Clinical Presentation, Treatment and Outcome of HIV-Associated Multicentric Castleman Disease

Multicentric Castleman disease (MCD) is a monotypic but non-clonal lymphoproliferation with increased incidence in HIV infection. It is characterized by human herpes virus 8 (HHV-8) infection of the lymphocytes. Signs and symptoms (sx) are largely mediated by HHV-8 induced production of IL-6. Although life expectancy in MCD appears to have improved in the era of highly active antiretroviral therapy (HAART), it remains poor, and the optimal treatment approach in patients (pts) not responding to HAART is undefined due to few large series in which to evaluate management. Contributing to poor outcome is a concomitant increased incidence of other HHV-8 related disorders such as Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL), particularly primary effusion lymphoma and plasmablastic lymphoma (PBL). We report the clinical presentation, treatment and outcome of 8 pts with HIV associated MCD diagnosed and treated at our center since 2005.

Pts with HIV-associated MCD were identified from the clinical database of the hematology practice. Charts were reviewed and the following data was extracted: baseline characteristics such as prior opportunistic infections or neoplasms, HAART received and response (CD4 count, HIV viral load [VL]), clinical and laboratory features (including HHV-8 in tissues and plasma HHV-8 VL), MCD course as well as treatment and outcome.

Median age at onset of MCD sx was 43 (range 31–63) years (y) and all pts were male. HIV risk was men who have sex with men (MSM) in all and 1 pt had a history of KS. Seven pts were receiving HAART at MCD presentation and the median CD4 count was 385 (140-950) cells/mL and HIV VL 318 (<40-2080) copies/mL. The most common MCD presenting sx were: drenching sweats, n=7; fever, n=6; fatigue, n=4; shortness of breath, n=4; nausea, vomiting and diarrhea, n=3. Signs included: lymphadenopathy, n=8; splenomegaly, n=8; edema, n=4; ascites, n=3; hepatomegaly, n=3; jaundice, n=3; maculopapular rash, n=3; cutaneous KS, n=2. The most striking feature was the waxing and waning course in all pts. Pts were moderately to severely ill for up to several weeks (3 pts required ICU admission; total 6 episodes). Near complete recovery lasting up to several weeks followed after which signs and sx recurred. Common findings on investigation were: anemia, n=8; thrombocytopenia, n=7; hyperbilirubinemia, n=6; and interstitial pulmonary infiltrates, n=5. The median hemoglobin and platelet counts at MCD dx were 89 (67-114) G/L and 128 (34-199) × 10⁹/L, respectively, and 4 pts each required transfusion support. MCD dx was made in the presence of characteristic morphologic features and demonstration of tissue HHV-8 staining on biopsy (excisional lymph node, n=7; splenectomy, n=1; clinical probability plus HHV-8 plasma VL [7 ×10⁶ HHV-8 copies/mL] with positive stains for HHV-8 in the bone marrow, n=1). The median interval from onset of MCD sx to diagnosis (dx) was 7.5 (2-13) months and the time to MCD dx following HIV dx was a median of 9 (0.2-20) y. Concomitant conditions were: KS, n=5 (limited to lymph nodes, n=3; extensive cutaneous, n=2); hemophagocytic lymphohistiocytosis (HLH), n=2; PBL, n=1; Henoch-Schonlein purpura (HSP), n=1. One or more plasma HHV-8 VL measurements were obtained in 5 pts, and 5 were started on valgancyclovir (VGCV) as anti-HHV-8 therapy with a 6th pre-treatment. The median follow-up from MCD dx is 2.6 (0.1-66) months. VGCV was well tolerated. One pt receiving VGCV after not responding to HAART sustained a long term remission of both MCD and KS and remains clinically well 6 y from the onset of sx (5.25 y from starting VGCV). One pt developed tumor lysis syndrome following the initiation of VGCV and is currently improving clinically, 3 are early in VGCV treatment (1-10 weeks). Two pts died, including the pt with PBL, before MCD could be confirmed and treatment started.

MCD can be challenging to diagnose due to its waxing and waning nature and frequently poor accessibility of tissue for biopsy. Simultaneous diagnoses such as KS, NHL, HLH and HSP further compound these difficulties. Anti-HHV-8 therapy is a potentially promising treatment for MCD and possibly other HHV-8 mediated conditions, with a long term remission achieved in OUR first pt treated with VGCV. The diagnosis and management of MCD requires a multi-disciplinary approach. To our knowledge, this is one of the largest single institution experiences with HIV-associated MCD reported.

No relevant conflicts of interest to declare.