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Chapter 71 Eosinophilia, Eosinophil-Associated Diseases, Eosinophilic Leukemias, and the Hypereosinophilic Syndromes 1159

DEFINITION AND CLASSIFICATION OF HE AND HES established. The demonstration of extensive extracellular deposition
of eosinophil-derived proteins supports the conclusion the organ
The term HES was initially proposed for a syndrome character- damage is “HE-related”. 7
ized by idiopathic HE and HE-related organ damage, as well as
by exclusion of various conditions and diseases that are typically
accompanied by HE. More recently, the definition of HES has been Classification of HE and HES
refined as any type of HE (not just idiopathic) associated with typical
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HE-related end-organ damage. According to the proposal of an The classification of HE and HES is essentially based on the related
international working group on eosinophil disorders (ICOG-EO), disease and underlying etiology. Accordingly, HE and HES are both
the term HES should be reserved for clinical syndromes fulfilling divided into a familial variant (HE F , HES F ), a primary/neoplastic form
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HES criteria, but not for underlying (hematologic) malignan- (HE N , HES N ), and reactive entities (HE R , HES R ; see Table 71.3). In
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cies or immunological disorders presenting with HE. In other a smaller fraction of patients, the etiology of HE and HES remains
words, the diagnosis HES must prompt the physician to search uncertain or two different causative factors are detected. When the
for (detect) an underlying (HES-triggering) disease. Accordingly, etiology of HE remains uncertain after a thorough investigation
the final diagnosis is either idiopathic HES or HES based on a and appropriate testing and no organ damage is detected, the final
recognized underlying disorder, and both need to be documented diagnosis is HE of uncertain (undetermined) significance (HE US );
in the final diagnosis. In previous WHO classifications, the term and if HES is diagnosed, but no underlying disease is detected, the
HES was sometimes used as a synonym of CEL, and sometimes to final diagnosis is idiopathic HES (HES I). 3
discriminate CEL from other less well-defined myeloid neoplasms In general, four major groups of underlying disorders (condi-
with HE. However, in the 2008 edition of the WHO monograph, tions) have to be considered in HE (HES) patients: (1) myeloid
the term HES was no longer recommended as a synonym of WHO- (and rarely myeloid/lymphoid) neoplasms including eosinophilic
defined neoplasms, a distinction that is in agreement with the leukemias (HE N ; HES N ), (2) lymphoid or nonhematopoietic neo-
proposal of the ICON group and the proposal of the ICOG-EO plasms (paraneoplastic HE, a special variant of HE R ), (3) common
group. 3 allergic, reactive, or immunologic conditions (HE R and HES R ), and
(4) clinically defined, rare syndromes and conditions accompanied
by HE, including rare inherited disorders and organ-restricted
Definition of HE inflammatory diseases with tissue HE. 3,17 Overall, the classification
of HE/HES remains an important step in the diagnostic algorithm
HE is currently defined as a persistent, microscopically confirmed (Fig. 71.3). Using generally accepted criteria and parameters, this
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increase in PB eosinophils above 1.5 × 10 /L. In previous definitions, approach should lead to a final diagnosis concerning the presence
persistent eosinophilia over 6 months was required to establish the or absence of HES and the presence or absence of an underlying
diagnosis HE. However, based on improved diagnostics and treat- disease.
ment, and the necessity to introduce such treatment rapidly to avoid
organ damage, the proposed definition of HE has recently been
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revised to a 4-week observation interval by the ICOG-EO group. CLINICAL MANIFESTATIONS OF HES IN VARIOUS
The term “tissue HE” has also been proposed by several experts, ORGAN SYSTEMS AND DIFFERENTIAL DIAGNOSIS
and it may be useful to apply it in certain conditions, especially in
the context of (to demonstrate) HE-related organ damage (HES). Depending on the type of disease and other factors, a number of dif-
However, isolated tissue HE (without blood HE) is rare, and the ferent organ systems may be involved in patients with HES. The most
documentation of tissue HE often requires special immunostains commonly involved organs are the skin, lungs, GI tract, heart, and
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directed against eosinophil granule proteins. Therefore, the presence the CNS (see Table 71.7). In some patients, the relationship between
of tissue HE is often overlooked or is not documented, and PB HE HE and the typical clinical signs and symptoms are pathognomonic,
clearly remains the key diagnostic marker in daily practice. In some whereas in other cases a tissue biopsy may be required to confirm
of these patients, criteria for blood HE are not met, but molecular HE-related organopathy.
and clinical signs are strongly indicative of a particular eosinophil
disorder with or without accompanying HES. These patients should
be followed closely, as they may progress to an overt eosinophil Cardiac Manifestations in Patients With HES
disease (neoplasm) over time. The same holds true for WHO-based
neoplasms presenting with PDGFR or FGFR1 fusion genes without Prior to the advent of improved diagnostics and management, and
overt HE. 14 novel therapeutic approaches, cardiac disease was the leading cause
of morbidity and mortality in patients with HES. Endomyocardial
thrombosis and fibrosis are often documented in HES N , particularly
Diagnostic Algorithm in association with the F/P fusion gene, but are also seen in other
variants of HES, including tropical forms induced by (persistent)
When arriving at the provisional diagnostic “checkpoint” HE, two parasitic infections and other reactive forms of HES. A thorough
critical questions have to be addressed in order to approach to a final cardiac evaluation including an ECG and echocardiogram is manda-
diagnosis: (1) is there any underlying disease or condition triggering tory in all patients with HE, and cardiac magnetic resonance imaging
HE? and (2) are there clinical signs and symptoms or laboratory abnor- (MRI) may be helpful in distinguishing a HE-related cardiac disease
malities that point to the presence of HE-induced organ damage, so from other etiologies. In uncertain cases, troponin levels and B-type
that the additional diagnosis of HES can be established? For example, natriuretic peptide levels may be helpful parameters. An endomyo-
the hematologic work-up in a patient with HE revealed CEL, and cardial biopsy may be required in some of these patients in order
staging investigations showed endocardial thrombus formation: the to establish the definitive diagnosis, but biopsies are usually not
final diagnosis in this patient is CEL with concomitant primary HES performed in daily practice.
(HES N ). A diagnostic algorithm is shown in Fig. 71.3. In patients The cardiac damage seen in HES usually progresses from early
with typical HES and typical clinical manifestation, histopathologic necrotic changes through thrombosis and fibrosis. The presence
evaluation is generally not warranted to confirm the presence of of eosinophils in the myocardium is always abnormal and highly
tissue HE. However, in patients with rare or atypical manifestations, suggestive of eosinophil-mediated organopathy. Identical forms of
such as renal failure, isolated myocarditis or bloody diarrhea, a tissue cardiac pathology can develop in patients with HES forms of diverse
biopsy is required to document the presence of tissue HE and to etiologies, including tropical eosinophilias caused by parasitic infec-
confirm HE-induced organ damage, so that the diagnosis HES can be tions, drug reactions, eosinophilic leukemias, MPN-eo, solid tumors,