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1Human Eosinophil Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, MD
Eosinophilia is associated with a wide variety of allergic, rheumatologic, infectious, neoplastic, and rare idiopathic
disorders. Clinical manifestations range from benign asymptomatic presentations to life-threatening complications,
including endomyocardial fibrosis and thromboembolism. The prognosis and choice of treatment depend not only on
the degree of eosinophilia and severity of organ involvement, but also on the etiology of the eosinophilia. Unfortunately,
despite recent advances in molecular and immunologic techniques, the etiology remains unproven in the overwhelm-
ing majority of cases. This review presents a practical approach to the diagnosis and treatment of patients presenting
with unexplained marked eosinophilia. A brief overview of the mechanisms of eosinophilia and eosinophil
pathogenesis is also provided.
Hematology 2015 93
Table 1. Classification of hypereosinophilic syndromes
Clinical subtype Definition Examples Features
M-HES HES with documented or presumed clonal PDGFR-associated MPN Male predominance (in PDGFR-
eosinophilic involvement CEL-NOS associated MPN)
Idiopathic HES with myeloproliferative High mortality if untreated
features*
L-HES HES with a demonstrable clonal or CD3⫺CD4⫹ L-HES Equally common in men and women
phenotypically aberrant lymphocyte Episodic eosinophilia and angioedema† High prevalence of skin and soft tissue
population producing cytokines that (Gleich’s syndrome) manifestations
drive eosinophilia Elevated IgE and TARC
Progression to lymphoma in 5%-25%
Overlap HES Eosinophilic disease restricted to a single Eosinophilic gastrointestinal disease Can be difficult to distinguish from
organ system accompanied by Chronic eosinophilic pneumonia idiopathic HES when AEC is
peripheral eosinophilia ⬎1.5 ⫻ 109/L Eosinophilic granulomatosis with elevated
polyangiitis
Associated HES Eosinophilia ⬎1.5 ⫻ 109/L in the setting of Primary immunodeficiency syndromes, Treatment directed at underlying
a distinct diagnosis, in which such as autoimmune cause
eosinophilia has been described in a lymphoproliferative disease and
subset of affected patients hyper-IgE syndrome
Sarcoidosis
Inflammatory bowel disease
Familial HES HES occurring in multiple members of a Autosomal dominant familial HE Progression to HES uncommon
single family
Idiopathic HES HES of unknown cause that does not meet Multisystem involvement
criteria for any of the other categories
*Such as dysplastic eosinophils, circulating myeloid precursors, anemia, thrombocytopenia, splenomegaly, elevated serum B12 and/or tryptase levels, atypical mast cells,
hypercellular marrow, and myelofibrosis.
†Episodic angioedema and eosinophilia is a distinct clinical syndrome characterized by multineage cycling and symptoms that occur at fixed intervals, an aberrant CD3-CD4⫹ T
overlap HES or eosinophilic disease restricted to a single organ for this purpose if the clinical situation is deteriorating. If there is
system; (4) associated HE/HES or HE/HES in the setting of a no reduction in eosinophil count after 1-2 days of high dose
distinct diagnosis (ie, parasitic helminth infection, drug hypersensi- corticosteroid therapy, a second agent should be selected using
tivity and primary immunodeficiency) in which eosinophilia has the clinical presentation and most likely underlying etiology as a
been described in a subset of affected patients; (5) familial HE/HES, guide (see below).
a rare autosomal dominant disorder; and (6) idiopathic HES.
Hypereosinophilia of unknown significance (HEUS) refers to un- Conventional agents for the treatment of HES include corticoste-
treated HE in the absence of clinical symptoms, evidence of a roids, hydroxyurea, interferon ␣, and imatinib (the only agent
myeloproliferative neoplasm or treatable secondary cause.26 HEUS FDA-approved for treatment of HES).21 Numerous additional
may progress to HES in some cases.28 This classification system agents, including chlorambucil, vincristine, etoposide, cladribine,
both differs from and overlaps with the 2008 WHO guidelines,23 cytarabine, methotrexate, cyclosporine, alemtuzumab, and cyclo-
which group myeloid and lymphoid neoplasms, including those phosphamide, have been used to treat small numbers of steroid-
characterized by marked eosinophilia, on the basis of a variety of unresponsive patients with varied success and may be appropriate in
genetic, histopathologic, and clinical criteria. some situations. Finally, renewed interest in the role of eosinophils
in allergic and inflammatory disorders has led to the development of
Treatment of HES a wide variety of biologic therapies that directly or indirectly target
When confronted with a patient with unexplained eosinophilia, the eosinophils.29
first question to be addressed is whether immediate therapy is
necessary to prevent potentially irreversible, eosinophil-mediated Because systemic corticosteroids are appropriate initial therapy for
end organ damage. Examples of findings that warrant urgent therapy most patients with HES, identification of subgroups of patients for
include clinical evidence of cardiac, neurologic, or thromboembolic whom therapies other than corticosteroids are preferable as initial
complications and/or the presence of extremely high (⬎100 ⫻ 109/L) therapy is an essential first step in any treatment algorithm. These
or rapidly increasing eosinophil counts. Corticosteroids (1 mg/kg include patients with secondary causes that require specific therapy
to 1 g methylprednisolone depending on the severity of clinical targeting the underlying cause (associated HE/HES), patients with
manifestations) are the initial treatment of choice except in known imatinib-sensitive mutations (such as PDGFR-associated
situations where an underlying etiology is identified and known MPN), patients with single-organ involvement that may be respon-
to be corticosteroid-resistant. Ivermectin (200 mcg/kg/d ⫻ 2 sive to topical corticosteroid therapy (overlap HES) and patients
days) should be administered concomitantly to all patients with a with familial eosinophilia or HEUS, who may not require any
history of potential exposure to the helminth, Strongyloides therapy at all. The remaining patients with presumed myeloprolifera-
stercoralis, to prevent the potentially fatal corticosteroid- tive neoplasms (M-HES), lymphocytic variant HES (L-HES),
induced hyperinfection syndrome. Although every effort should idiopathic HES, and some patients with overlap HES (those with
be made to obtain appropriate diagnostic studies (Table 2) before severe single organ manifestations or evidence of vasculitis) should
initiating corticosteroid therapy, treatment should not be delayed be treated with systemic corticosteroids. Dosing and duration should
be individualized based on the clinical manifestations, comorbidi- serum troponin levels, should receive high dose corticosteroids
ties and perceived risk of serious end-organ damage. Once the (ⱖ1 mg/kg prednisone or equivalent) during the first few days of
eosinophil count has normalized and symptoms have improved, the therapy to reduce the risk of myocardial necrosis.32 Although
corticosteroid dose should be tapered slowly. A second agent should resistance to imatinib is uncommon in PDGFRA-associated
be considered in patients who cannot be maintained on 10 mg MPN, it has been reported.30,33 Newer tyrosine kinase inhibitors
prednisone equivalent or less daily, or who experience significant (TKIs), including sorafenib, midostaurin, and ponatinib, which
side effects. have in vitro activity against cells carrying the FIP1L1-PDGFRA
fusion with imatinib-resistant mutations,34 should be considered
The choice of a second-line agent depends on a variety of factors, in such cases.
including the clinical and/or molecular variant of HES, site(s) of
organ involvement, side effect profile of the drug, and patient Some PDGFRA-negative patients presenting with HES and my-
preference. The most commonly used second line agents for the eloproliferative features have documented cytogenetic or molecular
treatment of idiopathic HES are hydroxyurea (1-2 g orally daily) abnormalities, such as rearrangements involving PDGFRB, FGFR1,
and interferon-␣ (1-3 mU subcutaneously daily), each of which is
or JAK2 or point mutations in KIT. In these cases, treatment should
effective in ⬃30% of patients.21 Although it is beyond the scope of
be guided by the underlying abnormality. Other patients have no
this review to provide a guide to therapy for all patients with HES
detectable cytogenetic or molecular abnormalities and do not meet
who fail first line therapy, certain situations deserve mention (a
WHO criteria for acute leukemia or CEL-NOS. Although high-dose
more complete approach can be found by Klion25).
corticosteroids are often effective in the short-term reduction of
Myeloproliferative HES (M-HES). Approximately 20% of pa- eosinophilia and clinical manifestations in these patients with
tients who present with HES have features suggestive of a myelopro- “idiopathic” M-HES and are useful in initial management, transient
liferative disorder, including the presence of dysplastic eosinophils or partial responses are common. Given the possibility of occult
and eosinophil precursors in the blood, anemia and/or thrombocyto- imatinib-sensitive mutations and the clinical similarity between
penia, elevated serum B12 and/or tryptase levels, splenomegaly, and patients with idiopathic M-HES and those with PDGFRA-
bone marrow hypercellularity and fibrosis. The majority of these associated disease, imatinib would seem a logical second-line agent
patients (as many as 80%) have a PDGFRA-associated MPN. As in steroid-resistant patients. In fact, recent data from our center
mentioned above, these patients are exquisitely sensitive to imatinib suggests that myeloproliferative features are an important predictor
mesylate and should receive treatment with this agent as first-line of imatinib response in steroid-resistant, PDGFRA-negative sub-
therapy.30,31 Starting doses of 100-400 mg daily are typically jects with HES. Alternative therapies for patients who do not
sufficient to induce hematologic remission within days, and respond to steroids or imatinib include hydroxyurea, interferon-␣,
molecular remission is almost universal. Patients with evidence second and third-generation tyrosine kinase inhibitors, and alloge-
of cardiac involvement, based on echocardiographic findings and neic transplantation.
Hematology 2015 95
Lymphocytic variant HES (L-HES). L-HES is defined by the cooperative cytokine network that promotes eosinophil precursor matu-
presence of clonal and/or aberrant lymphocytes that produce soluble ration. J Immunol. 2014;193(8):4043-4052.
mediators that drive eosinophilia. Patients with L-HES often present 4. Nussbaum JC, Van Dyken SJ, von Moltke J, et al. Type 2 innate
with skin and soft tissue manifestations, elevated serum IgE and lymphoid cells control eosinophil homeostasis. Nature. 2013;502(7470):
thymus and activation regulated chemokine (TARC) levels.35,36 245-248.
5. Mori Y, Iwasaki H, Kohno K, et al. Identification of the human
Although most patients with L-HES respond to corticosteroid
eosinophil lineage-committed progenitor: revision of phenotypic defini-
therapy, many require moderate to high doses. Interferon-␣ is often
tion of the human common myeloid progenitor. J Exp Med. 2009;206(1):
used as the preferred second-line therapy due to its dual effect on 183-193.
eosinophils and T lymphocytes. Other agents, including methotrex- 6. Ben Baruch-Morgenstern N, Shik D, Moshkovits I, et al. Paired
ate, cyclophosphamide, cyclosporine, and alemtuzumab have also immunoglobulin-like receptor A is an intrinsic, self-limited suppressor
been used as steroid-sparing agents in L-HES with variable success. of IL-5 induced eosinophil development. Nat Immunol. 2014;15(1):36-
Progression to lymphoma occurs in 5%-25% of patients with 44.
L-HES, often many years after the initial presentation,35-37 and may 7. Lu TX, Lim EJ, Itskovich S, et al. Targeted ablation of miR-21
be heralded by increasing or new lymphadenopathy, expansion of decreases murine eosinophil progenitor cell growth. PloS One. 2013;8(3):
the aberrant T-cell population, development of cytogenetic abnor- e59397.
malities, especially 6p-, and/or progressive resistance to treatment. 8. Lee JJ, Rosenberg H. Eosinophils in health and disease. In: Eosinophil
Trafficking. San Diego: Elsevier; 2013;121-167.
9. Schwartz C, Willebrand R, Huber S, et al. Eosinophil-specific deletion
Novel biologic agents of IB␣ in mice reveals a critical role of NF-B–induced Bcl-xL for
Despite the dramatic increase in novel biologics in clinical trials for inhibition of apoptosis. Blood. 2015;125(25):3896-3904.
asthma and atopic disease (for review, see Radonjic-Hoesli et al 29, 10. Jia Y, Yu H, Fernandes SM, et al. Expression of ligands for Siglec-8 and
and Fulkerson and Rothenberg40), data in HES is sparse. Following Siglec-9 in human airways and airway cells. J Allergy Clin Immunol.
promising pilot trials using two different monoclonal antibodies to 2015;135(3):799-810.
IL-5, reslizumab, and mepolizumab, to treat patients with treatment- 11. Aceves SS. Remodeling and fibrosis in chronic eosinophil inflamma-
refractory HES, a double-blind, placebo-controlled trial in 85 tion. Dig Dis. 2014;32(1-2):15-21.
PDGFRA-negative patients demonstrated that monthly mepoli- 12. Wang JG, Mahmud SA, Thompson JA, et al. The principal eosinophil
peroxidase product, HOSCN, is a uniquely potent phagocyte oxidant
zumab was safe and effective as a steroid-sparing agent in HES,
inducer of endothelial cell tissue factor activity: a potential mechanism
including L-HES.38 Long-term safety and efficacy of mepolizumab
for thrombosis in eosinophilic inflammatory states. Blood. 2006;107(2):
for the treatment of HES was confirmed in an open-label extension 558-565.
study.39 Mepolizumab is available on a compassionate use clinical 13. Khoury P, Grayson PC, Klion AD. Eosinophils in vasculitis: character-
protocol for patients with life-threatening HES refractory to stan- istics and roles in pathogenesis. Nat Rev Rheumatol. 2014;10(8):474-
dard therapies (http://www.clinicaltrials.gov). A clinical trial of 483.
benralizumab, an afucosylated monoclonal antibody to IL-5 recep- 14. Ueki S, Melo RC, Ghiran I, et al. Eosinophil extracellular DNA trap cell
tor that has shown efficacy in the treatment of eosinophilic asthma, death mediates lytic release of free secretion competent eosinophil
is also underway in patients with HES. Additional novel targeted granules in humans. Blood. 2013;121(11):2074-2083.
therapies directed at inhibitory receptors, eosinophilic chemokines 15. Yousefi S, Gold JA, Andina N, et al. Catapult-like release of mitochon-
and their receptors, and other molecules involved in the regulation drial DNA by eosinophils contributes to antibacterial defense. Nat Med.
of eosinophil development, activation, migration to tissues, and 2008;14(9):949-953.
apoptosis, are under development.29,40 These and other targeted 16. Melo RCN, Weller PF. Unraveling the complexity of lipid body
organelles in human eosinophils. J Leuk Biol. 2014;96(5):703-712.
therapies not only provide hope for patients with HES, but are
17. Landolina N, Gangwar RS, Levi-Schaffer F. Mast cells’ integrated
certain to help further define the role(s) of eosinophils in human
actions with eosinophils and fibroblasts in allergic inflammation:
health and disease. implications for therapy. Adv Immunol. 2015;125:41-85.
18. Spencer LA, Bonjour K, Melo RC, Weller PF. Eosinophil secretion of
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Correspondence 21. Ogbogu PU, Bochner BS, Butterfied JH, Gleich GJ, Huss-Marp
Amy D. Klion, Human Eosinophil Section, Laboratory of Parasitic J. Hypereosinophilic syndromes: a multicenter, retrospective analysis of
Diseases, National Institute of Allergy and Infectious Diseases, clinical characteristics and response to therapy. J Allergy Clin Immunol.
National Institutes of Health, Building 4, Room B1-29, 4 Center 2009;124(6):1319-1325.
22. Valent P, Klion AD, Horny H, Roufosse F, Gotlib J, Weller PF, et al.
Drive, Bethesda, MD 20892; Phone: 301-435-8903; Fax: 301-451-
Contemporary consensus proposal on criteria and classification of
2029; e-mail: aklion@nih.gov.
eosinophilic disorders and related syndromes. J Allergy Clin Immunol.
2012;130(3):607-612.
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