‘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!