Oral ulceration in HIV infection: Investigation and pathogenesis

Oral ulcerations associated with HIV infection include recurrent aphthous ulcers (RAU). Whereas RAU prevalence is not increased, lesion severity is: among a group of HIV⁺ patients, 66% had the more severe herpetiform or major RAU. This increased severity suggests that HIV disease-related changes in the immune system may exacerbate RAU. In the peripheral blood of healthy subjects with RAU, CD4:CD8 cell ratios may be reversed and the proportion of T cell receptor-γδ⁺ cells increased. HIV disease-related immune system changes are characterized by reversed CD4:CD8, lowered CD4 cell counts and an inverse correlation between CD4 cell counts and per cent activated γδ lymphocytes. Adhesion molecules and cytokines involved in lymphocyte homing may be important in RAU pathogenesis: ICAM-I and ELAM are strongly expressed, and TNFα production is increased in peripheral blood lymphocytes of healthy patients with RAU. In patients with active HIV disease/AIDS, serum TNFα levels are increased. Thalidomide, which inhibits TNFα production, is effective treatment for RAU. Some RAU patients have vitamin B12 or folate deficiencies, levels of which are commonly low in HIV⁺/AIDS patients. However, in a case control study of HIV⁺ patients, vitamin B12- or folate-deficiencies were not found to be significant risk factors for RAU.     

Oral lesions in HIV infection in developing countries: an overview

HIV infection is a major global health problem affecting developing and developed countries alike. Oral lesions that are associated with this disease are important, since they affect the quality of life of the patient and are useful markers of disease progression and immunosuppression. Oral lesions in HIV infection have been well-documented in developed countries, but there are fewer reports on oral lesions from developing countries. Oral candidiasis is the most common opportunistic infection seen in all continents. Kaposi's sarcoma has been reported only from Africa and Latin America, while histoplasmosis and penicilliosis were reported in patients with advanced disease from Thailand. HIV-associated salivary gland disease has a high prevalence in Africa and Latin America, especially in the pediatric group. It is clear that there are considerable regional variations in the oral manifestations of HIV infection, depending both on the populations studied and on the clinical expertise available, among other factors. Well-designed and -documented studies are necessary for the correct assessment of the nature and magnitude of the problem in developing countries, if oral health measures are to be effectively formulated for the HIV-infected.     

Salivary gland disease in pediatric HIV patients: an update

Oral manifestations are one of the earliest clinical indicators of HIV infection and progression in children. Prompt recognition of these signs and symptoms by dental providers can help in the diagnosis and intervention of delaying the progression of HIV disease to AIDS. Salivary gland disease is a common manifestation of HIV infection in pediatric patients, presenting either as gland enlargement and/or xerostomia. The parotid glands by far are most frequently affected, though the other major glands are commonly involved. Diseases of the salivary glands and the corresponding quantitative changes in saliva affect the homeostasis of the oral cavity and account for significant morbidity during the progression of HIV disease. This paper summarizes the research on HIV-related salivary gland disease and outlines treatment and management considerations.     

Salivary immunoglobulin A antibodies to gp41 in human immunodeficiency virus–seropositive patients: lack of correlation with disease progression

Mucous membranes are the main route of transmission of human immunodeficiency virus (HIV). Interestingly, some viral inhibitory activities have been found in saliva. The purpose of this study was to determine the level of salivary immunoglobulin A (IgA) antibodies to gp41 in HIV⁺ patients at various disease stages to identify whether gp41was able to induce vigorous humoral responses. Unstimulated saliva samples were obtained from three groups of subjects (n=37): group A (HIV^?), group B (HIV⁺, CD4⁺ <200/mm³), and group C (HIV⁺, CD4⁺ >200/mm³). IgA antibody levels to purified gp41 were determined by enzyme‐linked immunosorbent assay (ELISA). Western blot analyses were performed using HIV⁺ saliva to confirm IgA reactivity to gp41. ELISA demonstrated that HIV⁺ subjects had higher IgA antibody to gp41 than HIV^? individuals. No significant differences were noted between HIV⁺, CD4⁺ <200/mm³ and CD4⁺ >200/mm³ subjects. High (81.25%) IgA reactivity to gp41 was demonstrated by Western blotting of saliva from all HIV⁺ individuals. In conclusion, gp41 responses are important in the HIV disease process, as indicated by the high IgA levels and gp41 reactivity in saliva of HIV⁺ patients.     

Oral manifestations in 70 German HIV-infected women

OBJECTIVE: To describe the prevalence of oral lesions in HIV-infected women, and to determine the association of oral lesions with the level of immunosuppression and the route of transmission. PATIENTS: In a retrospective, cross-sectional study, a cohort of 70 HIV-infected women (median age: 32.5 y; median CD4⁺-cell count 262 per μl) comprising 18% of all HIV-infected individuals (n = 389) was selected in an outpatient clinic. Oral lesions strongly associated with HIV-infection were evaluated. RESULTS: The overall prevalence of oral lesions was 27/70 (39%). Among HIV-infected women with CD4⁺-cell counts <200 per μl, the prevalence was 65% (19/29); and with counts >200 per μl, the prevalence was 27% (11/41). The prevalence of candidiasis and hairy leukoplakia was similar among those infected heterosexually or by intravenous drug use. CONCLUSIONS: As reported in men, these findings demonstrate that oral lesions are common in HIV-infected women. Candidiasis is more likely to occur at low CD4⁺-cell counts, whereas no difference was seen regarding the level of immunosuppression and hairy leukoplakia. Interestingly, the route of transmission does not play a role regarding the presence of oral lesions among HIV-infected women.     

PLUNC protein expression in major salivary glands of HIV‐infected patients

Oral Diseases (2011) 17 , 258–264 Objective: To analyse and compare the expression of Palate, Lung, and Nasal Epithelium Clone (PLUNC) proteins in salivary glands from patients with and without AIDS (control group) using autopsy material. Methods: We analysed the expression of PLUNCs using immunohistochemistry in parotid (n = 45), submandibular (n = 47) and sublingual gland (n = 37) samples of AIDS patients [30 with normal histology, 21 with mycobacteriosis, 14 with cytomegalovirus (CMV) infection, 30 with chronic non‐specific sialadenitis, and 30 HIV‐negative controls. In situ hybridization (ISH) for SPLUNC 2 in the HIV‐negative group was performed. Results: SPLUNC 1 expression was detected in the mucous acini of submandibular and sublingual glands, and SPLUNC 2 were seen in the serous cells. LPLUNC 1 expression was only positive in the salivary ducts. There was a higher expression of SPLUNC 2 in AIDS patients with CMV infection and mycobacteriosis when compared with all other groups. The intensity of staining for SPLUNC 2 was greater around the lesions than the peripheral ones. ISH for SPLUNC 2 showed perinuclear positivity in the serous cells in all HIV‐negative cases. Conclusions: SPLUNC 1 and LPLUNC 1 proteins were similarly expressed in the salivary glands of AIDS patients and non‐HIV patients. CMV infection and mycobacteriosis increase SPLUNC 2 expression in serous cells in the salivary gland of AIDS patients.     

Reduced serum IgG reactivities with bacteria from dental plaque in HIV-infected persons with periodontitis

Abstract Serum samples were obtained from 44 HIV-seropositive (HIV⁺) and 37 HIV-seronegative (HIV^-) persons that were grouped according to periodontal status. Serum IgG and IgA reactivities towards Streptococcus mutans, Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis. Prevotella intermedia, Prevotella nigrescens and Fusobacterium nucleatum were measured by means of ELISA. HIV⁺ persons with chronic marginal periodontitis showed significantly lower IgG reactivities to the periodontal pathogens A. actinomycetemcomitans, P. gingivalis, P. intermedia and F. nucleatum as compared with their HIV^- counterparts (p<0.05). Specific serum IgA reactivities were similar in the two periodontitis groups, except for P.nigrescens where the HIV⁺ group with chronic marginal periodontitis had lower values than their systemically healthy counterparts (p<0.05). The results indicate that HIV infection affects the humoral serum immune responses against bacteria in dental plaque; the depressed antibody responses may contribute to the increased susceptibility for periodontal infections in HIV-infected patients.     

Prognostic factors in primary salivary gland mucoepidermoid carcinoma: an analysis of 376 cases in an Eastern Chinese population

Mucoepidermoid carcinoma (MEC) is an infrequent malignant neoplasm that originates most commonly in the salivary glands. The present study aimed to provide new information on prognostic factors in patients with salivary gland MEC. A retrospective analysis of the medical records of patients diagnosed with primary salivary gland MEC between 2003 and 2010 was conducted. The incidence of MEC in the minor salivary glands (62.2%) was almost twice that in the major salivary glands (37.8%). The most frequently affected sites were the parotid gland and palate. Lymph node metastasis was reported more frequently in male than female patients (P = 0.02), in high-grade than low/intermediate grade lesions (P < 0.001), and in lesions involving the submandibular gland (P < 0.001). The disease-free survival (DFS) at 5 years was 80.47%, with rates of 98.0%, 86.5%, and 38.5% for low-, intermediate-, and high-grade tumours, respectively. Among various clinicopathological factors, the only independent prognostic factor was histological grade (P < 0.001). Primary tumour site and histological grade are two important factors affecting cervical lymph node metastasis. Histological grade is the only independent factor affecting survival beyond tumor lymph node metastasis (TNM) staging in salivary gland MEC. Further advances in therapy are needed to improve the outcomes for patients with high-grade lesions.     

Multiple parotid lymphoepithelial cysts in patients with HIV-infection: report of two cases

OBJECTIVE: Bilateral and multiple lymphoepithelial cysts (LECs) of major salivary glands, in particular of parotid glands, are quite rare and have been reported in human immunodeficiency virus (HIV) infected patients with an incidence of about 3-6%. These lesions represent an early manifestation of HIV infection and are rarely found in patients with advanced acquired immunodeficiency syndrome. MATERIALS: Two cases of parotid LECs, the first occurring in a middle-age white woman and the second in a young white boy, both in advanced phases of HIV infection, are reported. RESULTS: Clinical, cytological, histological and immunohistochemical (cytokeratin AE1/AE3, CD20, CD45RA, CD8, kappa and lambda immunoglobulin light chains, S-100, MLA and Ki67) features are described. CONCLUSIONS: Fine needle aspiration (FNA), a relatively non-traumatic procedure, could represent both a diagnostic and a therapeutic tool in parotid LECs. No surgical therapy is usually required for these lesions and aspiration of cystic fluid with FNA is quite resolutive, although evidence of further relapses does exist. Surgical excision may become necessary when pain, because of persistent and progressive swelling of the parotid gland, occurs.     

Occurrence of oral lesions in relation to clinical and immunological status among HIV-infected adult Tanzanians

OBJECTIVE: To determine the association, if any, between the presence of oral lesions and clinical and immunological status of untreated HIV-infected adults in Tanzania. DESIGN: A cross-sectional study. SETTING: AIDS Clinical Trial Clinic (ATCC) at Muhimbili Medical Centre in Dar-es-Salaam, Tanzania. SUBJECTS: 192 HIV-infected individuals not receiving treatment; 156 individuals confirmed to be HIV-seronegative acted as a control group. METHODS: Examination of oral structures, determination of HIV serostatus, clinical status, and peripheral CD4+ T cell and total lymphocyte counts. MAIN OUTCOME MEASURE: Presence of oral lesions. RESULTS: Intra-oral lesions were seen among 7.7% of the HIV-seronegative, 10.4% of the HIV-seropositive and 36.8% of the AIDS groups, respectively. Enlarged parotid glands were seen in 20% of the AIDS patients, 11.9% of the HIV-seropositives, and 5.1% of the HIV seronegatives. Enlargement of submandibular salivary glands was seen in 29.6% of the AIDS patients, 31.3% of the HIV-seropositives compared with 14.7% among the HIV-seronegatives. Multiple regression analysis was used to calculate adjusted odds ratio (OR) for presence of oral lesions. OR for an intra-oral lesion was 1.6 (95% CI = 0.5; 5.0) among the HIV-seropositives and 8.2 (95% CI = 3.5; 19.7) among the AIDS patients using the HIV-seronegatives as reference. OR for an intra-oral lesion was 0.9 (95% CI = 0.3; 2.9) in HIV-infected patients with peripheral CD4+ T cell count of between 200-500 cells mm-3 and 2.7 (95% CI = 0.9; 7.7) in patients with less than 200 cells mm-3. OR for an intra-oral lesion was 0.4 (95% CI = 0.2; 0.9) for patients with peripheral total lymphocyte counts of between 1000-2000 cells mm-3 and 0.9 (95 CI = 0.4; 2.0) for patients with less than 1000 cells mm-3. CONCLUSION: The association of oral lesions with the clinical stage of HIV infection and to a lesser extent peripheral CD4+ T cell count does suggest that these lesions could be used as additional markers of immunosuppression and AIDS.     

Oral manifestations of HIV infection in 600 South African patients

Arendorf TM, Bredekamp B, Cloete CAC, Sauer G: Oral manifestations of HIV infection in 600 South African patients. J Oral Pathol Med 1998; 27: 176-9. C Munksgaard, 1998. Oral lesions associated with HIV infection, as classified by the EC-Clearinghouse on Oral Problems related to HIV infection and the WHO Collaborating Centre on Oral manifestations of the immunodeficiency virus, were studied in 600 consecutive HIV-infected patients in Cape Town, South Africa. One or more lesions were seen in 60.4% of cases. Combined candidal lesions were evident in 37.8%, hairy leukoplakia in 19.7% and combined gingival/periodontal lesions in 8.5% of patients seen. Lesions less commonly recorded include oral ulceration (2.9%) and Kaposi's sarcoma (1.5%). The clinical range of lesions seen is similar to those reported elsewhere, but socio-cultural differences allowed no reliable comparison. More than a quarter of our patients had oral soft tissue discomfort necessitating treatment; in 3.3% these were the presenting symptom. This indicates a potential major public health concern requiring education in recognition and appropriate referral and management.     

Th1/Th2 cytokine profiles in saliva of HIV‐positive smokers with oropharyngeal candidiasis

Oropharyngeal candidiasis (OPC) is a common opportunistic infection among HIV‐positive individuals and often correlates with a CD4 cell number < 200 cells/µl. This study further examined the association of smoking and OPC in HIV‐positive persons. A strong association between smoking and OPC was seen in HIV‐positive individuals with ≥ 200 CD4 cells/µl. In HIV‐positive persons with ≥ 200 CD4 cells/µl, OPC⁺ smokers had lower gamma‐interferon (IFN‐γ) concentrations and a trend toward higher interleukin (IL)‐4 concentrations in whole saliva compared to OPC^– persons with ≥ 200 CD4 cells/µl, a cytokine profile consistent with that observed in HIV⁺OPC⁺ persons with < 200 CD4 cells/µl. These results suggest that premature OPC in HIV‐positive smokers is associated with altered oral host defence mechanisms that cannot be overcome by levels of systemic CD4 cells that are otherwise sufficient to protect against OPC.     

Some unusual oral lesions in HIV infection: Comments on the current classification

Of the numerous oral lesions reported in HIV-infected patients, four entities will be discussed in this paper: linear gingival erythema; cystic lymphoid hyperplasia of the parotid gland; oral non-Hodgkin's lymphoma; and oral squamous cell carcinoma. Based on the literature and the author's personal experience, it appears that linear gingival erythema is perhaps a specific HIV-associated periodontal lesion, but that insufficient data are available in the literature yet to classify this periodontal lesion as a lesion that is strongly associated with HIV infection. On the other hand, cystic lymphoid hyperplasia of the parotid gland has been rather widely reported and has characteristic histopathological features that would justify consideration of this lesion as highly indicative of an underlying HIV infection. Oral non-Hodgkin's lymphoma, at present regarded as a lesion ‘strongly associated with HIV infection’, is less characteristic in this respect and should merely be classified as ‘a lesion seen in HIV infection’. Oral squamous cell carcinomas, not included in the most recent International Classification of Oral Manifestations of HIV infection, should be listed in Group 3 of that classification, representing ‘lesions seen in HIV infection’. Further criteria should be developed that will enable distinctions to be made between lesions ‘strongly associated with’, ‘less commonly associated with’, and ‘seen in’ HIV infection.     

Relationship of cytomegalovirus to salivary gland dysfunction in HIV-infected patients

In a previous retrospective study of HIV-infected patients we detected a relationship between xerostomia and the presence of cytomegalovirus in saliva. This prospective study compares 13 patients with HIV and a complaint of xerostomia and low salivary flow rates with a control group of 7 patients with HIV without xerostomia and normal salivary flow rates. Both groups were evaluated for the presence of cytomegalovirus in saliva, peripheral blood mononuclear cells, and labial minor salivary glands. Viral cultures, polymerase chain reaction, and histopathologic examination were used to detect cytomegalovirus. Xerostomia and low salivary flow rates were associated with the presence of CMV in saliva. The virus was detected in 10 of 13 xerostomia patients and 2 of 7 controls (p = 0.05, Fisher's exact test). Cytomegalovirus was detected in the saliva of patients who did not also have it in their blood suggesting a local source of virus replication such as the salivary glands. The minor salivary glands were not a major site of cytomegalovirus. Culture was more sensitive then polymerase chain reaction in detecting salivary cytomegalovirus as a result of the presence of inhibitors to the reaction in saliva. These results suggest a link between cytomegalovirus in saliva and salivary gland dysfunction in HIV-infected patients.     

Metastatic malignancy in the submandibular gland.

Metastatic disease in the major salivary glands has been observed and reported in the literature. Often the site of origin of the primary tumor is the skin or mucosal lining of the head and neck structures, and the primary tumors most commonly are melanomas or squamous-cell carcinomas. The most frequently involved salivary gland is the parotid. The submandibular and sublingual glands are rarely involved by mestastatic disease. Secondary lesions arising from distant primary tumors may occasionally involve the parotid gland, but they are extremely rare in the other major salivary glands. The second reported case of metastatic carcinoma in the submandibular gland is presented here. Our case and the previously reported case are similar in that both primary tumors originated in the breast. The clinical and morphologic features are reviewed.     

HIV-associated salivary gland disease: a review.

Human immunodeficiency virus-associated salivary gland disease (HIV-SGD) is defined as the presence of xerostomia and/or swelling of the major salivary glands. It is common among children but uncommon among adults. HIV-SGD includes lymphoepithelial lesions and cysts involving the salivary gland tissue and/or intraglandular lymph nodes, and Sj?gren's syndrome-like conditions, diffuse interstitial lymphocytosis syndrome, and other reported lesions of the major salivary glands. This article reviews the terminology, prevalence, symptoms, clinical features, diagnostic procedures, histopathology, serology, natural history, treatment, and pathogenesis of HIV-SGD.     

Fine-needle aspiration cytology: a reliable tool in the diagnosis of salivary gland lesions

J Oral Pathol Med (2012) 41 : 106–112 Background: Fine‐needle aspiration cytology (FNAC) is used as the main initial diagnostic investigation for lumps in the head and neck region. Major salivary glands and some minor salivary glands are easily accessible; therefore, they are optimal targets for FNAC. The aim of this study was to discuss the advantages and pitfalls of FNAC as compared to histopathology in the salivary gland lesions. Material and methods: A total of 127 FNAC were carried out on salivary gland lesions from January 2006 to December 2010 – a 5‐year period. Histopathological follow‐up data were obtained in 56 cases. The study was conducted to examine the sensitivity, specificity, and accuracy of FNAC for salivary gland swellings in comparison with histopathology. Results: The male‐to‐female ratio was 2.4:1. Parotid gland was involved in 51.1%, submandibular gland in 37%, sublingual gland in 4.7%, and minor salivary glands in 7% of patients. There were 55.9% cases of non‐neoplastic lesions and 44.1% cases of neoplastic lesions on biopsy. Sensitivity, specificity, positive predictive value, and negative predictive value of FNAC for malignant neoplastic lesions were 84.61%, 86.48%, 68.75%, and 94.11%, respectively, whereas for benign neoplastic lesions, they were 84.61%, 91.66%, 91.6%, and 85%, respectively. Conclusion: Fine‐needle aspiration cytology is found to be a good sensitive and specific technique for the diagnosis of most of the salivary gland lesions. FNAC should be adopted as an initial investigation for all salivary gland swellings in conjunction with other investigations where appropriate.     

Murine autoimmune exocrinopathy: the minor salivary gland network shows a dichotomous pattern of histopathologic involvement

The minor salivary gland network of the MRL/1 mouse was investigated in a kinetic study and compared with the major submandibular gland. We report that minor salivary glands adopt two mutually exclusive patterns of inflammatory lesions depending on the gland. The first pattern is characteristic of human Sjogren's syndrome. It developed during the second month, affected 89% of the animals over 20 weeks old, and consisted of an accumulation of mononuclear cells around the duct system. Only the anterior buccal gland (ABG) showed this pattern, which is shared by the major salivary glands. The ratio of CD44+ to CD8+ cells was the same in lesions and in healthy tissue. No neutrophils were found in these lesions. The second pattern affected all the minor salivary glands except the ABG. These lesions were never observed before the age of 20 weeks and affected 38% of MRL/1 mice between the ages of 10–32 weeks. In this pattern, neutrophils were frequently found, but mainly gathered at the periphery of the gland lobules. That a systemic immunoregulatory defect may be expressed as two different patterns of histopathology in the minor salivary glands suggest that the network behaves as a dichotomous entity depending on particular microenvironmental influences.     

CD8 T cells and E-cadherin in host responses against oropharyngeal candidiasis

Oral Diseases (2012) 18 , 153–161 Background: Oropharyngeal candidiasis (OPC) is the most common oral infection in HIV⁺ persons. Previous studies suggest a role for CD8⁺ T cells against OPC when CD4⁺ T cells are lost, but enhanced susceptibility to infection occurs when CD8⁺ T‐cell migration is inhibited by reduced tissue E‐cadherin. Objective: To conduct a longitudinal study of tissue CD8⁺ T‐cells and E‐cadherin expression before, during, and after the episodes of OPC. Methods: Oral fungal burden was monitored and tissue was evaluated for CD8⁺ T cells and E‐cadherin over a 1‐year period in HIV⁺ persons with a history of, or an acute episode of, OPC. Results: While longitudinal analyses precluded formal interpretations, point prevalence analyses of the data set revealed that when patients experiencing OPC were successfully treated, tissue E‐cadherin expression was similar to that in patients who had not experienced OPC, and higher numbers of CD8⁺ T cells were distributed throughout OPC^? tissue under normal expression of E‐cadherin. Conclusion: These results suggest that (1) reduction in tissue E‐cadherin expression in patients with OPC⁺ is not permanent, and (2) high numbers of CD8⁺ T cells can be distributed throughout OPC^? tissue under normal E‐cadherin expression. Together, these results extend our previous studies and continue to support a role for CD8⁺ T cells in host defense against OPC.     

Natural history of HIV-associated salivary gland disease.

To describe the natural history of HIV-associated salivary gland disease, which is characterized by enlarged major salivary glands and/or xerostomia in HIV-infected persons, we assessed 22 patients at an initial and follow-up examinations (median span of examinations, 15 months). Sixteen patients (73%) had bilateral parotid gland enlargement, 17 had symptoms of dry mouth, and 11 had both conditions. Parotid gland enlargement remained unchanged in 10 patients, it progressed in 2, and it regressed in 4 during treatment with zidovudine or steroids. Those patients with parotid gland enlargement had a significantly lower mean stimulated parotid flow rate (0.27 ml/min/per gland) than a control group of HIV+ persons without salivary gland disease (0.48 ml/min/per gland) (p less than 0.05), whereas the mean unstimulated whole salivary flow rates did not did not differ significantly between the two groups. The mean salivary flow rate of the study group did not change during the observation period. When HIV-associated salivary gland disease was diagnosed, 5 patients (23%) had AIDS, and at follow-up 10 (46%) had AIDS. Seven of these had Kaposi's sarcoma. The mean peripheral blood CD4 cell count was 280 and 225 per mm3 at the initial and follow-up examinations, respectively. The corresponding CD8 counts were 1138 and 900. The pathogenesis of HIV-associated salivary gland disease may include hyperplasia of intra-parotid lymphoid tissue. Because HIV-associated salivary gland disease can clinically resemble Sj?gren's syndrome, the differential diagnosis of bilateral parotid enlargement should include HIV infection.