found higher in patients belonging to the CDC group II/III than those in the CDC groups IV C1 and IV D (P < 0.001) and P < 0.01, respectively). TcR gamma delta+ lymphocyte counts were lower in patients with oral candidiasis (P < 0.01), and in association with pneumocystosis or toxoplasmosis (P < 0.001). In 81 patients with a detectable HIV-1 p24 antigenemia, TcR gamma delta+ lymphocyte counts were lower than those in nonantigenemic patients (P < 0.001). In the CDC II/III group, p24-antigenemic patients exhibited lower TcR gamma delta+ cell counts than those in patients without antigenemia (P = 0.06). Data suggest that depletion of the TcR gamma delta+ lymphocyte subset characterizes HIV-1-infected patients with oral candidiasis, pneumocystosis, toxoplasmosis, and/or HIV-1-antigenemia.

Human immunodeficiency virus-positive individuals with oral hairy leukoplakia are able to mount cytotoxic T lymphocyte responses to Epstein-Barr virus.

OBJECTIVE: Oral hairy leukoplakia (OHL) is a white lesion of the tongue that is caused by Epstein-Barr virus (EBV) and occurs mainly in people infected with human immunodeficiency virus (HIV). The aim of this study was to determine whether the presence of OHL reflects the absence of EBV-specific cytotoxic T lymphocyte (CTL) activity. SUBJECTS AND METHODS: EBV-specific CTL responses were measured in HIV-positive homosexual men with OHL, HIV-positive homosexual men without OHL, and HIV-negative homosexual men. Also, the phenotypes of cells responsible for EBV-specific responses were studied. RESULTS: Eighty percent (8/10) of HIV-positive subjects with OHL, 52% (12/23) of HIV-positive subjects without OHL, and 83% (15/18) HIV-negative subjects had a positive anti-EBV CTL response (P = 0.004, Kruskal-Wallis test). Two HIV-positive subjects showed a greater anti-EBV CTL response after developing OHL than before the appearance of OHL Additional experiments showed that CD8-positive T cells and CD4-positive T cells were responsible for the EBV-specific CTL responses. CONCLUSION: Our data show more EBV-specific CTL activities in HIV-positive individuals with OHL than in HIV-positive individuals without OHL. Whether the presence of EBV-specific CTL contributes to resolution of OHL remains to be clarified.