ID Case Conference February 13, 2008 Carlos M. Perez, MD, FACP Associate Professor of Medicine Pontificia Universidad Catolica de Chile

The Case HPI: ♂ 22 yo, HIV (+) diagnosed in May 2007 when he had elevated LFTs and positive CMV antigenemia (“Acute CMV infection with Hepatitis”). CD4 559 cells/mm3. HIV viral load 57,800 copies/mL. (-) RPR. (-) IgG Toxoplasma. (+) Anti core Ab Hepatitis B. (-) HBsAg. (-) Hepatitis C. CD4: 352 (June)  261 (July)  224 (August) HAART started in September: TDF+3TC+EFV

The Case HPI: Two weeks after initiation of HAART developed a generalized maculopapular erythematous rash, fever, nasal congestion and sore throat. Symptoms did not improve with antihistaminics and Ibuprofen and the patient was admitted for further work up.

PMH & PSH: “Viral meningitis” October 2006 Medications: TDF+3TC+EFV Allergies: Ketoprofen SH: MSM. Student. Tobacco ½ pack a day. Occasional ETOH. One sexual partner. No pets. No recent travel. ROS: As described

Physical exam P: 100 x min BP:110/70 T: 39 °C, RR: 22 x min. Normal saturation. Skin: Generalized erythematous maculo papular rash. No mucosal involvement. Generalized lymphadenopathy (cervical, axillary, inguinal): Variable sizes, some tenderness. HEENT: Nasal congestion. Congestive Pharynx. No exudates. Lungs and Heart wnl Abdomen: Hepatosplenomegaly 3- 4 cm below costal margin. Extremities and Neurological examination wnl

Discussion

Laboratory

7,9 Calcium 6,5 Proteins 3,0 Albumin 15 CRP 2,6 Phosphorus 122 Glucose 133 LDH 98 Alc P 20 ALT 0,52 Bili T 12 BUN 0,66 Creatinine Oct 20, 2007 Chemistry - T. Gondii IgM RSV Resp Viral Panel - Bartonella sp - IgM PVB19 +/- Ig G/IgM EBV - Ig M CMV/PP65 - Blood cultures Oct 22, 2007 Serologies

Imaging CT Neck, Chest, Abdomen and Pelvis: Multiple lymphadenopathy. Moderate hepatosplenomegaly. Mild bilateral pleural effusion and Ascites.

Imaging

Discussion

Lymph node Flow cytometry

Lymph node Pathology (1) Angiofollicullar hyperplasia with hyaline vessels penetrating follicles. Increase lymphocytes in mantle zone with an “onion-skin” arrangement around the germinal centers.

Lymph node Pathology (2) Spindle-shaped cells and neovascularization with aberrant proliferation of small vessels. Extravasations of erythrocytes and hemosiderin deposits.

Lymph node Pathology (3) Nuclear immunoreactivity to HHV-8/KS latency nuclear antigen

Conclusion: Multicentric Castleman’s Disease and Kaposi Sarcoma in an HIV- infected patient

Clinical course HAART was maintained and patient's symptoms slowly improved without specific treatment. Conclusion: Multicentric Castleman’s Disease and Kaposi Sarcoma as Immune Reconstitution Syndrome

Castleman´s disease Castleman's disease (CD, angiofollicular lymph node hyperplasia), is a lymphoproliferative disorder described in 1956 by Benjamin Castleman, who identified a series of patients with solitary hyperplastic mediastinal lymph nodes with small germinal centers resembling Hassall's corpuscles of the thymus. Two clinical foms: Unicentric and Multicentric (MCD). It is associated with HHV-8 (universally found in HIV+ MCD and 40-50% HIV- MCD).

Castleman´s disease There is an immunoblastic hyperplasia and plasma cell formation. The mantle zone lymphocytes in CD are polyclonal IgM or IgD- expressing cells. The plasma cells in the interfollicular areas are generally also polyclonal, although localized clonal expansions are sometimes seen. Associated with other malignacies: KS (70%), NHL (15-20%), HL, POEMS Syndrome (polineuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes)

Castleman´s disease Pathogenesis: It has been hypothesized that HHV-8 could be the triggering antigen for the induction of a pathological process via abnormal IL-6 production (viral and human IL-6). Clinical features: Median age yo. 65% male. Fever (10 %), night sweats, weight loss, fatigue, dyspnea, peripheral lymphadenopathy (100%), hepatosplenomegaly (50%). Laboratory abnormalities include nearly universal anemia, hypoalbuminemia, hypergammaglobulinemia, and elevated sedimentation rate.

Castleman´s disease Clinical course: Most patients with multicentric CD die of fulminant infection, progressive Castleman's disease or related malignancies. Treatment: Steroids, Chemotherapy, Antiviral agents (Cidofovir, Ganciclovir, Foscarnet), Inhibition of IL-6 ( Tocilizumab and Altlizumab), Thalidomide, Rituximab + HAART (median survival 48 months versus 14 months without HAART)

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