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‘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. - PowerPoint PPT Presentation
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‘Development of Diagnostic Criteria and Research Tools for the Study of Idiopathic Hypereosinophilic Syndromes’, 24-25 June 2003
Hypereosinophilic SyndromesAn historical overview
Christopher Spry
Eosinophils
“The goddess Eos, … rising now to bring light to immortals and to mortals.” Homer’s Odyssey 5.1
1871, Eosin Y was first marketed by BASF in Germany
1879, Paul Ehrlich stained eosinophils, suggested their bone marrow origin & discussed eosinophilic leukemia
1879
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
1919, Shapiro, L.G. illustrated ‘Eosinophilic (polymorphonuclear) leukemia’
Eosinophil morphology in HES
VacuolesNuclear hyper-segmentationReduced granules
Eosinophilia and heart disease 1893 Reinbach, & 1936 Löffler
“Left ventricular cavity in endomyocardiopathy with eosinophilia (case 2). Cavity is nearly filled withgranular friable thrombus firmly attached to thickened endocardium.”
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’
‘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’
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
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’.
1970, 3H-thymidine labelled cells, autoradiographs
Thoracic duct lymph Bone marrow eosinophil metaphase
T lymphocytes that induce eosinophilia in rats with trichinosis
Thoracic duct lymph
Normal Infected
Large pyroninophilic lymphocytes
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
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-PDGFRα tyrosine kinase detected in 9/16 patients
Idiopathic(?) HES
Roufosse F, Cogan E, Goldman M. The hypereosinophilic syndrome revisited. Annu Rev Med. 2003; 54:169-84.
“.. the term idiopathic should be abandoned in the classification of HES [now that we know there are] myeloproliferative and lymphocytic variants of the HES.
Defining patients who do not have HES
Nail ridges
Pruritic skin lesions
For example:
1981, Spanish toxic oil syndrome; eosinophilia myalgia syndrome
1985, M-4Eo variant of myelomonocytic leukemia
1984, Episodic angioedema associated with eosinophilia
Major causes of death in HES1. Eosinophilic endomyocardial disease
Fibrosis
Thrombus
Thrombus liquefaction
Hypertrophy
Left ventricle
Thrombosis in the late fibrotic stage
1981, eosinophilic endomyocardial disease
Left ventricular apex ‘blunted’ Resected tissue
1987, MBP in the heart in eosinophilic endomyocardial disease
Fluorescent anti-MBP
Endocardium
Adjacent sections
Eosinophil degranulating onto a heart cell in E-EMF
Electron-dense material
Eosinophil
Heart cell
Serum ECP levels in HES & EED
Ng/mlHighest levels were in patients with heart disease
Effects of eosinophil supernatants on isolated rat heart cells and mitochondria
Major causes of death in HES2. Thrombi & emboli
1982 Retinal vascular occlusions in HES
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)
<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’.
1992, onset & death, 30 patients with HES
M/F: 26/4, 6 died. There may be a bimodal age distribution.
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’.
Paul Ehrlich, 1854 - 1915
c 1900
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!