Keywords
Hemophagocytic lymphohistiocytosis
Children
Risk factors
Categories
How to Cite
Abstract
Children with hemophagocytic lymphohistiocytosis (HLH) triggered by Epstein-Barr virus (EBV) have a poor prognosis, and early detection is essential for improving outcomes. Genetic sequencing is constrained by limited turnaround time, and classical diagnostic criteria often apply only at advanced disease stages. Consequently, there is an urgent need to examine the trajectories of multidimensional clinical signs and biochemical and immunological risk factors during the very early phase of illness. Current research is progressively overcoming the limitations of single, static marker analysis by integrating multiple high-risk clinical features from early disease stages into machine learning algorithms. This paradigm shift toward high-precision, dynamic early-risk prediction models addresses the traditional challenges of differential diagnosis in emergency settings and lays the foundation for individualized, precision management of critically ill children at high risk. This article provides a comprehensive review of recent advances in risk factor identification and risk prediction model development for early-onset EBV-associated HLH in children.
References
[1] Tantipraphat L, Sudhinaraset N, Thongmee T, et al. Epstein-Barr virus seroprevalence in Thailand: a temporal and global perspective with health care and economic correlations. Am J Trop Med Hyg. 2025;113(1):86-93.
[2] Xu XJ, Wang HS, Ju XL, et al. Clinical presentation and outcome of pediatric patients with hemophagocytic lymphohistiocytosis in China: a retrospective multicenter study. Pediatr Blood Cancer. 2017;64(4):e26264.
[3] Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124-31.
[4] Trottestam H, Horne A, Aricò M, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577-84.
[5] Imashuku S, Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19(10):2665-73.
[6] Moons KGM, Wolff RF, Riley RD, et al. PROBAST: a tool to assess risk of bias and applicability of prediction model studies: explanation and elaboration. Ann Intern Med. 2019;170(1):W1-W33.
[7] Moons KG, Altman DG, Reitsma JB, et al. Transparent reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): explanation and elaboration. Ann Intern Med. 2015;162(1):W1-73.
[8] Pencina MJ, D'Agostino RB Sr. Evaluating discrimination of risk prediction models: the C statistic. JAMA. 2015;314(10):1063-4.
[9] Bouwmeester W, Zuithoff NP, Mallett S, et al. Reporting and methods in clinical prediction research: a systematic review. PLoS Med. 2012;9(5):1-12.
[10] Goecks J, Jalili V, Heiser LM, et al. How machine learning will transform biomedicine. Cell. 2020;181(1):92-101.
[11] Hancox Z, Pang A, Conaghan PG, et al. A systematic review of networks for prognostic prediction of health outcomes and diagnostic prediction of health conditions within Electronic Health Records. Artif Intell Med. 2024;158:102999.
[12] Van Calster B, Collins GS, Vickers AJ, et al. Evaluation of performance measures in predictive artificial intelligence models to support medical decisions: overview and guidance. Lancet Digit Health. 2025;7(12):100916.
[13] Marsh RA. Epstein-Barr virus and hemophagocytic lymphohistiocytosis. Front Immunol. 2017;8:1902.
[14] Cai L, Xing Y, Xia Y, et al. Comparative study of biomarkers for the early identification of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in infectious mononucleosis. BMC Infect Dis. 2023;23(1):728.
[15] Hattori A, Hamada Y, Kawabata H, et al. Acute liver injury secondary to hemophagocytic lymphohistiocytosis triggered by Epstein-Barr virus infection. JGH Open. 2021;5(1):166-8.
[16] Horne A, Trottestam H, Aricò M, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327-35.
[17] Horne A, Wickström R, Jordan MB, et al. How to treat involvement of the central nervous system in hemophagocytic lymphohistiocytosis? Curr Treat Options Neurol. 2017;19(1):3.
[18] Paolino J, Berliner N, Degar B. Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure. Front Oncol. 2022;12:1016318.
[19] Canna SW, Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. 2020;135(16):1332-43.
[20] Salvo N, Charles AM, Mohr AM. The intersection of trauma and immunity: immune dysfunction following hemorrhage. Biomedicines. 2024;12(12):2684.
[21] Diamond T, Bennett AD, Behrens EM. The liver in hemophagocytic lymphohistiocytosis: not an innocent bystander. J Pediatr Gastroenterol Nutr. 2023;77(2):153-9.
[22] Khan SA, Amir M. Hemophagocytic lymphohistiocytosis masquerading as autoimmune hepatitis. Cureus. 2023;15(3):e36543.
[23] Ding J, Karp JE, Emadi A. Elevated lactate dehydrogenase (LDH) can be a marker of immune suppression in cancer: interplay between hematologic and solid neoplastic clones and their microenvironments. Cancer Biomark. 2017;19(4):353-63.
[24] Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605-11.
[25] Tengku-Muhammad TS, Cryer A, Ramji DP. Synergism between interferon gamma and tumour necrosis factor alpha in the regulation of lipoprotein lipase in the macrophage J774.2 cell line. Cytokine. 1998;10(1):38-48.
[26] Sarangi R, Pathak M, Padhi S, et al. Ferritin in hemophagocytic lymphohistiocytosis (HLH): current concepts and controversies. Clin Chim Acta. 2020;510:408-15.
[27] Li Y, Xiang X. Prognostic value of laboratory biomarkers in risk stratification for short-term outcomes in Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Curr Med Sci. 2026;46(1):221-8.
[28] Shaw TY, Schivo M. Weathering a cytokine storm: a case of EBV-induced hemophagocytic lymphohistiocytosis. J Investig Med High Impact Case Rep. 2016;4(2):2324709616647409.
[29] Marsh RA. Epstein-Barr virus and hemophagocytic lymphohistiocytosis. Front Immunol. 2018;8:1902.
[30] Xu XJ, Luo ZB, Song H, et al. Simple evaluation of clinical situation and subtypes of pediatric hemophagocytic lymphohistiocytosis by cytokine patterns. Front Immunol. 2022;13:850443.
[31] Fox CP, Shannon-Lowe C, Gothard P, et al. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis in adults characterized by high viral genome load within circulating natural killer cells. Clin Infect Dis. 2010;51(1):66-9.
[32] Liu M, Brodeur KE, Bledsoe JR, et al. Features of hyperinflammation link the biology of Epstein-Barr virus infection and cytokine storm syndromes. J Allergy Clin Immunol. 2025;155(4):1346-56.e9.
[33] Claushuis TAM, Wondergem MJ, Beverloo HB, et al. A drop of blood to lead the way. Hematol Rep. 2025;17(4):58.
[34] Sepulveda FE, de Saint Basile G. Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol. 2017;49:20-6.
[35] Pachlopnik Schmid J, Canioni D, Moshous D, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood. 2011;117(5):1522-9.
[36] Ma Y, Bao Y, Wang J, et al. The lncRNA LINC02446 promotes tumor progression and HLH occurrence by regulating the expression of KLRs and IL-10 in EBV-NK-LPDs. Int Immunopharmacol. 2025;156:114696.
[37] Ramos-Casals M, Brito-Zerón P, López-Guillermo A, et al. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503-16.
[38] Li X, Yan H, Xiao Z, et al. Development of a screening score for hemophagocytic lymphohistiocytosis among pediatric patients with acute infection of Epstein-Barr virus. Front Immunol. 2022;13:981251.
[39] Su Y, Xu M, Cao M, et al. Construction of a forest plot prediction model based on Lasso regression for Epstein-Barr virus associated hemophagocytic lymphohistiocytosis in children. Ital J Pediatr. 2026;52(1):19.
[40] Shen J, He Y, Zheng H, et al. Biomarkers of pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis through single-cell transcriptomics. Nat Commun. 2025;16(1):6888.
[41] Xu XJ, Tang YM, Song H, et al. Diagnostic accuracy of a specific cytokine pattern in hemophagocytic lymphohistiocytosis in children. J Pediatr. 2012;160(6):984-90.e1.
[42] Cheng Y, Tong W, Li W, et al. Elevated CD4⁺/CD8⁺ ratio and D-dimer as diagnostic biomarkers for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis versus infectious mononucleosis in children: a retrospective case-control study. BMC Infect Dis. 2025;25(1):1003.
[43] Yang X, Lu X, Feng L, et al. Enhancing diagnostic precision in EBV-related HLH: a multifaceted approach using (18)F-FDG PET/CT and nomogram integration. Cancer Imaging. 2024;24(1):108.
[44] Wu L, Cao X, Wang J, et al. Etiological stratification and prognostic assessment of haemophagocytic lymphohistiocytosis by machine learning on onco-mNGS data and clinical data. Front Immunol. 2024;15:1390298.
[45] Gu J, An N, Wang X, et al. UNC13D c.2588G>A nucleotide variant impairs NK-cell cytotoxicity in adult-onset EBV-associated hemophagocytic lymphohistiocytosis: a pedigree study. Int J Mol Sci. 2025;26(17):7823.
This work is licensed under a Creative Commons Attribution 4.0 International License.
Copyright (c) 2026 Journal of Public Health and Preventive Medicine