SOLUBLE ST2 AND CD163 AS POTENTIALBIOMARKERS TO DIFFERENTIATE PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM MACROPHAGE ACTIVATION SYNDROME
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Abstract
Abstract
Background and Objective: The differentiation of primary haemophagocytic lymphohistiocytosis (pHLH) and macrophage activation syndrome (MAS) poses a challenge to hematologists. The aim of this study was (1) to compare the levels of soluble ST2 (sST2), sCD163, IL-10, IFN-?, TNF-? and IL-18 in patients with pHLH and MAS and (2) to investigate whether they can help differentiate the two diseases.
Methods: A total of 54 participants were recruited in this study, including 12 pHLH patients, 22 MAS patients and 20 healthy subjects. We measured the levels of sST2 and sCD163 in serum by ELISA. The serum levels of IL-10, IFN-?, TNF-? and IL-18 were detected using a Luminex 200 instrument.
Results: The serum levels of sST2 and sCD163 in MAS patients were markedly higher than that in pHLH patients (363.13 ± 307.24 ng/ml vs 80.75 ± 87.04 ng/ml, P = 0.004; 3532.72 ± 2479.68 ng/ml vs 1731.96 ± 1262.07 ng/ml, P = 0.046). There was no significant difference in the expression of IFN-? (306.89 ± 281.60 pg/ml vs 562.43 ± 399.86 pg/ml), IL-10 (20.40 ± 30.49 pg/ml vs 8.3 ± 13.14 pg/ml), IL-18 (463.33 ± 597.04 pg/ml vs 1247.82 ± 1318.58 pg/ml) and TNF-? (61.48 ± 84.69 pg/ml vs 106.10 ±77.21 pg/ml) between pHLH and MAS.
Conclusion: Patients with pHLH and MAS show some differences in cytokine profiles. The elevated levels of IFN-?, IL-10, IL-18 and TNF-? can contribute to the diagnosis of HLH, but may not discriminate pHLH from MAS. Levels of sST2 and sCD163 may serve as markers to distinguish pHLH from MAS.
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References
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24. Davi S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A, Cron RQ, Ravelli A; MAS Study Group. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011; 38(4): 764-8.
25. Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016; 174(2): 203-17.
26. Greisen SR, Moller HJ, Stengaard-Pedersen K, Hetland ML, Hørslev-Petersen K, Junker P, Østergaard M, Hvid M, Deleuran B. Macrophage activity assessed by soluble CD163 in early rheumatoid arthritis: association with disease activity but different response patterns to synthetic and biologic DMARDs. Clin Exp Rheumatol. 2015; 33(4): 498-502.
27. Trajkovic V, Sweet MJ, Xu D. T1/ST2--an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 2004; 15(2-3): 87-95.
28. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996; 17(3): 138-46.
29. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996; 383(6603): 787-93.
30. Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, Campbell CC, Xu D, Liew FY. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol. 2001; 166(11): 6633-9.
2. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007; 48(2): 124-31.
3. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford). 2001; 40(11): 1285-92.
4. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child. 2001; 85(5): 421-6.
5. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012; 63: 233-46.
6. Schulert GS, Grom AA. Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol. 2014; 28(2): 277-92.
7. Avcin T, Tse SM, Schneider R, Ngan B, Silverman ED. Macrophage activation syndrome as the presenting manifestation of rheumatic diseases in childhood. J Pediatr. 2006; 148(5): 683-6.
8. Kim JM, Kwok SK, Ju JH, Kim HY, Park SH. Reactive hemophagocytic syndrome in adult Korean patients with systemic lupus erythematosus: a case-control study and literature review. J Rheumatol. 2012; 39(1): 86-93.
9. Parodi A, Davi S, Pringe AB, Pistorio A, Ruperto N, Magni-Manzoni S, Miettunen P, Bader-Meunier B, Espada G, Sterba G, Ozen S, Wright D, Magalhães CS, Khubchandani R, Michels H, Woo P, Iglesias A, Guseinova D, Bracaglia C, Hayward K, Wouters C, Grom A, Vivarelli M, Fischer A, Breda L, Martini A, Ravelli A; Lupus Working Group of the Paediatric Rheumatology European Society. Macrophage activation syndrome in juvenile systemic lupus erythematosus: a multinational multicenter study of thirty-eight patients. Arthritis Rheum. 2009; 60(11): 3388-99.
10. Muise A, Tallett SE, Silverman ED. Are children with Kawasaki disease and prolonged fever at risk for macrophage activation syndrome? Pediatrics. 2003; 112(6 Pt 1): e495.
11. Al-Eid W, Al-Jefri A, Bahabri S, Al-Mayouf S. Hemophagocytosis complicating Kawasaki disease. Pediatr Hematol Oncol. 2000; 17(4): 323-9.
12. Atteritano M, David A, Bagnato G, Beninati C, Frisina A, Iaria C, Bagnato G, Cascio A. Haemophagocytic syndrome in rheumatic patients. A systematic review. Eur Rev Med Pharmacol Sci. 2012; 16(10): 1414-24.
13. Ramanan AV, Schneider R. Macrophage activation syndrome--what's in a name!. J Rheumatol. 2003; 30(12): 2513-6.
14. Campo M, Berliner N. Hemophagocytic Lymphohistiocytosis in Adults. Hematol Oncol Clin North Am. 2015; 29(5): 915-25.
15. Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013; 2013: 605-11.
16. Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012; 13(4): 289-98.
17. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004; 104(3): 735-43.
18. Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, Pan B, Zhao F, Liao C, Luo C. Early diagnostic and prognostic significance of a specific Th1/Th2 cytokine pattern in children with haemophagocytic syndrome. Br J Haematol. 2008; 143(1): 84-91.
19. Takada H, Nomura A, Ohga S, Hara T. Interleukin-18 in hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2001; 42(1-2): 21-8.
20. Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991; 78(11): 2918-22.
21. Xu XJ, Tang YM, Song H, Yang SL, Xu WQ, Zhao N, Shi SW, Shen HP, Mao JQ, Zhang LY, Pan BH. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012; 160(6): 984-90.
22. Rood JE, Rao S, Paessler M, Kreiger PA, Chu N, Stelekati E, Wherry EJ, Behrens EM. ST2 contributes to T-cell hyperactivation and fatal hemophagocytic lymphohistiocytosis in mice. Blood. 2016; 127(4): 426-35.
23. Schaer DJ, Schleiffenbaum B, Kurrer M, Imhof A, Bächli E, Fehr J, Moller HJ, Moestrup SK, Schaffner A. Soluble hemoglobin-haptoglobin scavenger receptor CD163 as a lineage-specific marker in the reactive hemophagocytic syndrome. Eur J Haematol. 2005; 74(1): 6-10.
24. Davi S, Consolaro A, Guseinova D, Pistorio A, Ruperto N, Martini A, Cron RQ, Ravelli A; MAS Study Group. An international consensus survey of diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis. J Rheumatol. 2011; 38(4): 764-8.
25. Brisse E, Wouters CH, Matthys P. Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol. 2016; 174(2): 203-17.
26. Greisen SR, Moller HJ, Stengaard-Pedersen K, Hetland ML, Hørslev-Petersen K, Junker P, Østergaard M, Hvid M, Deleuran B. Macrophage activity assessed by soluble CD163 in early rheumatoid arthritis: association with disease activity but different response patterns to synthetic and biologic DMARDs. Clin Exp Rheumatol. 2015; 33(4): 498-502.
27. Trajkovic V, Sweet MJ, Xu D. T1/ST2--an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 2004; 15(2-3): 87-95.
28. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996; 17(3): 138-46.
29. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature. 1996; 383(6603): 787-93.
30. Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, Campbell CC, Xu D, Liew FY. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol. 2001; 166(11): 6633-9.