HHV-8-Associated Multicentric Castleman Disease

HHV-8-associated multicentric Castleman disease (HHV-8+ MCD) is a rare lymphoproliferative disorder caused by lytic reactivation of Kaposi sarcoma herpesvirus (HHV-8, also called KSHV) within B-cells in lymph nodes. The reactivating virus produces viral IL-6 (vIL-6) and other cytokines that cause recurrent episodes of severe systemic inflammation — with high fevers, lymphadenopathy, splenomegaly, and organ dysfunction. It predominantly affects HIV-positive individuals and is classified as an AIDS-defining illness. Most patients with HHV-8+ MCD also have or have had Kaposi sarcoma, as both diseases share the same viral driver.

HHV-8+ MCD is caused by lytic reactivation of HHV-8 (KSHV) — a herpesvirus transmitted sexually, through saliva, and via blood. HIV-driven immune deficiency removes the normal T-cell immune control over HHV-8, allowing lytic reactivation and cytokine-driven disease. The disorder predominantly affects HIV-positive men who have sex with men (MSM), in whom HHV-8 seroprevalence is high. Low CD4 counts and uncontrolled HIV replication increase the risk of MCD flares. Rare cases occur in HIV-negative immunocompromised individuals.

Diagnosis requires lymph node biopsy demonstrating the characteristic histopathology — plasmablastic proliferation in lymph node mantle zones with HHV-8 LANA-1 immunohistochemistry confirming viral infection of the plasmablasts. This is combined with elevated plasma HHV-8 DNA (viral load) confirming active viral replication, and clinical features of systemic inflammatory syndrome. HIV status, CD4 count, and assessment for concurrent Kaposi sarcoma and other HHV-8-related disorders are integral to the initial evaluation.

Rituximab (anti-CD20) is highly effective for HHV-8+ MCD and has transformed the management of this disease. It depletes CD20-positive B-cells and HHV-8-infected plasmablasts in lymph nodes, reducing viral IL-6 production and resolving the inflammatory syndrome. The majority of patients achieve clinical and virologic remission after a standard 4-week course of rituximab infusions. HHV-8 viral load typically falls dramatically with effective rituximab therapy. However, HHV-8+ MCD is a relapsing disorder for most patients — repeat rituximab courses at each flare, or maintenance rituximab, are required for long-term disease control.

Yes — transformation to KSHV-associated diffuse large B-cell lymphoma (KSHV-DLBCL) is a recognized and serious complication of HHV-8+ MCD. It typically presents with worsening clinical status, development of a dominant lymph node mass, and rising LDH despite ongoing rituximab therapy. Rebiopsy is urgently required to confirm transformation, as KSHV-DLBCL requires lymphoma-directed chemotherapy rather than rituximab alone and carries a much worse prognosis than untransformed MCD. Any patient with HHV-8+ MCD who clinically deteriorates or develops a new dominant mass should be rebiopsied promptly.

There is concern that rituximab — by depleting HHV-8-specific cytotoxic T-cells through effects on B-cell cognate immunity — may paradoxically enable KS progression in some patients with concurrent Kaposi sarcoma. Clinical experience suggests this risk is real in a subset of patients. When active Kaposi sarcoma requires treatment simultaneously with HHV-8+ MCD, coordination between KS management (liposomal doxorubicin) and MCD management (rituximab) with close monitoring for KS progression after rituximab infusion is important. This complexity underscores the need for specialist multidisciplinary care in the MCD/KS overlap setting.

Optimized antiretroviral therapy is an essential component of HHV-8+ MCD management in HIV-positive patients. ART suppresses HIV replication, enabling CD4 T-cell count recovery and restoration of immune surveillance over HHV-8. Improved CD4 counts reduce the frequency and severity of HHV-8 reactivation and MCD flares. ART alone is insufficient to control active HHV-8+ MCD flares (rituximab is still required), but it is critical for long-term disease control and prevention of new flares. Patients not yet on ART should start as soon as possible; those with detectable HIV viral load on ART need regimen review and optimization.

Yes. CancerFax can connect patients with HHV-8-associated multicentric Castleman disease to specialist hematologists, HIV-related malignancy experts, and Castleman disease specialists for medical report review, second opinions on diagnosis and treatment strategy, and access to specialist programs. For patients with refractory HHV-8+ MCD, transformation concerns, or concurrent Kaposi sarcoma, CancerFax can facilitate evaluation at leading centers in India and internationally with experience in managing these complex HHV-8-related disorders and access to relevant clinical trials and novel agents.