Dr.

Tahani Abualteen

Infections of oral mucosa IV

HIV-related oral infections: HIV is transmitted by the exchange of body fluids particularly through sexual contact, blood transfusion, or from the mother to child Transmission of the HIV virus may be followed by the following stages: o First stage (sero-conversion): Detection of HIV antibodies in blood This usually occurs within 3 months of exposure Few patients have an acute HIV infection with acute symptoms at this time, such as: pyrexia, skin rash, headache, diarrhea, sore throat o Following sero-conversion, most patients remain symptom-free for many years (HIV seropositive) o In time, patients may develop persistent generalized lymphadenopathy (PGL) ** In both persistent generalized lymphadenopathy and asymptomatic HIV-sero-positive patients there may then be progression to the AIDS-related complex (ARC) which is characterized by lymphadenopathy, persistent pyrexia, diarrhea, weight loss, fatigue, and malaise o Final Stage (fully developed AIDS "acquired immune deficiency syndrome"): Characterized by opportunistic infections, Kaposi's sarcoma, non-Hodgkin's lymphoma, but patients may also develop thrombocytopenia, and neurological disease Infection by HIV involves the binding of the virus to many target cells (e.g. T-helper lymphocytes, macrophages, CNS cells, endothelial cells ) but binding to the CD4 receptor of T-helper lymphocytes plays a major role in the pathogenesis of HIV disease After this binding occurs, infected T-helper cells die with a consequent reduction in the number of T-helper cells This results in impaired immunity particularly against T-cell dependant antigens, such as: viruses, fungi and encapsulated bacteria, and this accounts for most of the clinical manifestations of the disease ** Neutrophils are considered part of the innate or first-line defense and are still somehow functional in AIDS patients, so here patients can still fight bacteria by neutrophils but not the encapsulated bacteria, viruses or fungi, because these microorganisms need a specific immune response mediated by CD4 T-helper cells, thats why infections by these microorganisms are likely to increase in AIDS patients who have depressed number of CD4 cells

Oral manifestations of HIV infection (fully developed AIDS): Oral manifestations of HIV infection are numerous and have been divided into three groups based on the strength of their association with HIV infection

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Dr. Tahani Abualteen

Classification of oral lesions associated with HIV: Group 1 "lesions strongly associated with HIV" Candidosis (erythematous, psuedomembranous, hyperplastic) Hairy leukoplakia (EBV) HIV-associated periodontal disease (HIV-gingivitis, NUG, HIV-periodontitis, necrotizing stomatitis) Kaposis sarcoma Non-Hodgkin's lymphoma Group 2 "lesions less commonly associated with HIV" Atypical ulceration (oropharyngeal) Idiopathic thrombocytopenic purpura Salivary glands disorders (dry mouth, decreased salivary flow rate, uni- or bilateral swelling of major glands) Viral infections "other than EBV" (HSV, VZV, CMV, HPV) Group 3 "lesions possibly associated with HIV" Bacterial infections other than gingivitis/periodontitis Fungal infections other than candidosis Melanotic hyper-pigmentation Neurological disorders (facial palsy, trigeminal neuralgia)

Oral candidosis The most frequent oral manifestation of HIV infection Candida albicans is the commonest cause but other species, including Azole-resistant species may be involved Infections are usually chronic, showing atypical presentation and are resistant to treatment Psuedomembranous (thrush) and erythematous varieties are seen most frequently o Unlike their counterparts in non-HIV infected patients, they are chronic and may persist for months o May involve any part of the oral mucosa and may be multifocal Hyperplastic candidosis is most frequently seen on the cheeks but the commissures are rarely involved (unlike its counterparts in non-HIV infected patients where it mostly involves the commissures) Prevalence of oral candidosis in HIV-infection varies but is about: o 20% in HIV sero-positive patients have oral candidosis o 70% or more in fully developed AIDS patients have oral candidosis ** However this prevalence is decreasing nowadays with introduction of Highly Active Anti-Retroviral Therapy (HAART) Viral Infections Infections with HSV and VZV in association with HIV infection are more severe and extensive than when occurring in HIV sero-negative patients, and frequently recur

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Viral warts are often seen in the mouths of patients infected with HIV, and unusual types of HPV have been identified in some of these lesions Disseminated CMV infection may be seen in AIDS (intraorally causes non-specific chronic ulceration) EBV is the cause of Hairy leukoplakia and may be associated with some lymphomas Kaposi's sarcoma is associated with HHV8 ** Prevalence of some of the lesions associated with viral infections, particularly hairy leukoplakia, has reduced significantly since the introduction of HAART ** Prevalence of oral warts has increased Hairy Leukoplakia: o Common in patients with late stage HIV infection, and its development may indicates the onset AIDS o Presents as a white patch that can't be removed o Occurs most frequently on the lateral borders of the tongue, bilaterally, but other areas of the oral mucosa are affected o Clinically: presents as vertical white folds on lateral border of the tongue, with a raised, corrugated, or hairy surface. However the lesions may also have a smooth flat surface o Candidal hyphae may be present but the candidosis is a secondary rather than a causal infection because hairy leukoplakia has a rough surface that favors Candidal overgrowth o Occurs in non-HIV infected patients receiving immunosuppressive therapy (e.g. renal transplant patients) o NOT an idiopathic leukoplakia (since it has a recognizable cause and the term leukoplakia is used to simply mean a white patch) & NOT a premalignant lesion o Caused by opportunistic infection of the oral epithelium by EBV o Primary infection (either subclinically or as glandular fever) followed by latency in lymphocytes of oropharynx & salivary glands (Long term carrier state for EBV) in immunecompromised patients followed by reactivation of the virus (continuous shedding of the virus from its latency sites into saliva) leading to repeated re-infection of oral epithelial cells (especially those of lateral border of the tongue) ** Infectious mononucleosis = primary infection of EBV ** Hairy leukoplakia = secondary infection of EBV (resulting from reactivation of the virus on immune-suppression) o Minor trauma to tongue facilitates infection with virus (allows access of EBV from saliva to re-infect epithelial cells) ** Since lateral border of the tongue is frequently traumatized by biting/chewing (which damage some of the cells), it is the most common site invaded by EBV o Marked reduction of langerhans cells (antigen presenting cells) is seen in hairy leukoplakia lesions resulting in impaired antigen handling in the mucosa o Hairy leukoplakia is seen in HIV-infected patients from all risk groups, with a prevalence of about 20-25% overall (which has now decreased with the introduction of the HAART) 3/6

Dr. Tahani Abualteen

o Microscopically: Acanthotic parakeratinized epithelium often with long finger-like surface projections of Parakeratin producing the hairy/corrugated appearance seen clinically Absence of associated inflammatory cells both in the epithelium and in the lamina propria Swollen or balloon cells with prominent cell boundaries are present as band in prickle cell layer below the Parakeratin - Swollen cells contain EBV and have been described as "koilocyte-like cells, having small darkly staining nuclei and perinuclear vacuolization" - The term "koilocyte" should be confined to cells infected with HPV Demonstration of EBV is essential for the diagnosis (the virus can be seen using special staining techniques called in-situ hybridization "a method for detection of RNA or DNA") ** Lesions associated with HIV infected patients are characterized by the absence of inflammatory cells and marked reduction in Langerhans cells UNLIKE lesions associated with non-HIV patients

Kaposis sarcoma o Despite its name, it is not considered a true sarcoma (not a tumor arising from connective tissue) BUT it is a malignant neoplasm of endothelial cells (which are the cells lining blood vessels) o Clinical features: Commonest tumor associated with AIDS (its prevelanact is now low, particular for patients on HAART) More common in males than in females Associated with infection by herpes virus referred to as HHV8 which appears to have a causal role Multifocal tumor (multiple lesions) involving skin & mucosal surfaces Presents first as reddish-purple patches (surface lesion) which then become nodular (soft tissue enlargement) Oral lesions may be the presenting feature and are seen most frequently on the palate Tip of the nose is the most frequent skin/facial site May be resistant to treatment (no curative treatment!) Recurrence BUT NO metastasis 4/6

Dr. Tahani Abualteen

o Histology: Kaposis sarcoma Consists of proliferating malignant endothelial cells ** The origin of malignant cells is proved by immunohistochemistry (a method of detection of certain antigens) It is a vascular lesion with atypical cleft-like or slit-like vascular channels with extravasated RBC, hemosiderine and inflammatory cells Occasional atypical spindle-shaped cells may be seen - In later stages, vascular component decreases and atypical spindle cells predominate - In early stages, it is difficult to differentiate Kaposi's sarcoma it from other vascular lesions (e.g. Hemangioma and Pyogenic granuloma) HIV associated periodontal diseases: 1. HIV-gingivitis (linear gingival Erythema) 2. NUG 3. NUP ** HIV infection is associated with atypical and sometimes severe periodontal diseases ** Prevalence is less than 10% of all cases (prevelanact is now low, particular for patients on HAART) HIV-Gingivitis (linear gingival Erythema): o Linear band of Erythema/redness involving the free gingival margin but doesnt appear to be related to the accumulation of dental plaque (patients may have good oral hygiene) o This gingivitis is NOT responsive to plaque control o It may represent gingival hyperemia due to the release of vasoactive cytokines rather than gingival inflammation o Has been associated with Candida albicans o Prevalence is less than 10% of AIDS patients Necrotizing Ulcerative gingivitis (NUG): o In HIV-infected patients, the lesions may be persistent and extensive & may NOT respond to conventional treatment Necrotizing Ulcerative Periodontitis NUP: o Severe rapidly destructive process in which there is necrosis of gingival and periodontal tissues with necrosis, exposure and sequestration of alveolar bone ** Sequestration = separation of necrotic bone from the rest of bone

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o Due to sever impairment of local defensive mechanisms like reduction in CD4 cells o Defects usually localized o Not responsive to conventional periodontal therapy Other HIV-related lesions Non-Hodgkin's lymphoma o Increased incidence of non-Hodgkin's lymphoma is seen in AIDS patients o Oral mucosa involvement has been described o Some of these lymphomas are associated with EBV Neurological disturbances: o HIV is neurotropic (capable of infecting nerve cells) and may directly involve CNS causing different manifestations such as: Facial nerve palsy, peripheral neuropathy, dementia Atypical ulceration: o Particularly of the oropharynx o Resemble aphthous stomatitis and may be associated with CMV Salivary gland disease: o Xerostomia o Salivary gland enlargement associated with lymphocytic infiltrate o Lymphoepithelial lesions or cysts Idiopathic thrombocytopenic purpura: o Present as superficial bleeding spots due to reduction in the platelets count by an autoimmune response Oral pigmentation: o Melanin pigmentation of the oral mucosa has been reported but it is not clear yet whether this is due to the infection or the drugs therapy

HIV-associated HSV infection

6/6 HIV-associated VZV infection

HIV-associated oral ulceration