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Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis

Florence Roufosse, MD
Amy D Klion, MD
Peter F Weller, MD, FACP
Section Editor
Bruce S Bochner, MD
Deputy Editors
Anna M Feldweg, MD
Alan G Rosmarin, MD


The hypereosinophilic syndromes (HES) are a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and mediator release cause damage to multiple organs. Although these disorders had long been considered idiopathic (eg, as in the "idiopathic hypereosinophilic syndrome," IHES), etiologies for some forms of HES have been described.

The clinical features, pathophysiology, and diagnosis of HES will be reviewed here. The treatment of these disorders is discussed separately, as is the initial approach to the patient with unexplained eosinophilia. (See "Hypereosinophilic syndromes: Treatment" and "Approach to the patient with unexplained eosinophilia".)


A panel of experts reached consensus on terminology pertaining to hypereosinophilic conditions and published recommendations in 2012 [1]:

Hypereosinophilia — Hypereosinophilia (HE) in the peripheral blood is defined as an absolute eosinophil count (AEC) >1.5 x 109/L (or >1500 cells/microL) on two examinations separated in time by at least one month and/or pathologic confirmation of tissue HE.

For these purposes, tissue HE is defined by:


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Literature review current through: Sep 2016. | This topic last updated: May 24, 2016.
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  1. Valent P, Klion AD, Horny HP, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012; 130:607.
  2. Protheroe C, Woodruff SA, de Petris G, et al. A novel histologic scoring system to evaluate mucosal biopsies from patients with eosinophilic esophagitis. Clin Gastroenterol Hepatol 2009; 7:749.
  3. Nair P, Ochkur SI, Protheroe C, et al. The identification of eosinophilic gastroenteritis in prednisone-dependent eosinophilic bronchitis and asthma. Allergy Asthma Clin Immunol 2011; 7:4.
  4. Crane MM, Chang CM, Kobayashi MG, Weller PF. Incidence of myeloproliferative hypereosinophilic syndrome in the United States and an estimate of all hypereosinophilic syndrome incidence. J Allergy Clin Immunol 2010; 126:179.
  5. Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood 1994; 83:2759.
  6. Farruggia P, D'Angelo P, Acquaviva A, et al. Hypereosinophilic syndrome in childhood: clinical and molecular features of two cases. Pediatr Hematol Oncol 2009; 26:129.
  7. Rapanotti MC, Caruso R, Ammatuna E, et al. Molecular characterization of paediatric idiopathic hypereosinophilia. Br J Haematol 2010; 151:440.
  8. Ogbogu PU, Bochner BS, Butterfield JH, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009; 124:1319.
  9. Cheah CY, Burbury K, Apperley JF, et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood 2014; 123:3574.
  10. Spry CJF. Idiopathic hypereosinophilic syndrome. In: Eosinophils: Biological and clinical aspects, Makino S, Fukuda T (Eds), CRC, Boca Raton 1992. p.403.
  11. Ackerman SJ, Bochner BS. Mechanisms of eosinophilia in the pathogenesis of hypereosinophilic disorders. Immunol Allergy Clin North Am 2007; 27:357.
  12. Pardanani A, Brockman SR, Paternoster SF, et al. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood 2004; 104:3038.
  13. Simon HU, Plötz SG, Dummer R, Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med 1999; 341:1112.
  14. Vaklavas C, Tefferi A, Butterfield J, et al. 'Idiopathic' eosinophilia with an Occult T-cell clone: prevalence and clinical course. Leuk Res 2007; 31:691.
  15. Roche-Lestienne C, Lepers S, Soenen-Cornu V, et al. Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics. Leukemia 2005; 19:792.
  16. Simon HU, Rothenberg ME, Bochner BS, et al. Refining the definition of hypereosinophilic syndrome. J Allergy Clin Immunol 2010; 126:45.
  17. Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med 2003; 54:169.
  18. Bain BJ, Fletcher SH. Chronic eosinophilic leukemias and the myeloproliferative variant of the hypereosinophilic syndrome. Immunol Allergy Clin North Am 2007; 27:377.
  19. Florian S, Esterbauer H, Binder T, et al. Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (SM-CEL): detection of FIP1L1/PDGFRalpha, classification by WHO criteria, and response to therapy with imatinib. Leuk Res 2006; 30:1201.
  20. Swerdlow SH, Campo E, Harris NL, et al. World Health Organization classification of tumours of haematopoietic and lymphoid tissues, IARC Press, Lyon 2008.
  21. Albano F, Anelli L, Zagaria A, et al. Extramedullary molecular evidence of the 5'KIAA1509/3'PDGFRB fusion gene in chronic eosinophilic leukemia. Leuk Res 2008; 32:347.
  22. Yoshida C, Takeuchi M, Sadahira Y. A novel t(1;8)(q25;p11.2) translocation associated with 8p11 myeloproliferative syndrome. Br J Haematol 2012; 156:271.
  23. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003; 348:1201.
  24. Griffin JH, Leung J, Bruner RJ, et al. Discovery of a fusion kinase in EOL-1 cells and idiopathic hypereosinophilic syndrome. Proc Natl Acad Sci U S A 2003; 100:7830.
  25. Safley AM, Sebastian S, Collins TS, et al. Molecular and cytogenetic characterization of a novel translocation t(4;22) involving the breakpoint cluster region and platelet-derived growth factor receptor-alpha genes in a patient with atypical chronic myeloid leukemia. Genes Chromosomes Cancer 2004; 40:44.
  26. Pardanani A, Tefferi A. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 2004; 104:1931.
  27. Legrand F, Renneville A, Macintyre E, et al. The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases. Medicine (Baltimore) 2013.
  28. Jovanovic JV, Score J, Waghorn K, et al. Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2007; 109:4635.
  29. Score J, Curtis C, Waghorn K, et al. Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia. Leukemia 2006; 20:827.
  30. Curtis CE, Grand FH, Musto P, et al. Two novel imatinib-responsive PDGFRA fusion genes in chronic eosinophilic leukaemia. Br J Haematol 2007; 138:77.
  31. Walz C, Haferlach C, Hänel A, et al. Identification of a MYO18A-PDGFRB fusion gene in an eosinophilia-associated atypical myeloproliferative neoplasm with a t(5;17)(q33-34;q11.2). Genes Chromosomes Cancer 2009; 48:179.
  32. Elling C, Erben P, Walz C, et al. Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Blood 2011; 117:2935.
  33. Dasari S, Naha K, Hande M, Vivek G. A novel subtype of myeloproliferative disorder? JAK2V617F-associated hypereosinophilia with hepatic venous thrombosis. BMJ Case Rep 2013; 2013.
  34. Rumi E, Milosevic JD, Casetti I, et al. Efficacy of ruxolitinib in chronic eosinophilic leukemia associated with a PCM1-JAK2 fusion gene. J Clin Oncol 2013; 31:e269.
  35. Patterer V, Schnittger S, Kern W, et al. Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1. Ann Hematol 2013; 92:759.
  36. Lierman E, Selleslag D, Smits S, et al. Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete cytogenetic remission in t(8;9)(p22;p24)/PCM1-JAK2-positive chronic eosinophilic leukemia. Blood 2012; 120:1529.
  37. Li B, Zhang G, Li C, et al. Identification of JAK2 as a mediator of FIP1L1-PDGFRA-induced eosinophil growth and function in CEL. PLoS One 2012; 7:e34912.
  38. Bacher U, Reiter A, Haferlach T, et al. A combination of cytomorphology, cytogenetic analysis, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction for establishing clonality in cases of persisting hypereosinophilia. Haematologica 2006; 91:817.
  39. Pardanani A, Tefferi A. Systemic mastocytosis in adults: a review on prognosis and treatment based on 342 Mayo Clinic patients and current literature. Curr Opin Hematol 2010; 17:125.
  40. Luppi M, Marasca R, Morselli M, et al. Clonal nature of hypereosinophilic syndrome. Blood 1994; 84:349.
  41. Chang HW, Leong KH, Koh DR, Lee SH. Clonality of isolated eosinophils in the hypereosinophilic syndrome. Blood 1999; 93:1651.
  42. Roufosse F, Cogan E, Goldman M. Lymphocytic variant hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007; 27:389.
  43. Lefèvre G, Copin MC, Staumont-Sallé D, et al. The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype. Medicine (Baltimore) 2014; 93:255.
  44. Walker S, Wang C, Walradt T, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood 2016; 127:948.
  45. Roufosse F, Schandené L, Sibille C, et al. Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome. Br J Haematol 2000; 109:540.
  46. Rioux JD, Stone VA, Daly MJ, et al. Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31-q33. Am J Hum Genet 1998; 63:1086.
  47. Collins MH, Blanchard C, Abonia JP, et al. Clinical, pathologic, and molecular characterization of familial eosinophilic esophagitis compared with sporadic cases. Clin Gastroenterol Hepatol 2008; 6:621.
  48. Rosenfeld K, Stodell MA. Eosinophilic fasciitis in a father and son. Ann Rheum Dis 1994; 53:281.
  49. Thomson GT, MacDougall B, Watson PH, Chalmers IM. Eosinophilic fasciitis in a pair of siblings. Arthritis Rheum 1989; 32:96.
  50. Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report. J Allergy Clin Immunol 2006; 117:1292.
  51. Renston JP, Goldman ES, Hsu RM, Tomashefski JF Jr. Peripheral blood eosinophilia in association with sarcoidosis. Mayo Clin Proc 2000; 75:586.
  52. Kim YJ, Dale JK, Noel P, et al. Eosinophilia is associated with a higher mortality rate among patients with autoimmune lymphoproliferative syndrome. Am J Hematol 2007; 82:615.
  53. Aspinall AI, Pinto A, Auer IA, et al. Identification of new Fas mutations in a patient with autoimmune lymphoproliferative syndrome (ALPS) and eosinophilia. Blood Cells Mol Dis 1999; 25:227.
  54. Smith KJ, Skelton HG, Drabick JJ, et al. Hypereosinophilia secondary to immunodysregulation in patients with HIV-1 disease. Arch Dermatol 1994; 130:119.
  55. Paganelli R, Scala E, Mazzone AM, et al. Th2-type cytokines, hypereosinophilia, and interleukin-5 in HIV disease. Allergy 1997; 52:110.
  56. Benfield GF, Asquith P. Blood eosinophilia and ulcerative colitis--influence of ethnic origin. Postgrad Med J 1986; 62:1101.
  57. Lanternier F, Pathan S, Vincent QB, et al. Deep dermatophytosis and inherited CARD9 deficiency. N Engl J Med 2013; 369:1704.
  58. Khoury P, Herold J, Alpaugh A, et al. Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder. Haematologica 2015; 100:300.
  59. Gleich GJ, Schroeter AL, Marcoux JP, et al. Episodic angioedema associated with eosinophilia. N Engl J Med 1984; 310:1621.
  60. Butterfield JH, Leiferman KM, Abrams J, et al. Elevated serum levels of interleukin-5 in patients with the syndrome of episodic angioedema and eosinophilia. Blood 1992; 79:688.
  61. Wright BL, Butterfield JH, Leiferman KM, Gleich GJ. Development of eosinophilic endomyocardial disease in a patient with episodic angioedema and eosinophilia. J Allergy Clin Immunol Pract 2016; 4:336.
  62. Bochner BS, Friedman B, Krishnaswami G, et al. Episodic eosinophilia-myalgia-like syndrome in a patient without L-tryptophan use: association with eosinophil activation and increased serum levels of granulocyte-macrophage colony-stimulating factor. J Allergy Clin Immunol 1991; 88:629.
  63. Khoury P, Zagallo P, Talar-Williams C, et al. Serum biomarkers are similar in Churg-Strauss syndrome and hypereosinophilic syndrome. Allergy 2012; 67:1149.
  64. Churg A. Recent advances in the diagnosis of Churg-Strauss syndrome. Mod Pathol 2001; 14:1284.
  65. Chen YY, Khoury P, Ware JM, et al. Marked and persistent eosinophilia in the absence of clinical manifestations. J Allergy Clin Immunol 2014; 133:1195.
  66. Helbig G, Hus M, Francuz T, et al. Characteristics and clinical outcome of patients with hypereosinophilia of undetermined significance. Med Oncol 2014; 31:815.
  67. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 1975; 54:1.
  68. Take M, Sekiguchi M, Hiroe M, et al. Clinical spectrum and endomyocardial biopsy findings in eosinophilic heart disease. Heart Vessels Suppl 1985; 1:243.
  69. Ogbogu PU, Rosing DR, Horne MK 3rd. Cardiovascular manifestations of hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007; 27:457.
  70. Chew CY, Ziady GM, Raphael MJ, et al. Primary restrictive cardiomyopathy. Non-tropical endomyocardial fibrosis and hypereosinophilic heart disease. Br Heart J 1977; 39:399.
  71. Klion AD, Noel P, Akin C, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood 2003; 101:4660.
  72. Pitini V, Arrigo C, Azzarello D, et al. Serum concentration of cardiac Troponin T in patients with hypereosinophilic syndrome treated with imatinib is predictive of adverse outcomes. Blood 2003; 102:3456.
  73. Gertz MA. Troponin in hematologic oncology. Leuk Lymphoma 2008; 49:194.
  74. Zaky J, Caraang C, Yu R, El-Bialy A. Elevated troponins and the Churg-Strauss syndrome: a case report. J Cardiovasc Pharmacol Ther 2005; 10:131.
  75. Debl K, Djavidani B, Buchner S, et al. Time course of eosinophilic myocarditis visualized by CMR. J Cardiovasc Magn Reson 2008; 10:21.
  76. Syed IS, Martinez MW, Feng DL, Glockner JF. Cardiac magnetic resonance imaging of eosinophilic endomyocardial disease. Int J Cardiol 2008; 126:e50.
  77. Wright BL, Leiferman KM, Gleich GJ. Eosinophil granule protein localization in eosinophilic endomyocardial disease. N Engl J Med 2011; 365:187.
  78. Wang JG, Mahmud SA, Thompson JA, et al. The principal eosinophil peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant inducer of endothelial cell tissue factor activity: a potential mechanism for thrombosis in eosinophilic inflammatory states. Blood 2006; 107:558.
  79. Moosbauer C, Morgenstern E, Cuvelier SL, et al. Eosinophils are a major intravascular location for tissue factor storage and exposure. Blood 2007; 109:995.
  80. Plastiras SC, Economopoulos N, Kelekis NL, Tzelepis GE. Magnetic resonance imaging of the heart in a patient with hypereosinophilic syndrome. Am J Med 2006; 119:130.
  81. Comarmond C, Pagnoux C, Khellaf M, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum 2013; 65:270.
  82. Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med 1985; 102:109.
  83. Aida L, Parkhutik V, Tembl JI, et al. Embolism and impaired washout: a possible explanation of border zone strokes in hypereosinophilic syndrome. J Neurol Sci 2013; 325:162.
  84. Kawata E, Kuroda J, Wada K, et al. Hypereosinophilic syndrome accompanied by Buerger's disease-like femoral arterial occlusions. Intern Med 2007; 46:1919.
  85. Sakuta R, Tomita Y, Ohashi M, et al. Idiopathic hypereosinophilic syndrome complicated by central sinovenous thrombosis. Brain Dev 2007; 29:182.
  86. Numagami Y, Tomita T, Murakami K, et al. Sinus thrombosis in idiopathic hypereosinophilic syndrome causing fatal cerebral haemorrhage. J Clin Neurosci 2008; 15:585.
  87. Spry CJ, Davies J, Tai PC, et al. Clinical features of fifteen patients with the hypereosinophilic syndrome. Q J Med 1983; 52:1.
  88. Liapis H, Ho AK, Brown D, et al. Thrombotic microangiopathy associated with the hypereosinophilic syndrome. Kidney Int 2005; 67:1806.
  89. Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med 1982; 97:78.
  90. Chaine G, Davies J, Kohner EM, et al. Ophthalmologic abnormalities in the hypereosinophilic syndrome. Ophthalmology 1982; 89:1348.
  91. Leiferman KM, Gleich GJ, Peters MS. Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am 2007; 27:415.
  92. McPherson T, Cowen EW, McBurney E, Klion AD. Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis. Br J Dermatol 2006; 155:824.
  93. Schooley RT, Flaum MA, Gralnick HR, Fauci AS. A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. II. Clinical manifestations. Blood 1981; 58:1021.
  94. Dulohery MM, Patel RR, Schneider F, Ryu JH. Lung involvement in hypereosinophilic syndromes. Respir Med 2011; 105:114.
  95. Flaum MA, Schooley RT, Fauci AS, Gralnick HR. A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. I. Hematologic manifestations. Blood 1981; 58:1012.
  96. Parreira L, Tavares de Castro J, Hibbin JA, et al. Chromosome and cell culture studies in eosinophilic leukaemia. Br J Haematol 1986; 62:659.
  97. Bain B. Philadelphia chromosome? Am J Hematol 2007; 82:414; author reply 414.
  98. Pardanani A, Ketterling RP, Brockman SR, et al. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Blood 2003; 102:3093.
  99. Bain BJ. Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. Am J Hematol 2004; 77:82.
  100. Schmitt-Graeff AH, Erben P, Schwaab J, et al. The FIP1L1-PDGFRA fusion gene and the KIT D816V mutation are coexisting in a small subset of myeloid/lymphoid neoplasms with eosinophilia. Blood 2014; 123:595.
  101. Cogan E, Schandené L, Crusiaux A, et al. Brief report: clonal proliferation of type 2 helper T cells in a man with the hypereosinophilic syndrome. N Engl J Med 1994; 330:535.
  102. Simon HU, Yousefi S, Dommann-Scherrer CC, et al. Expansion of cytokine-producing CD4-CD8- T cells associated with abnormal Fas expression and hypereosinophilia. J Exp Med 1996; 183:1071.
  103. Kitano K, Ichikawa N, Mahbub B, et al. Eosinophilia associated with proliferation of CD(3+)4-(8-) alpha beta+ T cells with chromosome 16 anomalies. Br J Haematol 1996; 92:315.
  104. Ravoet M, Sibille C, Roufosse F, et al. 6q- is an early and persistent chromosomal aberration in CD3-CD4+ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome. Haematologica 2005; 90:753.
  105. Klion AD, Mejia R, Cowen EW, et al. Chronic active Epstein-Barr virus infection: a novel cause of lymphocytic variant hypereosinophilic syndrome. Blood 2013; 121:2364.
  106. Chen R, Giliani S, Lanzi G, et al. Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias. J Allergy Clin Immunol 2013; 132:656.
  107. de Lavareille A, Roufosse F, Schmid-Grendelmeier P, et al. High serum thymus and activation-regulated chemokine levels in the lymphocytic variant of the hypereosinophilic syndrome. J Allergy Clin Immunol 2002; 110:476.
  108. Brito-Babapulle F. The eosinophilias, including the idiopathic hypereosinophilic syndrome. Br J Haematol 2003; 121:203.
  109. Bain BJ. Hypereosinophilia. Curr Opin Hematol 2000; 7:21.
  110. Fridman A, Sagiv Sh, Shvidel L, Berrebi A. Reversible Horner syndrome caused by solitary plasmacytoma of second thoracic vertebrae. Leuk Lymphoma 2004; 45:2531.
  111. Maric I, Robyn J, Metcalfe DD, et al. KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities. J Allergy Clin Immunol 2007; 120:680.
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