A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes

Yenan T. Bryceson, Daniela Pende, Andrea Maul-Pavicic, Kimberly C. Gilmour, Heike Ufheil, Thomas Vraetz, Samuel C. Chiang, Stefania Marcenaro, Raffaella Meazza, Ilka Bondzio, Denise Walshe, Gritta Janka, Kai Lehmberg, Karin Beutel, Udo Zur Stadt, Nadine Binder, Maurizio Arico, Lorenzo Moretta, Jan Inge Henter, Stephan Ehl

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2754-2763
Number of pages10
JournalBlood
Volume119
Issue number12
DOIs
Publication statusPublished - Mar 22 2012

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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