Hyperferritinemia Screening to Aid Identification and Differentiation of Patients with Hyperinflammatory Disorders.
Humans
Lymphohistiocytosis, Hemophagocytic
/ diagnosis
Biomarkers
/ blood
Female
Interleukin-18
/ blood
Male
Hyperferritinemia
/ diagnosis
Child
Ferritins
/ blood
Child, Preschool
Infant
Adolescent
Diagnosis, Differential
Intercellular Signaling Peptides and Proteins
/ blood
Chemokine CXCL9
/ blood
Inflammation
/ diagnosis
Retrospective Studies
Hemophagocytic lymphohistiocytosis (HLH)
Hyperferritinemia
Hyperinflammatory disorders
Interleukin-18
Macrophage activation syndrome (MAS)
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
12 Sep 2024
12 Sep 2024
Historique:
received:
03
06
2024
accepted:
29
08
2024
medline:
12
9
2024
pubmed:
12
9
2024
entrez:
12
9
2024
Statut:
epublish
Résumé
High ferritin is an important and sensitive biomarker for the various forms of 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 at UPMC Children's Hospital where serum ferritin > 1000 ng/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 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.
Identifiants
pubmed: 39264477
doi: 10.1007/s10875-024-01797-4
pii: 10.1007/s10875-024-01797-4
doi:
Substances chimiques
Biomarkers
0
Interleukin-18
0
Ferritins
9007-73-2
interleukin-18 binding protein
0
Intercellular Signaling Peptides and Proteins
0
Chemokine CXCL9
0
CXCL9 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
4Subventions
Organisme : NIAMS NIH HHS
ID : T32AR076951
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32AR076951
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01AR083424
Pays : United States
Organisme : National Institute of Child Health and Human Development
ID : R01HD098428
Organisme : National Institute of Child Health and Human Development
ID : R01HD098428
Organisme : National Institute of Child Health and Human Development
ID : R01HD098428
Organisme : Paul Calabresi K12 Career Development Award
ID : 5K12CA076931-24
Organisme : NIGMS NIH HHS
ID : K23GM148827-01
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Lin CI, Yu HH, Lee JH, Wang LC, Lin YT, Yang YH, et al. Clinical analysis of macrophage activation syndrome in pediatric patients with autoimmune diseases. Clin Rheumatol. 2012;31(8):1223–30.
doi: 10.1007/s10067-012-1998-0
pubmed: 22615046
Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med. 2015;66:145–59.
doi: 10.1146/annurev-med-061813-012806
pubmed: 25386930
Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001;85(5):421–6.
doi: 10.1136/adc.85.5.421
pubmed: 11668110
pmcid: 1718981
Canna SW, Cron RQ. Highways to hell: Mechanism-based management of cytokine storm syndromes. J Allergy Clin Immunol. 2020;146(5):949–59.
doi: 10.1016/j.jaci.2020.09.016
pubmed: 33007328
pmcid: 7522622
Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.
doi: 10.1002/pbc.21039
pubmed: 16937360
Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a european league against rheumatism/american college of rheumatology/paediatric rheumatology international trials organisation collaborative initiative. Arthritis Rheumatol. 2016;68(3):566–76.
doi: 10.1002/art.39332
pubmed: 26314788
Fardet L, Galicier L, Lambotte O, Marzac C, Aumont C, Chahwan D, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol. 2014;66(9):2613–20.
doi: 10.1002/art.38690
pubmed: 24782338
Shakoory B, Geerlinks A, Wilejto M, Kernan K, Hines M, Romano M, et al. The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS). Arthritis Rheumatol. 2023;75(10):1714–32.
doi: 10.1002/art.42636
pubmed: 37486733
pmcid: 11040593
Kernan KF, Carcillo JA. Hyperferritinemia and inflammation. Int Immunol. 2017;29(9):401–9.
doi: 10.1093/intimm/dxx031
pubmed: 28541437
pmcid: 5890889
Horvat CM, Bell J, Kantawala S, Au AK, Clark RSB, Carcillo JA. C-reactive protein and ferritin are associated with organ dysfunction and mortality in hospitalized children. Clin Pediatr (Phila). 2019;58(7):752–60.
doi: 10.1177/0009922819837352
pubmed: 30931590
Weiss ES, Girard-Guyonvarc’h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, et al. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood. 2018;131(13):1442–55.
doi: 10.1182/blood-2017-12-820852
pubmed: 29326099
pmcid: 5877443
Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med. 2020;382(19):1811–22.
doi: 10.1056/NEJMoa1911326
pubmed: 32374962
Bracaglia C, de Graaf K, PiresMarafon D, Guilhot F, Ferlin W, Prencipe G, et al. Elevated circulating levels of interferon-gamma and interferon-gamma-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76(1):166–72.
doi: 10.1136/annrheumdis-2015-209020
pubmed: 27296321
Segal JE, Daley JD, Barnum JL, Salgado CM, Reyes-Mugica M, Schneider C, et al. Systemic and nodular hyperinflammation in a patient with refractory familial hemophagocytic lymphohistiocytosis 2. J Clin Immunol. 2021; https://doi.org/10.1007/s10875-021-00986-9
Ravelli A, Minoia F, Davi S, Horne A, Bovis F, Pistorio A, et al. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. RMD Open. 2016;2(1):e000161.
doi: 10.1136/rmdopen-2015-000161
pubmed: 26848401
pmcid: 4731834
Butch AW. Dilution protocols for detection of hook effects/prozone phenomenon. Clin Chem. 2000;46(10):1719–21.
doi: 10.1093/clinchem/46.10.1719
pubmed: 11017960
Chen G, Deutsch GH, Schulert GS, Zheng H, Jang S, Trapnell B, et al. Identification of distinct inflammatory programs and biomarkers in systemic juvenile idiopathic arthritis and related lung disease by serum proteome analysis. Arthritis Rheumatol. 2022;74(7):1271–83.
doi: 10.1002/art.42099
pubmed: 35189047
pmcid: 9246966
Eloseily EMA, Minoia F, Crayne CB, Beukelman T, Ravelli A, Cron RQ. Ferritin to erythrocyte sedimentation rate ratio: simple measure to identify macrophage activation syndrome in systemic juvenile idiopathic arthritis. ACR Open Rheumatol. 2019;1(6):345–9.
doi: 10.1002/acr2.11048
pubmed: 31777812
pmcid: 6857981
Lachmann G, Knaak C, Vorderwulbecke G, La Rosee P, Balzer F, Schenk T, et al. Hyperferritinemia in critically Ill patients. Crit Care Med. 2020;48(4):459–65.
doi: 10.1097/CCM.0000000000004131
pubmed: 32205591
Otrock ZK, Hock KG, Riley SB, de Witte T, Eby CS, Scott MG. Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis. Ann Hematol. 2017;96(10):1667–72.
doi: 10.1007/s00277-017-3072-0
pubmed: 28762079
Saeed H, Woods RR, Lester J, Herzig R, Gul Z, Monohan G. Evaluating the optimal serum ferritin level to identify hemophagocytic lymphohistiocytosis in the critical care setting. Int J Hematol. 2015;102(2):195–9.
doi: 10.1007/s12185-015-1813-1
pubmed: 25997871
Castillo L, Carcillo J. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/ systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr Crit Care Med. 2009;10(3):387–92.
doi: 10.1097/PCC.0b013e3181a1ae08
pubmed: 19325510
Qin Y, Kernan KF, Fan Z, Park HJ, Kim S, Canna SW, et al. Machine learning derivation of four computable 24-h pediatric sepsis phenotypes to facilitate enrollment in early personalized anti-inflammatory clinical trials. Crit Care. 2022;26(1):128.
doi: 10.1186/s13054-022-03977-3
pubmed: 35526000
pmcid: 9077858
Allen CE, Yu X, Kozinetz CA, McClain KL. Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2008;50(6):1227–35.
doi: 10.1002/pbc.21423
pubmed: 18085676
Moore C Jr, Ormseth M, Fuchs H. Causes and significance of markedly elevated serum ferritin levels in an academic medical center. J Clin Rheumatol. 2013;19(6):324–8.
doi: 10.1097/RHU.0b013e31829ce01f
pubmed: 23965472
Krei JM, Moller HJ, Larsen JB. The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome - a systematic review. Clin Exp Immunol. 2021;203(2):174–82.
doi: 10.1111/cei.13543
pubmed: 33128796
Hinze T, Kessel C, Hinze CH, Seibert J, Gram H, Foell D. A dysregulated interleukin-18/interferon-gamma/CXCL9 axis impacts treatment response to canakinumab in systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2021;60(11):5165–74.
doi: 10.1093/rheumatology/keab113
pubmed: 33576397
Lehmberg K, Pink I, Eulenburg C, Beutel K, Maul-Pavicic A, Janka G. Differentiating macrophage activation syndrome in systemic juvenile idiopathic arthritis from other forms of hemophagocytic lymphohistiocytosis. J Pediatr. 2013;162(6):1245–51.
doi: 10.1016/j.jpeds.2012.11.081
pubmed: 23333131
Taylor ML, Hoyt KJ, Han J, Benson L, Case S, Chandler MT, et al. An Evidence-based guideline improves outcomes for patients with hemophagocytic lymphohistiocytosis and macrophage activation syndrome. J Rheumatol. 2022;49(9):1042–51.
doi: 10.3899/jrheum.211219
pubmed: 35840156
pmcid: 9588491
Lin H, Scull BP, Goldberg BR, Abhyankar HA, Eckstein OE, Zinn DJ, et al. IFN-gamma signature in the plasma proteome distinguishes pediatric hemophagocytic lymphohistiocytosis from sepsis and SIRS. Blood Adv. 2021;5(17):3457–67.
doi: 10.1182/bloodadvances.2021004287
pubmed: 34461635
pmcid: 8525230
Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.
doi: 10.1097/CCM.0000000000001402
pubmed: 26584195
pmcid: 5378312
Kyriazopoulou E, Leventogiannis K, Norrby-Teglund A, Dimopoulos G, Pantazi A, Orfanos SE, et al. Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis. BMC Med. 2017;15(1):172.
doi: 10.1186/s12916-017-0930-5
pubmed: 28918754
pmcid: 5603161
Kyriazopoulou E, Panagopoulos P, Metallidis S, Dalekos GN, Poulakou G, Gatselis N, et al. An open label trial of anakinra to prevent respiratory failure in COVID-19. Elife. 2021;10. https://doi.org/10.7554/eLife.66125
Anderko RR, Gomez H, Canna SW, Shakoory B, Angus DC, Yealy DM, et al. Sepsis with liver dysfunction and coagulopathy predicts an inflammatory pattern of macrophage activation. Intensiv Care Med Exp. 2022;10(1):6.
doi: 10.1186/s40635-022-00433-y
Van Nynatten LR, Slessarev M, Martin CM, Leligdowicz A, Miller MR, Patel MA, et al. Novel plasma protein biomarkers from critically ill sepsis patients. Clin Proteomics. 2022;19(1):50.
doi: 10.1186/s12014-022-09389-3
pubmed: 36572854
pmcid: 9792322
Zonneveld R, Jongman R, Juliana A, Zijlmans W, Plotz F, Molema G, et al. Low serum Angiopoietin-1, high serum Angiopoietin-2, and high Ang-2/Ang-1 protein ratio are associated with early onset sepsis in surinamese newborns. Shock. 2017;48(6):638–43.
doi: 10.1097/SHK.0000000000000903
pubmed: 28538018
pmcid: 5647105
Fiedler U, Augustin HG. Angiopoietins: a link between angiogenesis and inflammation. Trends Immunol. 2006;27(12):552–8.
doi: 10.1016/j.it.2006.10.004
pubmed: 17045842
Parikh SM. Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS. Virulence. 2013;4(6):517–24.
doi: 10.4161/viru.24906
pubmed: 23652985
pmcid: 5359737
Seol CH, Yong SH, Shin JH, Lee SH, Leem AY, Park MS, et al. The ratio of plasma angiopoietin-2 to angiopoietin-1 as a prognostic biomarker in patients with sepsis. Cytokine. 2020;129:155029.
doi: 10.1016/j.cyto.2020.155029
pubmed: 32059166
Lindell RB, Sayed S, Campos JS, Knight M, Mauracher AA, Hay CA, et al. Dysregulated STAT3 signaling and T cell immunometabolic dysfunction define a targetable, high mortality subphenotype of critically ill children. medRxiv. 2024;395:200.
Henter JI, Aricò M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28(5):342–7.
doi: 10.1002/(SICI)1096-911X(199705)28:5<342::AID-MPO3>3.0.CO;2-H
pubmed: 9121398
Voskoboinik I, Thia M-C, Trapani JA. A functional analysis of the putative polymorphisms A91V and N252S and 22 missense perforin mutations associated with familial hemophagocytic lymphohistiocytosis. Blood J. 2005;105:4700–6.
doi: 10.1182/blood-2004-12-4935