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Abstract Number: 2569

A Novel Hyperferritinemia Screen to Aid Differentiation of Hyperinflammatory Disorders

Hallie Carol1, Adam Mayer2, Jemy Varghese3, Zachary Martinez4, Caroline Diorio4, Paul Tsoukas5, Kate Kernan6 and Scott Canna7, 1Children's Hospital of Philadelphia, Philadelphia, 2University of Pennsylvania/Children's Hospital of Philadelphia, Philadelphia, PA, 3Division of Pediatric Rheumatology, The Children’s Hospital of Philadelphia, Philadelphia, PA, 4Division of Pediatric Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA, 5Hospital for Sick Children/University of Toronto, Toronto, ON, Canada, 6Department of Critical Care Medicine, University of Pittsburgh School of Medicine, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, 7Children's Hospital of Philadelphia, Philadelphia, PA

Meeting: ACR Convergence 2024

Keywords: Autoinflammatory diseases, Inflammation, macrophage activation syndrome, Pediatric rheumatology

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Session Information

Date: Monday, November 18, 2024

Title: Abstracts: Pediatric Rheumatology – Clinical I

Session Type: Abstract Session

Session Time: 1:00PM-2:30PM

Background/Purpose: High ferritin is an important and sensitive biomarker for the diverse and deadly group of cytokine storm syndromes grouped together under the term hemophagocytic lymphohistiocytosis (HLH). Early identification of the syndrome and its contributors are critical to guiding targeted treatments and preventing immunopathology, morbidity, and mortality. We lack specific diagnostic biomarkers, which complicates etiologic work-up and delays targeted intervention. Through implementing a hyperferritenemia alert system, we hoped to identify the landscape of hyperferritinemic patients, collect the earliest samples for research purposes, and test these samples for relevant biomarkers.

Methods: We instituted a single-center (UPMC Children’s Hospital of Pittsburgh) alert system from June 1st, 2017 to June 30th, 2019 wherein serum ferritin >1000ng/mL triggered via real-time chart review and attempted biobanking of remnant samples from willing patients deemed to have “inflammatory hyperferritnemia (IHF)” (Fig 1). From consenting patients we extracted relevant clinical data; retrospectively classified patients by etiology into infectious, rheumatic, or immune dysregulation; iteratively measured certain serum biomarkers (total IL-18, IL-18 binding protein, and CXCL9); and subjected a subgroup of samples to a 96-analyte O-link biomarker screen.

Results: The alert system identified 181 patients with hyperferritenemia, 30.5% of which had IHF (Fig 2A). Of the IHF patients, 14.5% were found to have a rheumatic cause, all of whom had systemic juvenile idiopathic arthritis (SJIA) (Fig 2A). Maximum ferritin levels were higher in IHF patients than either hemoglobinopathy or transplant but were not significantly different between subgroups of IHF (Fig 2B).  Highly elevated total IL-18 levels were distinctive to SJIA with or without MAS compared to other IHF, whereas CXCL9 did not differentiate IHF subcategories (Fig 2C). Other lab values—triglycerides, AST, platelets, and fibrinogen—did not significantly differ between IHF subcategories. Principal component analysis of a 96-analyte biomarker screen showed distributed elevation of proteins associated with T-cell activation and IFNg-activity (e.g. Granzyme B, CXCL9) in all IHF samples. Samples from patients with hyperferritinemic sepsis were distinctively lower in proteins involved in vessel homeostasis (e.g. ANGPT1, VEGFR2) and antigen presentation (CD40L) compared to other IHF subgroups and healthy controls (Figure 3).

Conclusion: This single-center, real-time IHF screen proved feasible and efficient, validated prior observations about the specificity of IL-18, expanded our understanding of IHF heterogeneity, and enabled early sample collection from a unique and rapidly-evolving population.

Supporting image 1

Figure 1. Steps in the hyperferritinemia screening protocol.

Supporting image 2

Figure 2. Clinical diagnoses and laboratory characteristics of patients with positive ferritin screens. A. Distribution of distinct patients triggering alerts by disease category and bar graphs display the number of distinct patients representing inflammatory hyperferritinemia subgroup. B. Distribution of ferritin values and maximum ferritin value per distinct patient by disease group and by subgroup of inflammatory hyperferritinemia. C. IL_18, IL_18BP and CXCL9 levels by subgroup of inflammatory hyperferritinemia. Patients with rheumatic disease had significantly higher IL_18 levels (P<0.0001 for both) and significantly lower IL_18BP levels (P<0.05, P<0.0001, respectively) compared to those with infection or immune dysregulation. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 Kruskal-Wallis with Dunn’s post-test; only comparisons with p<0.05 shown.

Supporting image 3

Figure 3. Biomarker screen using Olink. Principal component analysis shows unsupervised clustering of analyte NPX values with PC1 accounting for 27% of the variability and PC2 accounting for 18%. The analytes with the highest absolute value contribution to PC loading are listed on their respective axes. PC1 separate hyperferritinemic samples from healthy controls. PC2 separate hyperferritinemic sepsis samples from all other hyperferritinemic samples and healthy controls. Abbreviations: PDGF= PDGF subunit B.


Disclosures: H. Carol: None; A. Mayer: None; J. Varghese: None; Z. Martinez: None; C. Diorio: None; P. Tsoukas: None; K. Kernan: None; S. Canna: Apollo Therapeutics, 2, Bristol-Myers Squibb(BMS), 6, Novartis, 5, PracticePoint CME, 6, Simcha Therapeutics, 5.

To cite this abstract in AMA style:

Carol H, Mayer A, Varghese J, Martinez Z, Diorio C, Tsoukas P, Kernan K, Canna S. A Novel Hyperferritinemia Screen to Aid Differentiation of Hyperinflammatory Disorders [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/a-novel-hyperferritinemia-screen-to-aid-differentiation-of-hyperinflammatory-disorders/. Accessed .
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