Soon after the discovery of Kaposi sarcoma (KS)-associated herpesvirus (KSHV), it was appreciated that this virus was associated with most cases of multicentric Castleman disease (MCD) arising in patients infected with human immunodeficiency virus. It has subsequently been recognized that KSHV–MCD is a distinct entity from other forms of MCD. Like MCD that is unrelated to KSHV, the clinical presentation of KSHV–MCD is dominated by systemic inflammatory symptoms including fevers, cachexia, and laboratory abnormalities including cytopenias, hypoalbuminemia, hyponatremia, and elevated C-reactive protein. Pathologically KSHV–MCD is characterized by polyclonal, IgM-lambda restricted plasmacytoid cells in the intrafollicular areas of affected lymph nodes. A portion of these cells are infected with KSHV and a sizable subset of these cells express KSHV lytic genes including a viral homolog of interleukin-6 (vIL-6). Patients with KSHV–MCD generally have elevated KSHV viral loads in their peripheral blood. Production of vIL-6 and induction of human (h) IL-6 both contribute to symptoms, perhaps in combination with overproduction of IL-10 and other cytokines. Until recently, the prognosis of patients with KSHV–MCD was poor. Recent therapeutic advances targeting KSHV-infected B cells with the anti-CD20 monoclonal antibody rituximab and utilizing KSHV enzymes to target KSHV-infected cells have substantially improved patient outcomes. Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Its clinical manifestations resemble those of KSHV–MCD but lymphadenopathy is not prominent and the pathologic nodal changes of KSHV–MCD are absent. Patients with KICS exhibit elevated KSHV viral loads and elevation of vIL-6, homolog of human interleukin-6 and IL-10 comparable to those seen in KSHV–MCD; the cellular origin of these is a matter of investigation. KICS may contribute to the inflammatory symptoms seen in some patients with severe KS or primary effusion lymphoma. Additional research is needed to better define the clinical spectrum of KICS and its relationship to KSHV–MCD. In additional, research is needed to better understand the pathogenesis and epidemiology of both KICS and KSHV–MCD, as well as the optimal therapy for both of these disorders.

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Clinical Manifestations of Kaposi Sarcoma Herpesvirus Lytic Activation: Multicentric Castleman Disease (KSHV–MCD) and the KSHV Inflammatory Cytokine Syndrome

Human herpesvirus 8 (HHV8) is a gamma herpesvirus associated with Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma, lymphoproliferative diseases that are most commonly observed in immunocompromised individuals. The viral genome expresses genes responsible for inhibition of apoptosis, cell cycle entry, and angiogenesis. Viral homologs of human regulatory genes are expressed, providing stimuli for angiogenesis, B-cell proliferation, and immune evasion. Variations in expression of these factors give rise to the 3 known HHV8-associated malignancies. Identification of these pathogenetic mechanisms has led to exploration of targeted treatment approaches for all 3 of these disorders with success in Kaposi sarcoma and multicentric Castleman disease; primary effusion lymphoma remains a clinical challenge.

Human herpesvirus-8: Kaposi sarcoma, multicentric Castleman disease, and primary effusion lymphoma

Plasma HHV8 DNA predicts relapse in individuals with HIV-associated multicentric Castleman disease

Castleman's disease is a primary infectious disease of the lymph node that causes local symptoms or a systemic inflammatory syndrome. Histopathology reveals a destroyed lymph node architecture that can range from hyaline-vascular disease to plasma-cell disease. Viral interleukin 6 (vIL-6) produced during the replication of human herpesvirus type 8 (HHV8) is the key driver of systemic inflammation and cellular proliferation. Stage progression of Castleman's disease results from switches between viral latency and lytic replication, and lymphatic and hematogenous spread. Multicentric plasma-cell disease in HIV-1 patients is associated with HHV8 infection. Polyclonal plasmablast proliferation escapes control in the germinal center with eventual malignant transformation into non-Hodgkin lymphoma. Surgery produces excellent results in unicentric disease, while multicentric disease responds to anti-CD20 therapy or IL-6 and chemotherapy. Lymphovascular endothelium and naive B cells are infectious reservoir-opening options for antiangiogenic and anti-CD19 strategies to enhance outcomes in patients with systemic disease.

/pdf/castleman-s-disease-a-two-compartment-model-of-hhv8-4nmz1dzlgs.pdf

Castleman's disease—a two compartment model of HHV8 infection

Early in the human immunodeficiency virus (HIV) epidemic, infected patients presented to medical attention with striking abnormalities in each of the major blood cell lineages. The reasons for these derangements remain complex and multifactorial. HIV infects multipotent haematopoietic progenitor cells and establish latent cellular reservoirs, disturbs the bone marrow microenvironment and also causes immune dysregulation. These events lead to cytokine imbalances and disruption of other factors required for normal haematopoiesis. Activation of the reticulo-endothelial system can also result in increased blood cell destruction. The deleterious effects of medications, including first and second generation anti-retroviral agents, on haematopoiesis were well documented in the early years of HIV care; in the current era of HIV-care, the advent of newer and less toxic anti-retroviral drugs have had a more beneficial impact on haematopoiesis. Due to impaired regulation of the immune system and potential side effects of one or more anti-retroviral agents, there is also an increase in coagulation abnormalities such as thromboembolism, and less frequently, acquired disorders of coagulation including thrombotic thrombocytopenic purpura, immune thrombocytopenic purpura and acquired inhibitors of coagulation. In this article we review the epidemiology and aetiology of select non-oncological haematological disorders commonly seen in people living with HIV-acquired immune deficiency syndrome.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bjh.13783

Haematological manifestations of human immune deficiency virus infection

Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder. It is found with higher frequency in patients with HIV infection, with systemic symptoms and poor prognosis. We present the case of a 32-year old man with HIV disease, Kaposi's sarcoma, lymphadenopathy, fever and hemolytic anemia. A diagnosis of Castleman's disease is confirmed through biopsy and treatment is often based only on published case reports. Systemic treatments for MCD have included chemotherapy, anti-herpes virus, highly active antiretroviral therapy and, more recently, monoclonal antibodies against both IL6 and CD20.

https://journals.sagepub.com/doi/pdf/10.4081/rt.2012.e40

Carlos Saraiva Martins

Papers

HIV-associated multicentric Castleman's disease.