Hemophagocytic lymphohistiocytosis (HLH) is a syndrome caused by hypercytokinemia (notably Th1 cytokines – interferon-gamma, tumor necrosis factor-alpha, and IL-6). Clinical manifestations are dramatic, presenting as fever, hepatosplenomegaly, hemophagocytosis, and cytopenias. (See the addendum for diagnostic criteria of HLH). Primary forms of HLH are genetic disorders; secondary HLH is caused by drugs, autoimmune diseases, infections, or malignancies (predominantly lymphoproliferative diseases). (1)
Infections associated with HLH are bacterial (Brucella, gram-negative bacteria, tuberculosis), viral (Epstein–Barr virus, cytomegalovirus, parvovirus, herpes simplex, varicella zoster, measles, human herpes virus-8, and HIV infection), parasites (leishmaniasis), and fungal infections. (2) The general consensus is that Epstein-Barr virus is the most common infection associated with HLH. (3)
Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as Human herpesvirus 8 (HHV-8), is a member of the lymphotropic gammaherpesvirus subfamily and a human oncogenic virus. In addition to KS, HHV-8 is also involved in the development of primary effusion lymphoma (PEL) and certain types of multicentric Castleman’s disease (MCD). (4)
According to van Rhee et al, MCD often presents with lymphadenopathy, fever, weight loss, fatigue, edema, anemia, and hypoalbuminemia. MCD often concomitantly presents in the context of infection with HIV and/or HHV8. However, approximately 50% of patients with MCD who are negative for HIV and HHV8 comprise a subgroup that has recently been termed as idiopathic MCD (iMCD), as no etiology has been established. Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a pivotal role in the pathogenesis and clinical symptomatology in many patients with iMCD. Together with other cytokines, IL-6 causes immune dysregulation by a variety of mechanisms, including induction of polyclonal T-cell outgrowth reflected by activated CD8+ T-cells and increased soluble IL-2 receptor levels. Thus, monoclonal antibodies targeting the IL-6 signaling pathway are front-line therapies for severely ill patients with iMCD. (5)
Recently another KSHV-associated condition, the KSHV inflammatory cytokine syndrome (KICS) has been described. Polizzotto et al state: “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.” (6)
Prieto-Barrios et al reported a case of KICS in a HIV+, 50+ year-old man with progressive KS (despite treatment with doxyrubicin). He presented with high fever, respiratory distress, hemodynamic instability, pancytopenia, and acute-phase reactant elevation. By using PCR, the authors demonstrated that clinical flares correlated with the exacerbations of HLH. They opined: “the existence of HLH could justify all KICS clinical manifestations. KICS, MCD, and HHV8-related recurrent HLH could be considered different manifestations of the same disease spectrum mediated by lytic reactivation of KS herpesvirus.” Although the patient was treated with rituximab, doxorubicin, and valgangciciovir, the authors speculated that new therapies such as tocilizumab or siroliumus could be utilized. (7) Indeed, anti-IL-6 therapy with tocilizumab successfully treated a case of leishmaniasis-associated HLH in a 27-year-old woman. (2)
Whether you get your kicks by considering KICS a distinct entity, or view it as part of the HLH spectrum, you will be traveling route IL-6 more frequently in the future.
- Vick EJ, et al. Proliferation through activation: Hemophagocytic lymphohistiocytosis in hematologic malignancy. Blood Adv 2017; 1: 779-91.
- Rios-Fernández, et al. Tocizumab as an adjuvant therapy for hemophagocytic lymphohistiocytosis associated with visceral leishmaniasis. Am J Ther 2016; e1193-6.
- Marsh RA. Epstein-Barr virus and hemophagocytic lymphohistiocytosis. Front Immunol. 2018 Jan 8;8:1902.
- Li S, et al. Kaposi’s sarcoma-associated herpesvirus: Epidemiology and molecular biology. Adv Exp Med Biol 2017; 1018:91-127.
- van Rhee F, et al. Treatment of idiopathic Castleman disease. Treatment of idiopathic Castleman disease. Hematol Oncol Clin N Am 2018; 32: 89-106.
- Polizzotto MN, et al. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: Multicentric Castleman disease (KSHV-MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol 2012; 3:73. doi: 10.3389.
- Prieto-Barrios M, et al. Human herpesvirus 8-associated inflammatory cytokine syndrome. JAMA Dermatol 2018; 154: 228-30.
Point to Remember: KSHV inflammatory cytokine syndrome (KICS) presents as a hemophagocytic lymphohistiocytosis with IL-6 as a key pathogenic factor.
Diagnostic criteria of HLH with 5 of 8 of the following symptoms (from reference 1)
|Cytopenias affecting >2 lineages in peripheral blood|
|Hemoglobin <9 g/dL (<10 g/dL in infants <4 weeks of age)|
|Platelets <100 000/microliter|
|Hypertriglyceridemia: fasting triglycerides >265 mg/dL and/or hypofibrinogenemia: <1.5g/L|
|Hemophagocytosis in the BM, spleen, lymph nodes, or liver|
|Low or absent NK cell activity|
|Ferritin >500 microgram/L|
|Increased soluble CD25 (IL-2r) concentration: >2400 U/mL|
*Image of the hemophagocytic syndrome is from Wikimedia commons.
Dermatology Insights and Inquiries (DI&I) is the 2017 Recipient of the AAD Sulzberger Dermatologic Institute and Education Grants Committee’s Program for Innovative Continuing Medical Education in Dermatology (PICMED) Grant. The PICMED project and DI&I are funded by an endowment established by the Skin Disease Education Foundation and the Elsevier Foundation.