Hyperferritinemia screening to aid identification and differentiation of patients with hyperinflammatory disorders.

High ferritin is an important and sensitive biomarker for hemophagocytic lymphohistiocytosis (HLH), a diverse and deadly group of cytokine storm syndromes. Early action to prevent immunopathology in HLH often includes empiric immunomodulation, which can complicate etiologic work-up and prevent collection of early/pre-treatment research samples. To address this, we instituted an alert system where serum ferritin > 1000ng/mL triggered real-time chart review, assessment of whether the value reflected "inflammatory hyperferritnemia (IHF)", and biobanking of remnant samples from consenting IHF patients. We extracted relevant clinical data; periodically measured serum total IL-18, IL-18 binding protein (IL-18BP), and CXCL9; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; and subjected a subgroup of samples to a 96-analyte biomarker screen. 180 patients were identified, 30.5% of which had IHF. Maximum ferritin levels were significantly higher in patients with IHF than with either hemoglobinopathy or transplant, and highly elevated total IL-18 levels were distinctive to patients with Stills Disease and/or Macrophage Activation Syndrome (MAS). Multi-analyte analysis showed elevation in proteins associated with cytotoxic lymphocytes in all IHF samples when compared to healthy controls and depression of proteins such as ANGPT1 and VEGFR2 in samples from hyperferritinemic sepsis patients relative to non-sepsis controls. This single-center, real-time IFH screen proved feasible and efficient, validated prior observations about the specificity of IL-18, enabled early sample collection from a complex population, suggested a unique vascular biomarker signature in hyperferritinemic sepsis, and expanded our understanding of IHF heterogeneity.
Competing Interests: Hallie A. Carol: no disclosures Adam S. Mayer: no disclosures Michael S Zhang: previously employed at the University of Pittsburgh and University of Pittsburgh Medical Center, and currently employed at Regeneron Pharmaceuticals Inc. Michael S. Zhang contributed to this article as an employee of the University of Pittsburgh and University of Pittsburgh Medical Center and the views expressed do not necessarily represent the views of Regeneron Pharmaceuticals Inc. Vinh Dang: no disclosures Jemy Varghese: no disclosures Zachary Martinez: no disclosures Corinne Schneider: no disclosures Elizabeth (Joy) Baker: no disclosures Paul Tsoukas: no disclosures Ed Behrens Randy Q. Cron: Research support from Histiocytosis Association; consultant to Sobi and AbbVie; adjudication committee clinical trial work for AbbVie, Pfizer Caroline Diorio: no disclosures Lauren A. Henderson: Consulting for Sobi, adaptive biotechnologies. Investigator initiated grant support for BMS. Was on a grant review panel for Pfizer Grant Schulert: Research support from IpiNovyx, consultant for SOBI and Boehringer Ingelheim Pui Lee Kate F Kernan: no disclosures Scott W. Canna: Speaking fees for Sobi and PractivePointCME, Consulting for Simcha, Apollo, J&J, and Bristol Myers Squibb. Funding: National Institute of Arthritis and Musculoskeletal and Skin Diseases, T32AR076951 (HAC, ASM) The RK Mellon Institute for Pediatric Research and R01HD098428 (CS, VD, SWC) The Childhood Arthritis and Rheumatology Research Alliance (CARRA) (CS, VD, LAH, SWC). National Institute od Child Health and Human Development, R01HD098428 (CS, VD, SWC) SickKids Clinician Scientist training Program Scholarship (PT) Children’s Hospital of Philadelphia, Immune Dysregulation Frontiers Program (EMB, SWC) Histiocytosis Association (RQC) Paul Calabresi K12 Career Development Award, 5K12CA076931–24 (CJD) Canadian Institute for Health Research (CIHR) Fellowship Award(CJD) Alex’s Lemonade Stand Fund (ALSF) ‘A’ Award (CJD) National Institute of Arthritis and Musculoskeletal and Skin Diseases, R01AR083424 (LAH) IpiNovyx (GS) National Institute of General Medical Sciences, K23GM148827–01 (KFK)