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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
“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’
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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
Reduced granules
Nuclear hyper-segmentation
Vacuoles
Eosinophilia and heart disease
1893 Reinbach, & 1936 Löffler
“Left ventricular cavity in
endomyocardiopathy with
eosinophilia (case 2). Cavity
is nearly filled with
granular friable thrombus
firmly attached to thickened
endocardium.”
Definitions
Leukemia 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’
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‘Hypereosinophilic syndromes’
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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
Normal
Infected
Large
pyroninophilic
lymphocytes
Thoracic duct lymph
A circulating factor? From T lymphocytes?
1982 Patient and child with eosinophilia
 1985-6 Human IL-5 defined. GM-CSF & IL3 involved too.
 IL-5-producing T-cell clones found in
16/60 patients with HES
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A chromosomal defect?
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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 Phinegative 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
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
Major causes of death in HES
1. Eosinophilic endomyocardial disease
Left ventricle
Thrombosis in the late
fibrotic stage
Fibrosis
Thrombus
Thrombus liquefaction
Hypertrophy
1981, eosinophilic endomyocardial disease
Left ventricular apex ‘blunted’
Resected tissue
1987, MBP in the heart in eosinophilic
endomyocardial disease
Endocardium
Adjacent sections
Fluorescent anti-MBP
Eosinophil degranulating onto a heart cell in EEMF
Eosinophil
Heart cell
Electron-dense material
Serum ECP levels in HES & EED
Ng/ml
Highest levels
were in
patients with
heart disease
Effects of eosinophil supernatants on isolated rat
heart cells and mitochondria
Major causes of death in HES
2. 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 HES
About 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!