Hypereosinophilic Syndromes An historical overview Christopher Spry

2. ‘Development of Diagnostic Criteria and Research Tools for the Study of Idiopathic Hypereosinophilic Syndromes’, 24-25 June 2003 Hypereosinophilic Syndromes An historical overview Christopher Spry Eosinophils

3. “The goddess Eos, … rising now to bring light to immortals and to mortals.” Homer’s Odyssey 5.1

4. 1871, Eosin Y was first marketed by BASF in Germany

5. 1879, Paul Ehrlich stained eosinophils, suggested their bone marrow origin & discussed eosinophilic leukemia 1879

6. Early cases of ‘eosinophilic leukemia’ • 1861 & 1876, (Brown 1898) Eosinophilic leukemia diagnosed on unstained blood samples? • 1879 onwards, eosinophilic disorders were defined using Ehrlich’s triple stain on blood smears and H & E on tissue sections • 1910, water & acetone was introduced to lyse RBC so that accurate wet counts could be made of blood eosinophils

7. 1919, Shapiro, L.G. illustrated ‘Eosinophilic (polymorphonuclear) leukemia’

8. Eosinophil morphology in HES Reduced granules Nuclear hyper-segmentation Vacuoles

9. Eosinophilia and heart disease1893Reinbach, & 1936 Löffler “Left ventricular cavity in endomyocardiopathy with eosinophilia (case 2). Cavity is nearly filled with granular friable thrombus firmly attached to thickened endocardium.”

10. DefinitionsLeukemia or a persistent eosinophilia? • 1912, First patient reported in the USA: ‘myeloid leukemia’ • 1922, First HES patient reported in the UK: ‘Persistent eosinophilia’ • 1938, Review of 19 patients with HES: ‘unexplained eosinophilia’

11. ‘Hypereosinophilic syndromes’ • 1968, Hardy & Anderson introduced the term ‘hypereosinophilic syndromes’ to cover both malignant and non-malignant diseases of eosinophils • 1969, Benvenisti & Ultmann reviewed 48 cases of ‘eosinophilic leukaemia’

12. Eosinophilic leukemia is a distinct disease • 1957, Bousser: Questionnaire and analysis of patients in France and elsewhere with eosinophilic disorders: two diseases: treat the non-malignant disease with steroids and anticoagulants Bousser J. (1957) Eosinophilie et leucemie. Sang 28, 553-80

13. NIAID program defines HES • 1969, Sheldon Wolff set up a group to study vasculitic diseases: distinguished eosinophilic leukemia and HES; none had polyarteritis nodosa; proposed criteria for diagnosing ‘the hypereosinophilic syndrome’ (HES); several had laboratory features of CML without clinical progression to leukemia. • Tony Fauci with Victor Ferrans and others studied over 50 patients with HES, reported in 1982. ‘Idiopathic’ added to ‘HES’.

14. 1970, 3H-thymidine labelled cells, autoradiographs Thoracic duct lymph Bone marrow eosinophil metaphase

15. T lymphocytes that induce eosinophilia in rats with trichinosis Normal Infected Large pyroninophilic lymphocytes Thoracic duct lymph

16. A circulating factor? From T lymphocytes? • 1982 Patient and child with eosinophilia • 1985-6 Human IL-5 defined. GM-CSF & IL-3 involved too. • IL-5-producing T-cell clones found in 16/60 patients with HES

17. A chromosomal defect? • 1965 Abnormal acrocentric chromosome in two patients: Is this a type of CML? Subsequently, many chromosomal defects described in chromosomes 5,7, 8, 12, 16 and 22 • 1975 Several features of CML noted, but Phi-negative and no bcr-abl fusion protein tyrosine kinase was found • 1994 Clonality detected in some patients • 2003 Deletion of chromosome 4 (q12) and generation of a FIP1L1-PDGFRαtyrosine kinase detected in 9/16 patients

18. Idiopathic(?) HES Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med. 2003; 54:169-84. “.. the term idiopathicshould be abandoned in the classification of HES [now that we know there are] myeloproliferative and lymphocytic variants of the HES.

19. Defining patients who do not have HES For example: 1981, Spanish toxic oil syndrome; eosinophilia myalgia syndrome 1985, M-4Eo variant of myelomonocytic leukemia 1984, Episodic angioedema associated with eosinophilia Nail ridges Pruritic skin lesions

20. Major causes of death in HES1. Eosinophilic endomyocardial disease Left ventricle Thrombosis in the late fibrotic stage Fibrosis Thrombus Thrombus liquefaction Hypertrophy

21. 1981, eosinophilic endomyocardial disease Left ventricular apex ‘blunted’ Resected tissue

22. 1987, MBP in the heart in eosinophilic endomyocardial disease Endocardium Adjacent sections Fluorescent anti-MBP

23. Eosinophil degranulating onto a heart cell in E-EMF Eosinophil Heart cell Electron-dense material

24. Serum ECP levels in HES & EED Ng/ml Highest levels were in patients with heart disease

25. Effects of eosinophil supernatants on isolated rat heart cells and mitochondria

26. Major causes of death in HES2. Thrombi & emboli 1982 Retinal vascular occlusions in HES

27. Treatment of HES • 1912, Radiotherapy • 1919, Splenectomy and splenic irradiation • 1953, Steroids and ACTH • 1970s, Hydroxyurea • 1970s, Vincristine and other cytotoxic drugs • 1970s, Anticoagulants and anti-platelet drugs • 1974, Leukapheresis and plasma exchange • 1987, Bone marrow transplantation • 1994, Interferon alpha • 2002, Imatinib mesylate (Gleevec)

28. <1975 mean survival of 58 patients with HESAbout 12 months from diagnosis In some cases, the cause of death may have been aggressive chemotherapy attempting to induce ‘remission’.

29. 1992, onset & death, 30 patients with HES M/F: 26/4, 6 died. There may be a bimodal age distribution.

30. 1974-1994, mean survival of 54 patients with HES Over 14 years from diagnosis Treatment was symptomatic and no attempt was made to induce a ‘remission’.

31. Paul Ehrlich, 1854 - 1915 c 1900

32. Finally, thanks to all those present and many others! Particularly: 1968, Paul Beeson & Tony Basten for introducing me to eosinophils 1970, Gerry Gleich for leading the way 1974, John Goodwin for introducing me to my first patient with HES 2003, Amy Klion for the wonderful and unexpected invitation to be here! Many other eosinophil colleagues and friends, who have often tried and sometimes succeeded in keeping me on the right eosinophilic rails!