Hypereosinophilic Syndrome A Guided Work ow for Improved National Jewish (HES) Roadmap: Health Diagnosis and Treatment in HES

START HERE 1, 2, 3 DIAGNOSIS AND CLASSIFICATION Absolute count ≥ 1500/µl A 1 AND/OR Tissue ?

Consider other causes Table 1 no 1, 4 Monitor for progression Table 1 Secondary causes of eosinophilia and hypereosinophilia Category with examples (not inclusive) yes

Allergic disorders Immunologic disorders •, atopic dermatitis, allergic rhinitis •Immunodeciency: hyper-IgE syndrome, Drug hypersensitivity Omenn’s syndrome, DOCK8 deciency •Autoimmune diseases: sarcoidosis, Infection in ammatory bowel disease, IgG4 disease, Initial workup •Helminthic/Ectoparasite other connective tissue disorders 2 •Protozoan •Fungal Miscellaneous •Bacterial •Radiation exposure •Viral, including HIV infection •Cholesterol emboli •Hypoadrenalism Neoplasms •IL-2 therapy •Leukemia History Physical exam Lab Tests Studies •Lymphoma • Onset, magnitude, temporal • Sinus disease • CBC with di • ECG •Adenocarcinoma associations of eosinophilia • Mucosal ulcers • Peripheral smear • Echocardiogram • Comorbid conditions • Adventitious lung sounds • Serum tryptase • PFTs • Exposures, travel • Heart murmurs, rubs • Serum B12 • Pulse oximetry • Medications • Lymphadenopathy • Stool ova & parasites • CXR • Infection • Liver/spleen enlargement • Liver/kidney tests • Family history of eosinophilia • Abdominal tenderness • Amylase/lipase • Symptoms: Organ specic, • Joint/muscle abnormality • Troponin Additional workup to evaluate for evidence of end-organ fever, constitutional 3 • Skin rash, edema • ANA damage or dysfunction • Neuropathy, weakness • ANCA • HIV serology • Serum immunoglobulins Cardiac GI Vascular • Cardiac MRI • Abdomen & pelvis CT • Angiography • Strongyloides IgG • ESR/CRP • Endomyocardial biopsy • Endoscopy with biopsy • LDH Pulmonary Dermatologic Neurologic • Urinalysis • Chest CT (high resolution) • Skin biopsy • Brain MRI or CT with contrast • Bronchoalveolar lavage • EEG • Lung biopsy Renal • Nerve conduction studies/EMG • 24 hour urine test • Nerve biopsy Evidence of end-organ Hematologic • Kidney biopsy 4 damage or dysfunction? • Bone marrow biopsy with cytogenetics • Peripheral FISH/RT-PCR for FIP1L1-PDGFRA • Lymphocyte phenotyping ( ow cytometry) • T- and B-cell rearrangement studies • PET scan Secondary causes of yes no • Lymph node biopsy hypereosinophilia excluded? 5

no Hypereosinophilia

yes Consider other causes Table 1

• Consider HEUS 2 • Consider subspecialty referral HYPEREOSINOPHILIA: • Monitor for progression C INITIAL TREATMENT APPROACH B Absolute eosinophil DETERMINE HES CLINICAL VARIANT 1 count ≥ 1500/µl

1, 2, 4, 5 Table 2 Symptoms? 2 HES CLINICAL VARIANT ETIOLOGIES/CHARACTERISTICS Clinically-dened MHES, FIP1L1/PDGFRA positive, or chronic Myeloproliferative variant Clinical manifestation of eosinophilic leukemia no myeloid neoplasm? no HEUS Lymphocyte population with aberrant phenotype by ow cytometry OR clonal T cell population by PCR analysis; yes Consider close monitoring Lymphocytic variant o therapy; obtain family history lymphocytes secrete IL-5 or other that drive eosinophilia Proceed as if symptomatic Family history of documented persistent eosinophilia. yes Familial eosinophilia Autosomal dominant. Mutations associated with IL-5 overexpression

Incomplete criteria OR apparent restriction to specic Overlap tissues/organs (eg, eosinophil-associated GI disorders (EGID), chronic eosinophilic pneumonia, eosinophilic fasciitis); EGPA Life- no Benign (asymptomatic with no evidence of organ involve- 3 yes Idiopathic ment), complex (symptomatic with organ involvement but threatening? idiopathic), or episodic (cyclic angioedema and eosinophilia) Comprehensive evaluation: see algorithm for HES Peripheral eosinophilia ≥ 1500/µl associated with a dened Diagnosis and Classication diagnosis (eg, in ammatory bowel disease, sarcoidosis, Associated autoimmune lymphoproliferative syndrome, other Initiate therapy secondary causes (Table 1)) based on clinical variant

Table 3 1, 2, 4, 5 HES CLINICAL VARIANT TREATMENT Begin diagnostic workup Imatinib, a tyrosine kinase inhibitor, is rst line for known or but do not delay treatment; suspected PDGFR-associated myeloid neoplasms prioritize tests that are aected Myeloproliferative variant Add glucocorticoid if cardiac involvement or by glucocorticoid therapy insucient control with imatinib

Short-term glucocorticoid is rst line 4 Hydroxyurea is preferred second line Lymphocytic variant Imatinib, interferon-α, pegylated interferon, methotrexate, Suspected or proven cyclosporine are other second line PDGFR-associated neoplasm? Monitor clinically if no symptoms or tissue organ damage Glucocorticoid if symptomatic and/or evidence of organ involvement Familial eosinophilia Immunomodulators such as hydroxyurea, interferon-α, or anti-IL5 therapy yes no Glucocorticoid and/or immunomodulators if symptomatic and/or evidence of tissue damage Swallowed glucocorticoid and/or diet modication for EGID Overlap Short-term glucocorticoid is rst line for EGPA , cyclophosphamide, methotrexate are second line for EGPA Features of EGPA?

Monitor clinically if no symptoms or tissue organ damage no yes Idiopathic Glucocorticoid if symptomatic and/or evidence of tissue damage Immunomodulators such as hydroxyurea, interferon-α, or anti-IL5 therapy

Associated Identify and treat underlying cause of hypereosinophilia HES HES

Imatinib +/- glucocorticoid High-dose High-dose glucocorticoid* (high-dose* if cardiac involvement) glucocorticoid* + cyclophosphamide Abbreviations

EGPA, eosinophilic granulomatosis with polyangiitis HEUS, hypereosinophilia of unknown signicance *If potential exposure to Strongyloides at any time, treat empirically with concomitant ivermectin for 2 days. (formerly Churg-Strauss syndrome) MHES, myeloid hypereosinophilic syndrome HES, hypereosinophilic syndrome PDGFR, platelet-derived growth factor receptor gene

References 1) Khoury P, Bochner BS. Consultation for elevated blood : clinical presentations, high value diagnostic tests, and treatment options. J Clin Immunol Pract. 2018;6(5):1446-1453. | 2) Klion A. Hypereosinophilic syndrome: approach to treatment in the era of precision medicine. Hematology Am Soc Hematol Educ Program. 2018;2018(1):326-331. | 3) Schuster B, Zink A, Eyerich K. Medical algorithm: diagnosis and treatment of hypereosinophilic syndrome. Allergy. 2020;00:1-4. | 4) Klion AD. Eosinophilia: a pragmatic approach to diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2015;2015:92-97. | 5) Klion AD, Ackerman SJ, Bochner BS. Contributions of eosinophils to human health and disease. Annu Rev Pathol. 2020;15:179-209.

This reference aid was developed as part of an educational activity supported by an educational grant from GlaxoSmithKline.

© 2021 National Jewish Health