Top

Italian Journal of Pediatrics

Published in:

Open Access 01-12-2016 | Research

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

Authors: Yuanyuan Chen, Zhujun Wang, Zebin Luo, Ning Zhao, Shilong Yang, Yongmin Tang

Published in: Italian Journal of Pediatrics | Issue 1/2016

Abstract

Background

Haemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation, and HLH patients with mutations in genes including PRF1, UNC13D, STX11, STXBP2, SH2D1A, XIAP, and ITK were reported to be primary HLH. Due to the different treatment options, the differentiation between primary and secondary HLH is critical. Our previous studies have showed that a Th1/Th2 cytokine profile is diagnostic for HLH, yet the cytokine profiles between primary and secondary HLH have not been compared. The aim of the study was to test whether the Th1/Th2 cytokine profile could be used as a tool to differentiate between primary and secondary HLH.

Methods

A total of 45 hospitalized Chinese children with HLH during the period of February 2010 through September 2012 were enrolled in the study. Fifty healthy children were enrolled as controls. Primary HLH related genes were sequenced using genomic DNA samples. The Th1/Th2 cytokine levels including interferon-γ (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-10, IL-6, IL-4 and IL-2 were quantitatively determined by cytometric bead assay techniques.

Results

Primary HLH group (n = 4) included one patient with biallelic heterozygous mutations in PRF1 gene, and three patients with hemizygous mutation in SH2D1A gene. Based on the available genetic data, the other 41 patients were classified into the secondary HLH group. When compared the cytokine levels between the two groups, IL-4 level in primary-HLH was significantly lower than that in secondary HLH (P = 0.025), while IFN-γ level in primary HLH had a tendency of statistically lower than that in secondary HLH (P = 0.051). Area under receiver operating characteristic (ROC) curves of IL-4 and IFN-γ, IL-10, TNF-α, IL-2, and IL-6 levels were 0.841, 0.799, 0.506, 0.494, 0.457, and 0.250, respectively. ROC curves showed that 1.7 pg/ml of IL-4 had sensitivity and specificity for differentiation between primary and secondary HLH as 70.7 and 100.0 %, while 433.9 pg/ml of IFN-γ had sensitivity and specificity as 51.2 and 100.0 %, respectively.

Conclusions

HLH patients with lower IL-4 and IFN-γ levels have higher possibility to be primary HLH. The cytokine profile may be used as an additional tool for the quick differential diagnosis between primary and secondary HLH.

Available only for authorised users

Tang YM, Xu XJ. Advances in hemophagocytic lymphohistiocytosis: pathogenesis, early diagnosis/differential diagnosis, and treatment. ScientificWorldJournal. 2011;11:697–708.CrossRefPubMed

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.CrossRefPubMed

Xiao L, Xian Y, Dai BT, Su YC, Xiao JW, Zheng QC, et al. Clinical features and outcome analysis of 83 childhood Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis with HLH-2004 protocol. Zhonghua Xue Ye Xue Za Zhi. 2011;32(10):668–72.PubMed

Koh KN, Im HJ, Chung NG, Cho B, Kang HJ, Shin HY, et al. Clinical features, genetics, and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in Korea: report of a nationwide survey from Korea Histiocytosis Working Party. Eur J Haematol. 2015;94(1):51–9.CrossRefPubMed

Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86(1):58–65.CrossRefPubMed

My LT, le Lien B, Hsieh WC, Imamura T, Anh TN, Anh PN, et al. Comprehensive analyses and characterization of haemophagocytic lymphohistiocytosis in Vietnamese children. Br J Haematol. 2010;148(2):301–10.CrossRefPubMed

Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. Indian Pediatr. 2011;48(1):31–5.CrossRefPubMed

Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Annu Rev Med. 2012;63:233–46.CrossRefPubMed

Frederiksen JK, Ross CW. Cytomegalovirus-associated hemophagocytic lymphohistiocytosis in a patient with myasthenia gravis treated with azathioprine. Blood. 2014;123(15):2290.CrossRefPubMed

10.

Janka GE, Lehmberg K. Hemophagocytic syndromes--an update. Blood Rev. 2014;28(4):135–42.CrossRefPubMed

11.

Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, et al. Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet. 1999;64(1):165–71.CrossRefPubMedPubMedCentral

12.

Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.CrossRefPubMed

13.

Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461–73.CrossRefPubMed

14.

zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827–34.CrossRefPubMed

15.

zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85(4):482–92.CrossRefPubMedPubMedCentral

16.

Cote M, Menager MM, Burgess A, Mahlaoui N, Picard C, Schaffner C, et al. Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest. 2009;119(12):3765–73.CrossRefPubMedPubMedCentral

17.

Schwartzberg PL, Mueller KL, Qi H, Cannons JL. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol. 2009;9(1):39–46.CrossRefPubMed

18.

Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature. 2006;444(7115):110–4.CrossRefPubMed

19.

Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009;119(5):1350–8.CrossRefPubMedPubMedCentral

20.

Henter JI, Elinder G, Soder O, Hansson M, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78(11):2918–22.PubMed

21.

Tang Y, Xu X, Song H, Yang S, Shi S, Wei J, et al. 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.CrossRefPubMed

22.

Xu XJ, Tang YM, Liao C, Song H, Yang SL, Xu WQ, et al. Inflammatory cytokine measurement quickly discriminates gram-negative from gram-positive bacteremia in pediatric hematology/oncology patients with septic shock. Intensive Care Med. 2013;39(2):319–26.CrossRefPubMed

23.

Xu XJ, Tang YM, Song H, Yang SL, Xu WQ, Zhao N, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012;160(6):984–90. e1.CrossRefPubMed

24.

Marcenaro S, Gallo F, Martini S, Santoro A, Griffiths GM, Arico M, et al. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood. 2006;108(7):2316–23.CrossRefPubMed

25.

Chen Y, Wang Z, Cheng Y, Tang Y. Novel mutations in the UNC13D gene carried by a Chinese neonate with hemophagocytic lymphohistiocytosis. Yonsei Med J. 2013;54(4):1053–7.CrossRefPubMedPubMedCentral

26.

Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, et al. A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood. 2012;119(12):2754–63.CrossRefPubMed

27.

Zhizhuo H, Junmei X, Yuelin S, Qiang Q, Chunyan L, Zhengde X, et al. Screening the PRF1, UNC13D, STX11, SH2D1A, XIAP, and ITK gene mutations in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2012;58(3):410–4.CrossRefPubMed

28.

Spessott WA, Sanmillan ML, McCormick ME, Patel N, Villanueva J, Zhang K, et al. Hemophagocytic lymphohistiocytosis caused by dominant-negative mutations in STXBP2 that inhibit SNARE-mediated membrane fusion. Blood. 2015;125(10):1566–77.CrossRefPubMedPubMedCentral

29.

Entesarian M, Chiang SC, Schlums H, Meeths M, Chan MY, Mya SN, et al. Novel deep intronic and missense UNC13D mutations in familial haemophagocytic lymphohistiocytosis type 3. Br J Haematol. 2013;162(3):415–8.CrossRefPubMed

30.

Seo JY, Song JS, Lee KO, Won HH, Kim JW, Kim SH, et al. Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea. Ann Hematol. 2013;92(3):357–64.CrossRefPubMed

31.

Meeths M, Chiang SC, Wood SM, Entesarian M, Schlums H, Bang B, et al. Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood. 2011;118(22):5783–93.CrossRefPubMed

32.

Yasumi T, Hori M, Hiejima E, Shibata H, Izawa K, Oda H, et al. Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis. Br J Haematol. 2015;170(4):532–8.CrossRefPubMed

33.

Kobayashi Y, Salih HM, Kajiume T, Nakamura K, Miyagawa S, Sato T, et al. Successful treatment with liposteroid followed by reduced intensity stem cell transplantation in an infant with perforin deficiency presenting with hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29(3):178–82.CrossRefPubMed

34.

Overwater E, Smulders Y, van der Burg M, Lombardi MP, Meijers-Heijboer HE, Kuijpers TW, et al. The value of DNA storage and pedigree analysis in rare diseases: a 17-year-old boy with X-linked lymphoproliferative disease (XLP) caused by a de novo SH2D1A mutation. Eur J Pediatr. 2014;173(12):1695–8.CrossRefPubMed

35.

Sumegi J, Huang D, Lanyi A, Davis JD, Seemayer TA, Maeda A, et al. Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood. 2000;96(9):3118–25.PubMed

36.

Meazza R, Tuberosa C, Cetica V, Falco M, Parolini S, Grieve S, et al. Diagnosing XLP1 in patients with hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol. 2014;134(6):1381–7. e7.CrossRefPubMed

37.

Coffey AJ, Brooksbank RA, Brandau O, Oohashi T, Howell GR, Bye JM, et al. Host response to EBV infection in X-linked lymphoproliferative disease results from mutations in an SH2-domain encoding gene. Nat Genet. 1998;20(2):129–35.CrossRefPubMed

38.

Mougiakakos D, Machaczka M, Jitschin R, Klimkowska M, Entesarian M, Bryceson YT, et al. Treatment of familial hemophagocytic lymphohistiocytosis with third-party mesenchymal stromal cells. Stem Cells Dev. 2012;21(17):3147–51.CrossRefPubMed

39.

Qian Y, Johnson JA, Connor JA, Valencia CA, Barasa N, Schubert J, et al. The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. Pediatr Blood Cancer. 2014;61(6):1034–40.CrossRefPubMed

40.

Ameratunga R, Woon ST. Customised molecular diagnosis of primary immune deficiency disorders in New Zealand: an efficient strategy for a small developed country. N Z Med J. 2009;122(1304):46–53.PubMed

41.

Weiss KH, Runz H, Noe B, Gotthardt DN, Merle U, Ferenci P, et al. Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. J Inherit Metab Dis. 2010;33 Suppl 3:S233–40.CrossRefPubMed

42.

Ferretti M, Gattorno M, Chiocchetti A, Mesturini R, Orilieri E, Bensi T, et al. The 423Q polymorphism of the X-linked inhibitor of apoptosis gene influences monocyte function and is associated with periodic fever. Arthritis Rheum. 2009;60(11):3476–84.CrossRefPubMed

43.

Li W, Gao C, Cui L, Liu S, Zhao X, Zhang R, et al. DNMT3A mutations and prognostic significance in childhood acute lymphoblastic leukemia. Leuk Lymphoma. 2015;56(4):1066–71.CrossRefPubMed

Title: Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis
Authors: Yuanyuan Chen
Zhujun Wang
Zebin Luo
Ning Zhao
Shilong Yang
Yongmin Tang
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Italian Journal of Pediatrics / Issue 1/2016
Electronic ISSN: 1824-7288
DOI: https://doi.org/10.1186/s13052-016-0262-7

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Comparison of Th1/Th2 cytokine profiles between primary and secondary haemophagocytic lymphohistiocytosis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2016

White coat hypertension in pediatrics

Peripheral quantitative computed tomography (pQCT) for the assessment of bone strength in most of bone affecting conditions in developmental age: a review

Neuroblastoma presenting with symptoms of epidural compression at birth: a case report

Failure to thrive as presentation in a patient with 22q11.2 microdeletion

A conceptual framework for rationalized and standardized Universal Newborn Hearing Screening (UNHS) programs

A randomized clinical trial comparing 3 different replacement regimens of vitamin D in clinically asymptomatic pediatrics and adolescents with vitamin D insufficiency