Clinical syndromes associated with Kaposi Sarcoma Herpesvirus lytic replication: Comparing features of KSHV Inflammatory Cytokine Syndrome, Multicentric Castleman Disease and Hemophagocytic Lymphohistiocytosis
Background: Kaposi Sarcoma Herpesvirus (KSHV) is the causative agent for Kaposi Sarcoma (KS), Primary Effusion Lymphoma (PEL) and Multicentric Castleman Disease (MCD). The recently described entity KSHV Inflammatory Cytokine Syndrome (KICS) shares features of systemic inflammation with MCD but lacks the characteristic pathology.
Methods: Symptomatic patients with plasma KSHV DNA > 4 log copies/mL were identified at Harborview Medical Center in Seattle, WA. They were categorized according to the National Cancer Institute HIV/AIDS Malignancy Branch working case definition of KICS and Hemophagocytic Lymphohistiocytosis (HLH)-2004 criteria. KSHV DNA was measured by an in-house PCR assay for ORF73; Interleukin-6 (IL-6) by sandwich immunoassay (Viracor-IBT); and Immunohistochemistry by monoclonal antibody for LANA-1.
Results: In a 1 year period, we treated 3 patients with inflammatory syndromes associated with KSHV lytic replication. All were HIV infected, with CD4 counts 506, 216 and 230 cell/µL, HIV plasma RNA 5.0, 2.3, 1.9 log copies/mL, with antiretroviral therapy used by the latter 2 patients. Each had fever > 40oC, fatigue and respiratory or neurologic symptoms. Labs revealed marked thrombocytopenia, anemia, hypoalbuminemia and elevated plasma CRP (100, 147, 94 mg/L), IL-6 (n/a, 243, 94, normal < 17 pg/mL) and KSHV PCR (7.2, 4.8, 6.1 log copies/mL). Radiography showed diffuse lymphadenopathy (3/3), splenomegaly (2/3) and pleural effusion (1/3). Patient 1 had reactive hyperplasia on lymph node (LN) biopsy, was diagnosed with HLH and treated with cyclosporine and dexamethasone; patient 2 had KS with non-specific MCD-like changes (see Figure), was diagnosed with KICS and treated with valganciclovir and rituximab + doxorubicin (val + R-Dox); and patient 3 had flare of MCD and was treated with val + R-Dox. All patients are alive at mean (range) 204 (23 – 373) days with median 1 relapse.
Conclusion: KSHV can cause critical illness by an IL-6 mediated inflammatory process clinically similar to severe sepsis or HLH. KICS and MCD are different by subtle findings on pathology and diagnostic uncertainty persisted after applying the case definition. Antiviral, immunomodulatory and cytotoxic chemotherapies were used with good outcome in these 3 patients.
A. Kalapila, None
D. Drozd, None
R. Bender-Ignacio, None
X. Chen, None
G. Gottlieb, None
V. Broudy, None
C. Casper, None