Dermatologic Manifestations of Hypereosinophilic Syndrome 

  • Author: Noah S Scheinfeld, MD, JD, FAAD; Chief Editor: Dirk M Elston, MD   more...
 
Updated: Aug 2, 2011
 

Background

Hypereosinophilic syndrome (HES) encompasses a wide range of clinical manifestations sharing 3 features defined by Chusid et al[1] : (1) a peripheral eosinophil count of greater than 1.5 X 109/L for longer than 6 months; (2) evidence of organ involvement, thus excluding benign eosinophilia; and (3) an absence of other causes of eosinophilia, such as parasite infestation (most common cause of eosinophilia worldwide), allergy (most common cause of eosinophilia in the United States), malignancy, and collagen-vascular disease.

Also see the eMedicine Pediatrics article Hypereosinophilic Syndrome and the Hematology article Hypereosinophilic Syndrome.

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Pathophysiology

Hypereosinophilic syndrome etiology can involve (1) primitive involvement of myeloid cells, essentially due to the occurrence of an interstitial chromosomal deletion on band 4q12 leading to the creation of the FIP1L1-PDGFRA fusion gene (F/P+ variant), or (2) increased interleukin (IL)–5 production by a clonally expanded T-cell population (lymphocytic variant), most frequently characterized by a CD3- CD4+ phenotype.[2, 3]

Multiple cytokines stimulate eosinophil production, including IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-5.[4] In 3 patients with T-cell lymphomas, eosinophilia has been correlated with increased production of these cytokines by the lymphomas. IL-3 and GM-CSF act on other bone marrow–derived lineages, whereas the stimulatory activity of IL-5 appears to be limited to eosinophils and thus suggests it to be the dominant factor in eosinophil proliferation. At present, the source of IL-5 in hypereosinophilic syndrome has not been definitively determined, but evidence points to increased production by CD4+ T-lymphocyte clones.

However, IL-5 mRNA and protein have been found in eosinophils; therefore, the increase in this cytokine cannot be attributed merely to T cells. Also, because some patients with hypereosinophilic syndrome have concomitant neutrophilia, factors other than IL-5 are likely involved. GM-CSF and IL-3 have been shown to be produced by eosinophils, and GM-CSF production was demonstrated in the T-cell clones from patients with hypereosinophilic syndrome.

Eosinophils in hypereosinophilic syndrome infiltrate multiple organs where they inflict tissue damage through the release of granule proteins, including eosinophil peroxidase, major basic protein, eosinophil-derived neurotoxin, and eosinophil cationic protein. They also release proinflammatory cytokines (ie, interleukin 1 alpha, tumor necrosis factor–alpha, interleukin 6, interleukin 8, IL-3, IL-5, GM-CSF, macrophage inflammatory protein), which attract more eosinophils and other inflammatory cells to the area. Cardiac involvement is the most common cause of mortality in hypereosinophilic syndrome. In the heart, the infiltration by eosinophils results in endomyocardial fibrosis, with subsequent development of congestive heart failure (CHF) and death. This infiltration is necessary for tissue damage to occur because patients with peripheral eosinophilia due to other causes (eg, eosinophilic pneumonia) do not develop pathology similar to hypereosinophilic syndrome.

Fip1-like1-platelet-derived growth factor receptor alpha chain (FIP1L1-PDGFRA) mutation has been described in adult patients with hypereosinophilic syndrome.[5] Specifically, a novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-alpha (PDGFRA), has been invariably associated with a primary eosinophilic disorder and results in clonal lines of pathologic cells.[6]

Pardanani et al[7] examined both the prevalence and the associated clinicopathologic features of the mutation in FIP1L1-PDGFRA in 89 adults presenting with an absolute eosinophil count of higher than 1.5 X 109/L. Pardanani and his team[7] used a fluorescence in situ hybridization–based strategy to identify FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia demonstrated defects in FIP1L1-PDGFRA, whereas the rate of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with hypereosinophilic syndrome but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the mutated FIP1L1-PDGFRA. Thus, it seems FIP1L1-PDGFRA is not solely responsible for hypereosinophilic syndrome. However, a 40% partial response rate was observed in 10 hypereosinophilic syndrome cases after treatment with imatinib.

McPherson et al[8] reported a 33-year-old man with recurrent papular skin lesions and marked peripheral eosinophilia whose skin histopathology showed a proliferation of CD30+ T cells consistent with lymphomatoid papulosis and in whom molecular analysis of peripheral blood mononuclear cells demonstrated the presence of the FIP1L1/PDGFRA fusion gene.

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Epidemiology

Frequency

United States

The exact incidence of hypereosinophilic syndrome is hard to determine because it is a diagnosis of exclusion. It is a rare condition, although numerous reports exist in the literature. At the National Institutes of Health (NIH) between 1971 and 1982, 50 cases of hypereosinophilic syndrome were diagnosed and followed up.[9] The disease is rare in children.

International

Hypereosinophilic syndrome is rare, and the exact incidence is uncertain.

Mortality/Morbidity

The course of hypereosinophilic syndrome varies from relatively indolent to fulminant and rapidly fatal. The prognosis of hypereosinophilic syndrome has improved significantly since definition of hypereosinophilic syndrome and the development of imatinib. Ultimately, the mortality associated with hypereosinophilic syndrome id due to the occurrence of hypereosinophilic syndrome-related irreversible heart failure and the eventuality of malignant transformation of myeloid or lymphoid cells into a frank eosinophilic leukemia.[2]

Survival statistics vary. A review of 57 patients with advanced disease had a mean survival rate of 9 months and a 3-year survival rate of 12%; in another analysis of 40 patients, the 5-year survival rate was 80% and the 10-year survival rate was 42%. A study from the NIH in 1982[9] noted a mean duration of disease of 4.8 years (range, 1-24 y). How newer treatments, such as cyclosporine, have affected mortality and morbidity is unclear.

Race

No racial predilection is recognized for hypereosinophilic syndrome.

Sex

Male predominance (4-9:1 ratio) has been reported in historic series, but this is likely to reflect the quasi-exclusive male distribution of a sporadic hematopoietic stem cell mutation found in a characterized disease variant.[2]

Age

A study from the NIH[9] of 50 patients reported that the mean age of onset was 33 years. In 70% of patients, the onset of disease occurs between 20-50 years. Although rare, this disease hypereosinophilic syndrome does occur in children.[10] A review in 1987[11] from Wales found 18 published reports of hypereosinophilic syndrome in children younger than 16 years. The incidence seems to decrease in elderly persons. Kim et al reported encephalitis in idiopathic hypereosinophilic syndrome in a 14-year-old girl.[12]

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Contributor Information and Disclosures
Author

Noah S Scheinfeld, MD, JD, FAAD  Assistant Clinical Professor, Department of Dermatology, Columbia University College of Physicians and Surgeons; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, and New York Eye and Ear Infirmary; Private Practice

Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Optigenex Consulting fee Independent contractor

Coauthor(s)

Felix Urman, MD  Staff Physician, Department of Dermatology, St Luke's Roosevelt Hospital Center

Disclosure: Nothing to disclose.

Specialty Editor Board

Takeji Nishikawa, MD  Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

David F Butler, MD  Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic

David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD  Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology

Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Consulting fee Consulting; Celgene Honoraria Safety Monitoring Committee; GSK - Glaxo Smith Kline Consulting fee Consulting; TenXBioPharma Consulting fee Safety Monitoring Committee

Catherine M Quirk, MD  Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Catherine M Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD  Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

References

  1. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). Jan 1975;54(1):1-27. [Medline].

  2. Roufosse FE, Goldman M, Cogan E. Hypereosinophilic syndromes. Orphanet J Rare Dis. Sep 11 2007;2:37. [Medline].

  3. Gonzalez Delgado P, de la Sen Fernandez ML, Soriano Gomis V, Perez Crespo M, Munoz Ruiz C, Hernandez Niveiro E. Cyclical hypereosinophilia with skin manifestations and a clonal T cell population. J Investig Allergol Clin Immunol. 2008;18(5):401-3. [Medline].

  4. Simon HU, Plötz SG, Dummer R, Blaser K. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med. Oct 7 1999;341(15):1112-20. [Medline].

  5. Chung KF, Hew M, Score J, et al. Cough and hypereosinophilia due to FIP1L1-PDGFRA fusion gene with tyrosine kinase activity. Eur Respir J. Jan 2006;27(1):230-2. [Medline].

  6. Martinaud C, Souraud JB, Cournac JM, Pons S, Ménard G, de Jaureguiberry JP, et al. [Synchronous detection of T-cell clonality and FIP1L1-PDGFRA fusion gene in a hypereosinophilic syndrome.]. Rev Med Interne. Jul 2010;[Medline].

  7. 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. Nov 15 2004;104(10):3038-45. [Medline].

  8. McPherson T, Cowen EW, McBurney E, Klion AD. Platelet-derived growth factor receptor-alpha-associated hypereosinophilic syndrome and lymphomatoid papulosis. Br J Dermatol. Oct 2006;155(4):824-6. [Medline].

  9. Fauci AS, Harley JB, Roberts WC, Ferrans VJ, Gralnick HR, Bjornson BH. NIH conference. The idiopathic hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic considerations. Ann Intern Med. Jul 1982;97(1):78-92. [Medline].

  10. Farruggia P, D'Angelo P, Acquaviva A, et al. Hypereosinophilic syndrome in childhood: clinical and molecular features of two cases. Pediatr Hematol Oncol. Apr-May 2009;26(3):129-35. [Medline].

  11. Alfaham MA, Ferguson SD, Sihra B, Davies J. The idiopathic hypereosinophilic syndrome. Arch Dis Child. Jun 1987;62(6):601-13. [Medline].

  12. Kim HY, Kim YM, Kim SH, Kim HJ. Encephalitis in idiopathic hypereosinophilic syndrome in childhood. Pediatr Radiol. Jun 2010;[Medline].

  13. Sundaramurthi VL, Prabhavathy D, Somasundaram SV, Wahab AJ. Hypereosinophilic syndrome: cutaneous involvement as the sole manifestation. Indian J Dermatol. Jan 2011;56(1):107-9. [Medline]. [Full Text].

  14. Habibagahi Z, Ali Nazarinia M, Aaflaki E, Ali Ostovan M, Hadi Bagheri M. Systemic lupus erythematosus and hyper-eosinophilic syndrome: an unusual association. West Indian Med J. Jan 2009;58(1):69-71. [Medline].

  15. Kanamori M, Suzuki H, Sato I, Ohyama K, Tezuka F, Katakura R. A case of idiopathic hypereosinophilic syndrome with leptomeningeal dissemination and intraventricular mass lesion: an autopsy report. Clin Neuropathol. May-Jun 2009;28(3):197-202. [Medline].

  16. Leiferman KM, Gleich GJ, Peters MS. Dermatologic manifestations of the hypereosinophilic syndromes. Immunol Allergy Clin North Am. Aug 2007;27(3):415-41. [Medline].

  17. Ionescu MA, Murata H, Janin A. Oral mucosa lesions in hypereosinophilic syndrome--an update. Oral Dis. Mar 2008;2:115-22. [Medline].

  18. Newton JA, Singh AK, Greaves MW, Spry CJ. Aquagenic pruritus associated with the idiopathic hypereosinophilic syndrome. Br J Dermatol. Jan 1990;122(1):103-6. [Medline].

  19. Bogenrieder T, Griese DP, Schiffner R, et al. Wells' syndrome associated with idiopathic hypereosinophilic syndrome. Br J Dermatol. Dec 1997;137(6):978-82. [Medline].

  20. Takekawa M, Imai K, Adachi M, et al. Hypereosinophilic syndrome accompanied with necrosis of finger tips. Intern Med. Nov 1992;31(11):1262-6. [Medline].

  21. Hofmann SC, Technau K, Muller AM, Lubbert M, Bruckner-Tuderman L. Bullous pemphigoid associated with hypereosinophilic syndrome: simultaneous response to imatinib. J Am Acad Dermatol. May 2007;56(5 Suppl):S68-72. [Medline].

  22. Brockington IF, Olsen EG. Loffler's endocarditis and Davies endomyocardial fibrosis. Am Heart J. 1973;85:308.

  23. Davies J, Spry CJ, Sapsford R, et al. Cardiovascular features of 11 patients with eosinophilic endomyocardial disease. Q J Med. Winter 1983;52(205):23-39. [Medline].

  24. Rauch AE, Amyot KM, Dunn HG, Ng B, Wilner G. Hypereosinophilic syndrome and myocardial infarction in a 15-year-old. Pediatr Pathol Lab Med. May-Jun 1997;17(3):469-86. [Medline].

  25. Tan SA, Duggal A. Pericardial involvement as a rare manifestation of hypereosinophilic syndrome. South Med J. Jul 2009;102(7):751-3. [Medline].

  26. Fernandez AB, Ahmed S, Duncan B, Firshein S, Kluger J. Cardiac tamponade: a rare complication of idiopathic hypereosinophilic syndrome. J Cardiovasc Med (Hagerstown). Feb 2009;10(2):188-91. [Medline].

  27. Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hypereosinophilic syndrome. Ann Intern Med. Jan 1985;102(1):109-14. [Medline].

  28. Grigoryan M, Geisler SD, St Louis EK, Baumbach GL, Davis PH. Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome. Arch Neurol. Apr 2009;66(4):528-31. [Medline].

  29. Chang WL, Lin HJ, Cheng HH. Hypereosinophilic syndrome with recurrent strokes: a case report. Acta Neurol Taiwan. Sep 2008;17(3):184-8. [Medline].

  30. Flaum MA, Schooley RT, Fauci AS, Gralnick HR. A clinicopathologic correlation of the idiopathic hypereosinophilic syndrome. I. Hematologic manifestations. Blood. Nov 1981;58(5):1012-20. [Medline].

  31. Numagami Y, Tomita T, Murakami K, Masaki I, Kubo K, Michiharu N. Sinus thrombosis in idiopathic hypereosinophilic syndrome causing fatal cerebral haemorrhage. J Clin Neurosci. May 2008;15(5):585-7. [Medline].

  32. Watanabe M, Matsui N, Hamada S, et al. A rare case of idiopathic hypereosinophilic syndrome involving the oral cavity associated with the esophagus and gastrointestinal tract. Intern Med. Apr 2004;43(4):336-9. [Medline].

  33. Darki A, Kodali PP, McPheters JP, Virk H, Patel MR, Jacobs W. Hypereosinophilic syndrome with cardiac involvement in a pregnant patient with multiple sclerosis. Tex Heart Inst J. 2011;38(2):163-5. [Medline]. [Full Text].

  34. Kahn JE, Bletry O, Guillevin L. Hypereosinophilic syndromes. Best Pract Res Clin Rheumatol. Oct 2008;22(5):863-82. [Medline].

  35. Zittoun J, Farcet JP, Marquet J, Sultan C, Zittoun R. Cobalamin (vitamin B12) and B12 binding proteins in hypereosinophilic syndromes and secondary eosinophilia. Blood. Apr 1984;63(4):779-83. [Medline].

  36. Rothenberg ME. Molecular diagnostics and treatment of patients with the hypereosinophilic syndrome. Clin Adv Hematol Oncol. Jan 2009;7(1):43-4. [Medline].

  37. Adams JC, Dal-Bianco JP, Kumar G, Callahan MJ. Hypereosinophilic syndrome with characteristic left ventricular thrombus demonstrated bycontrast echocardiography. Neth Heart J. Apr 2009;4:169-70. [Medline].

  38. Scheinfeld N. A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases. J Drugs Dermatol. Feb 2006;5(2):117-22. [Medline].

  39. Coutre S, Gotlib J. Targeted treatment of hypereosinophilic syndromes and chronic eosinophilic leukemias with imatinib mesylate. Semin Cancer Biol. Aug 2004;14(4):307-15. [Medline].

  40. Kobayashi M, Kubota T, Uemura Y, Taguchi H. A case of hypereosinophilic syndrome presenting with chronic cough successfully treated with imatinib. Respirology. Mar 2009;14(2):302-4. [Medline].

  41. Gleich GJ, Leiferman KM. The hypereosinophilic syndromes: current concepts and treatments. Br J Haematol. May 2009;145(3):271-85. [Medline].

  42. Wagner LA, Speckart S, Cutter B, Gleich GJ. Treatment of FIP1L1/PDGFRA-negative hypereosinophilic syndrome with alemtuzumab, an anti-CD52 antibody. J Allergy Clin Immunol. Jun 2009;123(6):1407-8. [Medline].

  43. Verstovsek S, Tefferi A, Kantarjian H, et al. Alemtuzumab therapy for hypereosinophilic syndrome and chronic eosinophilic leukemia. Clin Cancer Res. Jan 1 2009;15(1):368-73. [Medline].

  44. Quintas-Cardama A, Cortes J. Therapeutic options for patients with clonal and idiopathic hypereosinophia. Expert Opin Investig Drugs. Jul 2008;17(7):1039-50. [Medline].

  45. Wechsler ME. Combating the eosinophil with anti-interleukin-5 therapy. N Engl J Med. Mar 20 2008;358(12):1293-4. [Medline].

  46. Marshall GM, White L. Effective therapy for a severe case of the idiopathic hypereosinophilic syndrome. Am J Pediatr Hematol Oncol. Summer 1989;11(2):178-83. [Medline].

  47. Parrillo JE, Fauci AS, Wolff SM. Therapy of the hypereosinophilic syndrome. Ann Intern Med. Aug 1978;89(2):167-72. [Medline].

  48. Razaq W, Beautyman E. Successful Treatment of Refractory Idiopathic Hypereosinophilic Syndrome With Etoposide. Am J Ther. Jan 8 2009;[Medline].

  49. Walsh GM. Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions. Curr Opin Mol Ther. Jun 2009;11(3):329-36. [Medline].

  50. Donald CE, Kahn MJ. Successful treatment of hypereosinophilic syndrome with cyclosporine. Am J Med Sci. Jan 2009;337(1):65-6. [Medline].

  51. Taverna JA, Lerner A, Goldberg L, Werth S, Demierre MF. Infliximab as a therapy for idiopathic hypereosinophilic syndrome. Arch Dermatol. Sep 2007;143(9):1110-2. [Medline].

 
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Petechiae on an erythematous base.
 
 
 
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