Hypereosinophilic syndrome: a historical overview

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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
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The goddess Eos, rising now to bring light to
immortals and to mortals. Homers Odyssey 5.1
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1871, Eosin Y was first marketed by BASF in
Germany
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1879, Paul Ehrlich stained eosinophils, suggested
their bone marrow origin discussed eosinophilic
leukemia
1879
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Early cases of eosinophilic leukemia

• 1861 1876, (Brown 1898) Eosinophilic leukemia
  diagnosed on unstained blood samples?
• 1879 onwards, eosinophilic disorders were defined
  using Ehrlichs 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

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1919, Shapiro, L.G. illustrated Eosinophilic
(polymorphonuclear) leukemia
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Eosinophil morphology in HES
Nuclear hyper-segmentation
Reduced granules
Vacuoles
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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.
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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

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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

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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
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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.

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1970, 3H-thymidine labelled cells,
autoradiographs
Thoracic duct lymph
Bone marrow eosinophil metaphase
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T lymphocytes that induce eosinophilia in rats
with trichinosis
Normal
Infected
Large pyroninophilic lymphocytes
Thoracic duct lymph
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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

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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-PDGFRa tyrosine kinase
  detected in 9/16 patients

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Idiopathic(?) HES

• Roufosse F, Cogan E, Goldman M. The
  hypereosinophilic syndrome revisited. Annu Rev
  Med. 2003 54169-84.
• .. the term idiopathic should be abandoned in
  the classification of HES now that we know there
  are myeloproliferative and lymphocytic variants
  of the HES.

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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
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Major causes of death in HES1. Eosinophilic
endomyocardial disease
Left ventricle
Thrombosis in the late fibrotic stage
Fibrosis
Thrombus
Thrombus liquefaction
Hypertrophy
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1981, eosinophilic endomyocardial disease
Left ventricular apex blunted
Resected tissue
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1987, MBP in the heart in eosinophilic
endomyocardial disease
Endocardium
Adjacent sections
Fluorescent anti-MBP
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Eosinophil degranulating onto a heart cell in
E-EMF
Eosinophil
Heart cell
Electron-dense material
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Serum ECP levels in HES EED
Ng/ml
Highest levels were in patients with heart disease
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Effects of eosinophil supernatants on isolated
rat heart cells and mitochondria
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Major causes of death in HES2. Thrombi emboli
1982 Retinal vascular occlusions in HES
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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)

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lt1975 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.
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1992, onset death, 30 patients with HES
M/F 26/4, 6 died. There may be a bimodal age
distribution.
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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.
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Paul Ehrlich, 1854 - 1915
c 1900
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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!
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