Case 3 -

Erosive Herpes Simplex Infection, Immune Restoration Inflammatory Syndrome Ann Marie Nelson Armed Forces Institute of Pathology Washington DC

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Clinical History: 57 y/o man with AIDS who presented with chronic, severe penile ulcerations and a previous diagnosis of genital herpes simplex. He received empiric therapy for herpes and fungal infections, with no improvement. RPR and FTA are negative. His antiretroviral therapy consists of Lopinavir, Efavirenz, Abacavir, and Tenfovir. His CD4 count increased from a nadir of 20/µl to 243/µl and his viral load decreased from >750,000 copies to undetectable over a period of 6 months. Case 3 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 3 - Figure 1 Penis, biopsy (HE 4x) shows ulceration and a diffuse sub-cutaneous infiltrate. Case 3 - Figure 2 Penis, biopsy (HE, 10x) higher power showing the edge of the ulceration with acute inflammation. Case 3 - Figure 3 Penis biopsy (HE 40x) High power of infiltrate show a mixed inflammatory infiltrate of lymphocytes, plasma cells and eosinophils. Note the epithelial cells with viral inclusions in the left side of the image Case 3 - Figure 4 Penis biopsy (HE 40x) The lymphocytic infiltrate seen here raised concern of a lymphoproliferative process. Immunostained revealed a predominance of CD3+/CD8+ T-cells. Case 3 - Figure 5 Penis biopsy (HE 40x) Edge of ulcer showing necrosis, hemorrhage and a large cell at the surface with smudged nuclear chromatin. Immunostaining for HSV 1,2 was reactive in this cell. Histologic Findings: Penile biopsy shows ulceration with a dense inflammatory infiltrate in the submucosa comprised of plasma cells, atypical lymphocytes and eosinophils. Neutrophils are abundant in the areas of ulceration. Islands of epithelial cells are present within the lesion, some of which show reactive atypia with rare viral cytopathic changes. Immunostains show a reactive profile with a predominance of CD8+ lymphocytes. HSV 1, 2 is reactive in epithelial cells. Warthin-Starry was negative. Diagnosis: Erosive herpes simplex infection, immune restoration inflammatory syndrome. Discussion: This is an unusual case of recurrent herpes simplex infection. The dense lymphoplasmacytic infiltration and lack of response to herpes therapy, lead the submitting pathologist to consider a lymphoproliferative lesion. Chemotherapy and radical excision were considered by the treating physicians. Other sexually transmitted infections such as syphilis and chancroid would also be considered, but were ruled out by special stains and syphilis serology. Herpes virus inclusions were not seen on HE in the original sections but were suspected on recuts and Immunohistochemistry confirmed that diagnosis. Herpes simplex is an AIDS-indicator infection when it causes chronic ulcers, bronchitis, pneumonitis, or esophagitis. Herpes simplex and varicella zoster virus infections characteristically are manifest by an intraepidermal acantholytic vesicular dermatitis associated with characteristic cytopathic effects in epithelial cells. Margination of the chromatin occurs, along with ballooning nuclear degeneration associated with pinkish intracytoplasmic and intranuclear inclusions known as Cowdry bodies. Cells float freely within a vesicle space and are associated with a variable amount of inflammatory infiltrate in the dermis, consisting of lymphocytes, histiocytes, eosinophils, neutrophils, and plasma cells. Untreated lesions may continue to enlarge dramatically and become quite deeply situated and extremely painful. Other lesions may appear verrucous and hyperplastic. Epithelial sites other than mucocutaneous, may be involved, including the cornea, tracheobronchial tree, and esophagus as well as visceral sites such as the lung, pericardium, liver, and brain. Immune Restoration/Reconstitution Syndrome: Following the initiation of highly active antiretroviral therapy (HAART) some patients develop exaggerated local and systemic inflammatory reactions. The immune restoration syndrome usually occurs within the first few months of initiating therapy and coincides with a decrease in viral load and an increase in CD4+ T-lymphocytes. The reaction is thought to be due to increased hypersensitivity to the antigens. Patients with low nadir CD4 counts are at higher risk for this condition. as seen in the present case. These paradoxical reactions have been reported most commonly in cases of tuberculosis and MAC disease involving lymph nodes. Histologic features include reactive lymphadenopathy, edema and granulomatous reactions, often with few or no acid-fast bacilli identified. CNS conditions include retinitis, uveitis and vitritis due to CMV, symptomatic cryptococcal meningitis, toxoplasmosis and exacerbation of progressive multifocal encephalopathy. Other reported conditions include acute viral hepatitis B and/or C, HPV-associated oral warts, recurrent herpes zoster, erosive HSV, and sarcoidosis. This diagnosis should be considered in patients recently (within the past year) who have worsening symptoms of inflammation or infection that cannot be explained by a newly acquired infection or disease or the natural course of a preexisting infection. References: Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: Validating a case definition and identifying clinical predictors in persons initiation antiretroviral therapy. Clinical Infectious Disease 2006, 42:1639-43. Fox PA, Barton SE, Francis N et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Medicine 1999, 1:10-18. Nadal SR, Calore EE, Manzione CR et al. Hypertrophic herpes simples simulation anal neoplasia in AIDS patients: report of five cases. Dis Colon Rectum, 2005, 48:2289-93. Hofman P, Nelson AM. The pathology induced by highly active antiretroviral therapy against human immunodeficiency virus: an update. Current Medicinal Chemistry, 2006, 13:3121-32.