title: A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes.
abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is a life-threatening disorder of immune regulation caused by defects in lymphocyte cytotoxicity. Rapid differentiation of primary, genetic forms from secondary forms of hemophagocytic lymphohistiocytosis (HLH) is crucial for treatment decisions. We prospectively evaluated the performance of degranulation assays based on surface up-regulation of CD107a on natural killer (NK) cells and cytotoxic T lymphocytes in a cohort of 494 patients referred for evaluation for suspected HLH. Seventy-five of 77 patients (97%) with FHL3-5 and 11 of 13 patients (85%) with Griscelli syndrome type 2 or Chediak-Higashi syndrome had abnormal resting NK-cell degranulation. In contrast, NK-cell degranulation was normal in 14 of 16 patients (88%) with X-linked lymphoproliferative disease and in 8 of 14 patients (57%) with FHL2, who were identified by diminished intracellular SLAM-associated protein (SAP), X-linked inhibitor of apoptosis protein (XIAP), and perforin expression, respectively. Among 66 patients with a clinical diagnosis of secondary HLH, 13 of 59 (22%) had abnormal resting NK-cell degranulation, whereas 0 of 43 had abnormal degranulation using IL-2-activated NK cells. Active disease or immunosuppressive therapy did not impair the assay performance. Overall, resting NK-cell degranulation below 5% provided a 96% sensitivity for a genetic degranulation disorder and a specificity of 88%. Therefore, degranulation assays allow a rapid and reliable classification of patients, benefiting treatment decisions.
authors.affiliation: Centre for Infectious Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.forename: Daniela
authors.initials: D
authors.lastname: Pende
authors.forename: Andrea
authors.initials: A
authors.lastname: Maul-Pavicic
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.forename: Heike
authors.initials: H
authors.lastname: Ufheil
authors.forename: Thomas
authors.initials: T
authors.lastname: Vraetz
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Chiang
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcenaro
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.forename: Ilka
authors.initials: I
authors.lastname: Bondzio
authors.forename: Denise
authors.initials: D
authors.lastname: Walshe
authors.forename: Gritta
authors.initials: G
authors.lastname: Janka
authors.forename: Kai
authors.initials: K
authors.lastname: Lehmberg
authors.forename: Karin
authors.initials: K
authors.lastname: Beutel
authors.forename: Udo
authors.initials: U
authors.lastname: zur Stadt
authors.forename: Nadine
authors.initials: N
authors.lastname: Binder
authors.forename: Maurizio
authors.initials: M
authors.lastname: Arico
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Stephan
authors.initials: S
authors.lastname: Ehl
mesh_terms: D015550:Cell Degranulation / Q000502:physiology*; D006801:Humans; D007159:Immunologic Tests / Q000379:methods*; D007694:Killer Cells, Natural / Q000502:physiology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis* / Q000276:immunology / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D013997:Time Factors
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1