title: Perforin and CD107a testing is superior to NK cell function testing for screening patients for genetic HLH.
abstract: Primary hemophagocytic lymphohistiocytosis (HLH) can be caused by biallelic mutations inPRF1, encoding perforin, orUNC13D,STXBP2,STX11,RAB27A,LYST, andAP3B1, encoding proteins involved in cytotoxic lymphocyte degranulation. Natural killer (NK)-cell cytotoxicity assays can quickly screen for all of these genetic diseases, facilitating treatment, but combining NK-cell perforin expression and CD107a upregulation tests can as well. To determine the relative diagnostic accuracies for each approach, we retrospectively reviewed screening test performance in 1614 patients referred for HLH evaluation. For each test, we generated a receiver operating characteristic (ROC) curve, and calculated area under the curve (AUC) and diagnostic parameters at optimal threshold. We generated an AUC for combining perforin and CD107a tests by creating a logistic regression model and applying model-generated coefficients to patient values. Sensitivities of NK-cell function, perforin mean channel fluorescence (MCF), and CD107a MCF to detect biallelic mutations were 59.5%, 96.6%, and 93.8%, with specificities of 72.0%, 99.5%, and 73%. AUCs for NK-cell cytotoxicity, perforin MCF, CD107a MCF, and combined perforin and CD107a MCFs were 0.690, 0.971, 0.860, and 0.838. Perforin and CD107a tests are more sensitive and no less specific compared with NK cytotoxicity testing for screening for genetic HLH and should be considered for addition to current HLH criteria.
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency and.
authors.forename: Tamar S
authors.initials: TS
authors.lastname: Rubin
authors.affiliation: Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; and.
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency and.
authors.forename: Carrie
authors.initials: C
authors.lastname: Gifford
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency and.
authors.forename: Adam
authors.initials: A
authors.lastname: Lane
authors.affiliation: Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency and.
authors.forename: Jack J
authors.initials: JJ
authors.lastname: Bleesing
authors.affiliation: Division of Bone Marrow Transplantation and Immune Deficiency and.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Marsh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015550:Cell Degranulation; D002648:Child; D002675:Child, Preschool; D003601:Cytotoxicity Tests, Immunologic; D004252:DNA Mutational Analysis; D005260:Female; D005434:Flow Cytometry; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D016015:Logistic Models; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054353:Perforin / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; C510468:PRF1 protein, human; D054353:Perforin