Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a final common pathway resulting from diverse immune processes. Most of the current understanding of HLH is based on studies involving pediatric patients (pHLH). Adult HLH (aHLH) is distinct from pHLH, with less frequent genetic basis, higher frequency of chemo-resistance and a higher mortality. Immunological processes underlying aHLH are poorly understood. So far, no immunophenotypic abnormalities associated with aHLH have been described, and their etiopathologic and prognostic significance has not been explored. We reviewed all adult patients with bone marrow hemophagocytosis and identified 21 who fulfilled the criteria for HLH. We then analyzed abnormalities in their lymphocyte subsets and immunophenotype and tested association of these abnormalities with survival. Twenty of 21 patients showed abnormalities in either lymphocyte subsets and/or immunophenotype: 10 showed increased CD8+ cells and decreased CD4:CD8 ratio, 8 had decreased CD3+ cells, 3 each had increased CD56+ cells, increased CD7−/CD4+ cells, and increased CD3+/CD4−/CD8− (DN) cells, and one had increased CD3–/CD4+ cells. Six of 10 patients with increased numbers of CD8+ cells and decreased CD4:CD8 ratio are alive, compared to 2/11 with normal values (p = 0.0385). On the other hand, all 8 patients with decreased CD3+ cells are dead, compared to 8/13 with normal numbers (p = 0.0417). Those who survived were younger than those who did not (median, range: 29 years, 19–88, vs 62 years, 24–81; p = 0.0272). In conclusion, most aHLH patients show diverse abnormalities in either lymphocytes and/or immunophenotype. Young age, increased numbers of CD8+ cells or decreased CD4:CD8 ratio are favorably associated with survival, while a decreased number of CD3+ cells is adversely associated with survival in aHLH patients.
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References
Filipovich AH (2009) Hemophagocytic lymphohistiocytosis (HLH) and related disorders. Hematol Am Soc Hematol Educ Program 127-131
Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131
Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL (2011) How I treat hemophagocytic lymphohistiocytosis. Blood 118:4041–4052
Emmenegger U, Schaer DJ, Larroche C, Neftel KA (2005) Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly 135:299–314
Richards, Mikhyla J, Sreenivasan, Gayatri M, Dhingra, Vinay, Sweet, David D, Chen, Luke YC (2011) Hemophagocytic syndromes in adult intensive care units: response to Okabe et al. J Intensive Care Med 26:343–344
Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, Yamamoto K, Horiuchi H, Takada K, Ohshima K, Nakamura S, Kinukawa N, Oshimi K, Kawa K (2007) Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol 86:58–65
Lehmberg K, Ehl S (2013) Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 160:275–287
Lin MT, Chang HM, Huang CJ, Chen WL, Lin CY, Lin CY, Chuang SS (2007) Massive expansion of EBV+ monoclonal T cells with CD5 down regulation in EBV-associated haemophagocytic lymphohistiocytosis. J Clin Pathol 60:101–103
Toga A, Wada T, Sakakibara Y, Mase S, Araki R, Tone Y, Toma T, Kurokawa T, Yanagisawa R, Tamura K, Nishida N, Taneichi H, Kanegane H, Yachie A (2010) Clinical significance of cloned expansion and CD5 down-regulation in Epstein-Barr Virus (EBV)-infected CD8+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. J Infect Dis 201:1923–1932
McCall CM, Mudali S, Arceci RJ, Small D, Fuller S, Gocke CD, Vuica-Ross M, Burns KH, Borowitz MJ, Duffield AS (2012) Flow cytometric findings in hemophagocytic lymphohistiocytosis. Am J Clin Pathol 137:786–794
Noguchi M, Kawano Y, Sato N, Oshimi K (1997) T-cell lymphoma of CD3+CD4+CD56+granular lymphocytes with hemophagocytic syndrome. Leuk Lymphoma 26:349–358
Wong KF, Chan JK, Ma SK, Lai KY (1995) Aggressive pleomorphic CD2+, CD3−, CD56+ lymphoma with t(5; 9)(q31;q34) abnormality. Cancer Genet Cytogenet 82:73–75
Kogawa, Kazuhiro, Lee, Susan M, Villanueva, Joyce, Marmer, Daniel, Sumegi, Janos, Filipovich, Alexandra H (2002) Perforin expression in cytotoxic lymphocytes from patients with hemophagocytic lymphohistiocytosis and their family members. Blood 99:61–66
Marcenaro S, Gallo F, Martini S, Santoro A, Griffiths GM, Arico M, Moretta L, Pende D (2006) 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 108:2316–2323
Dalal BI, Mansoor S, Manna M, Pi S, Sauro GD, Hogge DE (2012) Detection of CD34, TdT, CD56, CD2, CD4, and CD14 by flow cytometry is associated with NPM1 and FLT3 mutation status in cytogenetically normal acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 12:274–279
Khoury H, Dalal BI, Nevill TJ, Horsman DE, Barnett MJ, Shepherd JD, Toze CL, Conneally EA, Sutherland HJ, Hogge DE, Nantel SH (2003) Acute myelogenous leukemia with t(8;21)—identification of a specific immunophenotype. Leuk Lymphoma 44:1713–1718
Juvet SC, Zhang L (2012) Double negative regulatory T cells in transplantation and autoimmunity: recent progress and future directions. J Mol Cell Biol 4:48–58
Crosbie OM, Costello PJ, O’Farrelly C, Hegarty JE (1998) Changes in peripheral blood double-negative T-lymphocyte (CD3+ CD4−CD8−) populations associated with acute cellular rejection after liver transplantation. Liver Transpl Surg 4:141–145
Russell TB, Kurre P (2010) Double-negative T cells are non-ALPS-specific markers of immune dysregulation found in patients with aplastic anemia. Blood 116:5072–5073
Santagostino A, Garbaccio G, Pistorio A, Bolis V, Camisasca G, Pagliaro P, Girotto M (1999) An Italian national multicenter study for the definition of reference ranges for normal values of peripheral blood lymphocyte subsets in healthy adults. Haematologica 84:499–504
Reichert T, DeBruyere M, Deneys V, Totterman T, Lydyard P, Yuksel F, Chapel H, Jewell D, Van HL, Linden J (1991) Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol 60:190–208
Ghia P, Prato G, Stella S, Scielzo C, Geuna M, Caligaris-Cappio F (2007) Age-dependent accumulation of monoclonal CD4+CD8+ double positive T lymphocytes in the peripheral blood of the elderly. Br J Haematol 139:780–790
Jentsch-Ullrich K, Koenigsmann M, Mohren M, Franke A (2005) Lymphocyte subsets’ reference ranges in an age- and gender-balanced population of 100 healthy adults—a monocentric German study. Clin Immunol 116:192–197
Wada T, Kurokawa T, Toma T, Shibata F, Tone Y, Hashida Y, Kaya H, Yoshida T, Yachie A (2007) Immunophenotypic analysis of Epstein-Barr virus (EBV)-infected CD8(+) T cells in a patient with EBV-associated hemophagocytic lymphohistiocytosis. Eur J Haematol 79:72–75
Rohr J, Beutel K, Maul-Pavicic A, Vraetz T, Thiel J, Warnatz K, Bondzio I, Gross-Wieltsch U, Schundeln M, Schutz B, Woessmann W, Groll AH, Strahm B, Pagel J, Speckmann C, Janka G, Griffiths G, Schwarz K, zur Stadt U, Ehl S (2010) Atypical familial hemophagocytic lymphohistiocytosis due to mutations in UNC13D and STXBP2 overlaps with primary immunodeficiency diseases. Haematologica 95:2080–2087
Acknowledgments
Contributions of co-authors: BID conceived the project, re-analyzed the data, performed the statistical analysis, and wrote the manuscript. APV re-analyzed the data, performed the statistical analysis, and helped write the manuscript. NSK compiled the patient list and re-analyzed the data. SYW and MJR assisted in study design, data collection, and analysis. LYCC assisted in study design, data collection, and analysis and helped write the manuscript.
We acknowledge the expertise and efforts of competent flow cytometry laboratory staff, the divisional hematopathologists, and clinical hematologists of the VGH.
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All authors declare no conflicts of interest.
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Dalal, B.I., Vakil, A.P., Khare, N.S. et al. Abnormalities of the lymphocyte subsets and their immunophenotype, and their prognostic significance in adult patients with hemophagocytic lymphohistiocytosis. Ann Hematol 94, 1111–1117 (2015). https://doi.org/10.1007/s00277-015-2350-y
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DOI: https://doi.org/10.1007/s00277-015-2350-y