title: Clinical Features and Outcomes of Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV)-associated Inflammation: Prospective Characterization of KSHV Inflammatory Cytokine Syndrome (KICS).
abstract: BACKGROUND
  Kaposi sarcoma herpesvirus (KSHV) is the cause of Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a form of Castleman disease (KSHV-MCD). Recently a KSHV-associated inflammatory cytokine syndrome (KICS) distinct from KSHV-MCD was reported.
  
  
  METHODS
  We prospectively characterized the clinical, laboratory, virologic and immunologic features of KICS by evaluating symptomatic adults with KSHV using a prespecified definition. These features and overall survival were compared with controls from 2 prospectively characterized human immunodeficiency virus (HIV)-infected cohorts, including 1 with KSHV coinfection.
  
  
  RESULTS
  All 10 KICS subjects were HIV infected males; 5 had HIV viral load (VL) suppressed <50 copies mL (median 72, range <50-74 375); all had KS and 2 also had PEL. All had multiple severe symptoms attributable to KICS: median number of symptoms 8 (6-11), median grade of worst symptom 3 (2-4). These included gastrointestinal disturbance (present in 9); edema (9); respiratory (6); and effusions (5). Laboratory abnormalities included anemia (all); hypoalbuminemia (all) and thrombocytopenia (6). None developed KSHV-MCD; 6 died with median survival from KICS diagnosis 13.6 months. KICS subjects compared with controls had more severe symptoms; lower hemoglobin and albumin; higher C-reactive protein; higher KSHV VL; elevated interleukin (IL)-6 and IL-10; and an increased risk of death (all P < .05). Anemia and hypoalbuminemia at presentation were independently associated with early death.
  
  
  CONCLUSIONS
  KICS subjects demonstrated diverse severe symptoms, a high rate of KSHV-associated tumors, high mortality, and a distinct IL-6/IL-10 signature. KICS may be an important unrecognized cause of morbidity and mortality, including symptoms previously ascribed to HIV. Exploration of KSHV-directed therapy is warranted.
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Polizzotto
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Uldrick
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Wyvill
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Karen
authors.initials: K
authors.lastname: Aleman
authors.affiliation: Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research.
authors.forename: Vickie
authors.initials: V
authors.lastname: Marshall
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Victoria
authors.initials: V
authors.lastname: Wang
authors.affiliation: Viral Oncology Section, AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research.
authors.forename: Denise
authors.initials: D
authors.lastname: Whitby
authors.affiliation: Laboratory of Pathology.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Laboratory of Pathology.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Positron Emission Tomography Department, Clinical Center, National Institutes of Health.
authors.forename: Corina
authors.initials: C
authors.lastname: Millo
authors.affiliation: Laboratory of Cellular Oncology.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Little
authors.affiliation: Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda.
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.affiliation: HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
authors.forename: Irini
authors.initials: I
authors.lastname: Sereti
authors.affiliation: HIV and AIDS Malignancy Branch.
authors.forename: Robert
authors.initials: R
authors.lastname: Yarchoan
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis; D060085:Coinfection / Q000821:virology; D016207:Cytokines / Q000009:adverse effects* / Q000097:blood; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000401:mortality / Q000503:physiopathology* / Q000821:virology*; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D063868:Patient Outcome Assessment; D011446:Prospective Studies; D012514:Sarcoma, Kaposi / Q000453:epidemiology / Q000276:immunology* / Q000401:mortality / Q000821:virology*; D019562:Viral Load; D055815:Young Adult
chemical_list: D016207:Cytokines; C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016753:Interleukin-10; D002097:C-Reactive Protein
keywords: HIV; Human Herpesvirus 8 (HHV-8); IL-10; IL-6; Kaposi sarcoma herpesvirus (KSHV)