HES and EGPA: Two Sides of the Same Coin

Abstract

Elevated eosinophil counts are implicated in multiple diseases, from relatively prevalent organ-specific disorders such as severe eosinophilic asthma, to rare multisystem disorders such as hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA). Patients with these multisystem diseases, often associated with markedly elevated eosinophil counts, have a substantial risk of morbidity and mortality due to delayed diagnosis or inadequate treatment. A thorough workup of symptomatic patients presenting with elevated eosinophil counts is essential, although in some cases the differential diagnosis may remain difficult because of overlapping presentations between HES and EGPA. Notably, first- and second-line treatment options and response to therapy may differ for specific HES and EGPA variants. Oral corticosteroids are the first line of treatment for HES and EGPA, except when HES is the result of specific mutations driving clonal eosinophilia that are amenable to targeted treatment with a kinase inhibitor. Cytotoxic or immunomodulatory agents may be required for those with severe disease. Novel eosinophil-depleting therapies, such as those targeting interleukin 5 or its receptor, have shown great promise in reducing blood eosinophil counts, and reducing disease flares and relapses in patients with HES and EGPA. Such therapies could reduce the side effects associated with long-term oral corticosteroids or immunosuppressant use. This review provides a pragmatic guide to approaching the diagnosis and clinical management of patients with systemic hypereosinophilic disorders. We highlight practical considerations for clinicians and present cases from real-world clinical practice to show the complexity and challenges associated with diagnosing and treating patients with HES and EGPA.

Figure.. Diagnostic work-up for identifying patients with HES and EGPA^{, , –}

^aBone marrow exam should be considered in the following situations: phenotyping and/or cytogenetic tests suggesting myeloid or lymphoid variant HES, blood eosinophilia >5000/mm, elevated serum tryptase, lack of response to systemic corticosteroid treatment; ^btesting which can be performed on bone marrow; ^ca further category of potential diagnoses includes HE of undetermined significance, where unexplained hypereosinophilia is present but patients do not have associated eosinophil-related end organ damage or complications; this is not discussed further as it lies outside the scope of this review; ^deg, anemia/thrombocytopenia, splenomegaly, elevated serum vitamin B12/tryptase or lack of response to systemic corticosteroid therapy; ^ecurrent ACR/EULAR EGPA classification criteria require a total score ≥6 across the following seven criteria: obstructive airway disease (+3), nasal polyps (+3), mononeuritis multiplex (+1), blood eosinophil count ≥1 × 10⁹cells/L (+5), extravascular eosinophilic-predominant inflammation on biopsy (+2), positive test for cytoplasmic ANCA or anti-PR3 antibodies (−3), hematuria (−1). ACR/EULAR, American college of rheumatology/European alliance of associations for rheumatology; ANCA, antineutrophil cytoplasmic antibody; CT, computed tomography; ECG, electrocardiogram; EGPA, eosinophilic granulomatosis with polyangiitis; FDG-PET, fluorodeoxyglucose-positron emission tomography; FGFR1, fibroblast growth factor receptor 1; HE, hypereosinophilia; HES, hypereosinophilic syndrome; IFN, interferon; Ig, immunoglobulin; JAK, Janus kinase; MPO, myeloperoxidase; MRI, magnetic resonance imaging; NGS, next-generation sequencing; NOS, not otherwise specified; PCR, polymerase chain reaction; PDGFRA, platelet-derived growth factor receptor alpha; PDGFRB, platelet-derived growth factor receptor beta; PR3, proteinase 3; TCR, T-cell receptor.