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C H A P T E R 71

EOSINOPHILIA, EOSINOPHIL-ASSOCIATED DISEASES,

EOSINOPHILIC LEUKEMIAS, AND THE

HYPEREOSINOPHILIC SYNDROMES

Peter Valent, Andreas Reiter, and Jason Gotlib

Eosinophils are highly specialized granulocytic effector cells that Eosinophil disorders and related syndromes are a heterogeneous
produce and store numerous biologically active mediators, including group of diseases characterized by marked expansion and persistent
cytotoxic proteins, lipid mediators, chemotactic peptides, and cyto- accumulation of eosinophils in the peripheral blood (PB) and other
kines (Table 71.1). Under various pathologic conditions, blood organ systems. In general, eosinophil disorders can be divided into
eosinophils transmigrate through the endothelial layer and invade (A) neoplastic states where eosinophils are found to be monoclonal,
various target organs, where they secrete their products into the and (B) reactive states where eosinophil expansion is considered to
surrounding tissues, thereby triggering inflammation, toxic damage, be “poly-clonal” and triggered by eosinotropic cytokines, such as
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and tissue remodeling. Since their initial characterization by Paul interleukin-5 (IL-5). In both instances, hypereosinophilia (HE),
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Ehrlich in 1879, eosinophilic granulocytes have been implicated in a defined by a persistent eosinophil count of ≥1.5 × 10 /L blood, is
growing number of systemic diseases and conditions characterized by typically present. Depending on the underlying disease and other
blood and/or tissue eosinophilia (Table 71.2). During the past few factors, the HE state may or may not be accompanied by specific
years, researchers have also gained a better understanding of the (HE-mediated) organ damage, also referred to as hypereosinophilic
unique features and functions of activated eosinophils, and of the syndrome (HES). In many instances, HES-related organ damage
specific roles some of their granule proteins and inducible lipid manifests as overt thromboembolism (thrombosis) or fibrosis. In
mediators may play in the pathogenesis of allergic, parasitic, neoplas- other patients, organ damage is associated with less specific findings,
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tic, and other diseases. In addition, recognition of the eosinophil as and may involve the skin, gastrointestinal (GI) tract, or the CNS.
a major proinflammatory and tissue-remodeling effector cell has Based on the underlying condition, both HE and HES can be divided
fueled a surge of interest in this granulocyte in recent years. into familial, primary (neoplastic), and secondary (reactive) forms
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Studies of the biochemistry, biologic activities, and tissue localiza- (Table 71.3). Apart from these classical forms of HES, more specific
tion of distinct enzymatic and nonenzymatic cationic proteins derived syndromes associated with HE and HE-related organopathy have
from eosinophils have provided convincing evidence for their role in been described. Some of these syndromes are associated with a genetic
the pathogenesis of inflammation and tissue damage in eosinophil- (germ-line) defect, whereas others are accompanied by distinct
associated diseases. The five cationic granule proteins that may play immunological abnormalities (Table 71.4A). Finally, HE may develop
a role in eosinophil-related pathologies include two major basic in the context of organ-restricted inflammatory conditions such as
proteins (MBP-1, MBP-2), eosinophil peroxidase (EPX), and two eosinophilic pneumonia or eosinophilic colitis (Table 71.4B).
ribonucleases, namely eosinophil cationic protein (ECP) and A thorough examination of all clinical and laboratory parameters,
eosinophil-derived neurotoxin (EDN; see Table 71.1). Eosinophils including radiologic and imaging studies, bone marrow (BM) inves-
also have the capacity to express toxic oxidative intermediates and tigations, cytogenetics, and molecular studies, are required in order
other mediators of inflammation, as well as mediators of thrombosis to establish the correct diagnosis (underlying disease and organ
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and fibrosis. In addition, eosinophils are a rich source of DNA traps damage) in patients with initially unexplained HE. The current
that may facilitate fibrin deposition as well as the killing of microbial chapter provides an overview on the epidemiology, pathogenesis,
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invaders. A clinically important aspect is that the various mediators course, prognosis, and clinical features of various eosinophil disorders.
produced and released by (activated) eosinophils often act together We also discuss recent developments in the field and the impact of
to trigger thrombosis and tissue damage, especially when eosinophil molecular markers and targets. In addition, this chapter provides
expansion and activation is chronic and “treatment-resistant”. diagnostic algorithms and recommendations for the management and
The process of determining the cause of eosinophilia is often treatment of patients with eosinophil disorders.
frustrating for both the physician and the patient, and in many
instances, the resulting diagnosis is “eosinophilia of unknown
etiology”. Depending on laboratory standards and local guidelines, EPIDEMIOLOGY
eosinophilia is defined as more than 450–500 eosinophils/µL blood,
confirmed by visual microscopy. Diurnal variations in eosinophil Little is known about the prevalence and incidence of primary
counts are well documented, with minimum numbers appearing eosinophil disorders (eosinophil neoplasms) and HE-related syn-
early in the morning and greatest numbers appearing late at night, dromes, including HES. Based on the available literature, most
mirroring circadian rhythms in adrenal corticosteroids. Although eosinophil neoplasms and all types of HES are rare, and the same
these variations are usually limited to a certain extent, basal holds true for other HE-related conditions, such as the Gleich syn-
eosinophil counts should be routinely measured during daytime. drome or Churg-Strauss syndrome (CSS). In an attempt to estimate
Transient mild eosinophilia is commonly seen in allergic reac- the incidence of HES, data collected by the Surveillance, Epidemiol-
tions, during and shortly after a bacterial infection, and in many ogy and End Results (SEER) database, sponsored by the National
other reactive states. Sometimes, transient eosinophilia may be Cancer Institute, have been reviewed. A crude incidence of 0.035
substantial or even excessive. Such transient (<4 weeks) form of cases per 100,000 person-years was found, and the male-to-female
reactive eosinophilia per se, if present, is considered harmless in ratio was reported to be 1.47 to 1. The average age at diagnosis was
most instances, but should prompt the physician to search for certain 52.5 years, and the peak incidence was recorded in individuals aged
underlying diseases, such as an occult allergy or an unrecognized 65–74 years. Childhood cases of HES have been reported but are
infection. very rare. Unfortunately, all these data have serious limitations and

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