Hypereosinophilic syndrome (HES) refers to overproduction of eosinophils with sustained eosinophil counts over 1.5 × 10⁹/L on CBC on two separate examinations >1 mo apart in which eosinophilic infiltration of tissues (skin, lungs, heart, liver, spleen, bone marrow) and mediator release cause organ damage or dysfunction.¹

• Primary (or neoplastic) hypereosinophilic syndrome (HESN)
• Secondary (or reactive) hypereosinophilic syndrome (HESR)
• Idiopathic hypereosinophilic syndrome (IHES)

HES is rare, and the true prevalence is unknown.

• •Clinical presentation of HES may vary from an incidental finding of eosinophilia to sudden onset of cardiac or neurologic symptoms.
• •The frequency of specific symptoms at presentation includes dermatologic (e.g., rash) in 37% of cases; pulmonary (cough and breathlessness) in 25%; gastrointestinal in 14%; cardiac in 5%; and neurologic in 4%. Additionally, 6% of patients presented with incidentally detected and clinically asymptomatic hypereosinophilia.¹
• •Cutaneous manifestations (37%): Commonly include eczema (involving hands, flexural areas, or dispersed plaques), erythroderma, lichenification, dermographism, recurrent urticaria, and angioedema. Adult patients without a history of eczema who develop new-onset cutaneous symptoms should be investigated for cutaneous T-cell lymphoma. Patients who experience angioedema and urticaria, with or without other symptoms, are likely to have a benign course without cardiac or neurologic complications. Patients with mucosal ulcerations are more likely to have FIP1L1-PDGFRA-positive HES.
• •Pulmonary manifestations (25%): The most common presenting symptoms are dyspnea (45%), cough (39%), and wheezing (24%). Abnormal chest radiography or computed tomography (CT) findings are seen in 43% of patients, including parenchymal infiltrates (37%), pleural effusion (14%), intrathoracic lymphadenopathy (12%), and pulmonary emboli (4%).
• •GI manifestations (14%): Eosinophilic gastritis, enteritis, and/or colitis may occur and cause weight loss, abdominal pain, vomiting, and/or severe diarrhea. Hepatic involvement may manifest as chronic active hepatitis, focal hepatic lesions, eosinophilic cholangitis, or Budd-Chiari syndrome.
• •Cardiac manifestations (5%) include dyspnea, orthopnea, and signs and symptoms of congestive heart failure (CHF). Includes three stages: Acute necrotic stage secondary to endocardial infiltration of eosinophils, thrombus formation, and fibrotic stage. The latter two stages often result in a restrictive or dilated cardiomyopathy and/or valvular heart disease. The development of cardiac disease in HES is unpredictable. Some patients with sustained eosinophilia never develop cardiac involvement, and the severity of cardiac injury does not clearly correlate with the degree of peripheral eosinophilia. Platelet-derived growth factor receptor alpha (PDGFRA)-associated HES has an increased incidence of incapacitating and potentially lethal cardiac involvement in the absence of therapy.
• •Neurologic manifestations (4%) may present in three forms:
  1. 1.Cerebral thromboemboli: Cardiac emboli or local vascular thrombosis
  2. 2.Encephalopathy: Confusion, loss of memory, ataxia, upper motor neuron signs, seizures, and behavior changes
  3. 3.Peripheral neuropathy (most common) may be symmetric or asymmetric, sensory or mixed sensory, and motor deficits
• •Ocular manifestations (23%) are thought to be the result of retinal microemboli.
• •Vascular manifestations include venous or arterial thrombosis of unknown mechanism, such as femoral artery occlusion, intracranial sinus thrombosis, and digital gangrene.

HES has been categorized into several clinically relevant variants: Primary/neoplastic HES, which includes myeloproliferative variants (M-HES) and T-lymphocytic variants (L-HES); secondary/reactive HES; familial HES; idiopathic HES (IHES); and organ-restricted hypereosinophilic syndromes.

• •Myeloproliferative variants of HES (M-HES) are classified into various subtypes. These include the FIP1L1-PDGFRA fusion gene (F/P-positive variant), which results from an interstitial chromosomal deletion on 4q12; PDGFRA fusion with other partner genes or point mutations; PDGFRB rearrangements such as t(5;12) (q31-35;p13); Janus kinase 2 (JAK2) point mutations, and translocations like t(8;9)(p22;p24); fibroblast growth factor receptor 1 (FGFR1) rearrangements such as (8p11-12); chronic eosinophilic leukemia (CEL); and HES with myeloid features without known mutations.
• •Lymphocytic variant HES (L-HES) is primarily characterized by skin and soft tissue involvement, with IL-5-producing T-cell subsets identified in the peripheral blood. The most commonly reported abnormal T-cell phenotype is CD3^–CD4⁺. Besides IL-5, these abnormal T cells also produce other T helper type 2 (Th2) cytokines, such as IL-4 and IL-13, as well as GM-CSF. The molecular mechanisms of the disease remain largely unknown, and this disorder may progress to lymphoma.
• •Secondary (reactive) HES occurs in response to an identified stimulus such as an infectious or inflammatory process. Examples include helminth infections, episodic angioedema, and eosinophilic granulomatosis with polyangiitis (EGPA).
• •Familial HES has been reported when there is a family history of documented persistent hypereosinophilia of unknown cause. Autosomal dominant transmission of marked eosinophilia has been reported.
• •Idiopathic HES: Despite careful evaluation of HE, the etiology in as many as 75% of cases of presumed HES remains undefined.
• •Organ-restricted hypereosinophilic: When tissue hypereosinophilia is present, it causes end-organ damage, but HES blood criteria are unmet.

The differential diagnosis of HES varies depending on the extent of eosinophilia. In mild to moderate eosinophilia cases, consideration is given to reactive eosinophilia attributed to atopic conditions or infectious causes. It is also important to rule out drugs or natural supplements as primary etiologies. In cases of more moderate to severe manifestations of HES, hematologic and other neoplastic diseases should be considered, for example, acute eosinophilic leukemia, chronic myeloid leukemia, systemic mastocytosis with eosinophilia, and eosinophilic granulomatosis with polyangiitis (EGPA).

Fig. E1 illustrates a diagnostic algorithm for patients with eosinophil disorders.

Figure E1 Diagnostic algorithm for patients with eosinophil disorders.

The first important step in the algorithm is to confirm the presence of HE, defined by a persistent (>4 wk) increase in eosinophils above 1500/μL blood. The next important question is whether HE is reactive (HE_R) or neoplastic (clonal = HE_N) in nature. In patients with HE_N, WHO criteria should be applied in order to define the underlying molecular lesion and the WHO category of disease. *In patients with HEN associated with oncogenic fusion genes involving, for example, PDGFRs, the WHO diagnosis is myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions (MLN-TK). In addition, morphologic and histopathologic criteria are used to arrive at a final diagnosis regarding the underlying disease. In patients with HE_R, an underlying disease must also be defined. In both groups of patients, the next important question is whether (or not) HE-related organ damage is present. If such pathological changes (tissue damage) are found, it is appropriate to diagnose an HES. According to the underlying etiology (disease), HES is classified again into HES_R and HES_N. In some patients with HES, a clonal T-cell population (but no overt lymphoma) is detected. In these patients, the HES_L variant is diagnosed. If no clonal T cells and no underlying reactive or neoplastic condition is detected in a patient with HES, the (provisional) diagnosis of an HES_I is established. If no underlying disease and no HES are detected, the patient has HE_US by definition. Familial cases of HE or HES are very rare, and the same holds true for hereditary syndromes and mono-organ syndromes accompanied by HE. HE, Hypereosinophilia; HES, hypereosinophilic syndrome; HESF, familial HES; HESI, idiopathic HES; HESL, lymphoid variant of HES; HESN, primary (neoplastic) HES; HESR, reactive HES; HEUS, HE of undermined (unknown) significance; WHO, World Health Organization.

(From Hoffman R et al: Hematology, basic principles and practice, ed 8, Philadelphia, 2023, Elsevier.)

Evaluation of patients presenting with eosinophilia should start with a focused history that identifies known and treatable causes. This includes screening for parasites and investigating potential adverse drug reactions to exclude other causes mentioned in the "Differential Diagnosis" section leading to peripheral eosinophilia. Subsequent steps should detect any evidence of end-organ involvement.

• •CBC with differential; anemia may be present, especially in patients with myeloproliferative variants. Either thrombocytopenia or thrombocytosis may be noted. Total leukocyte counts in excess of 90 × 10⁹/L are associated with a poor prognosis
• •Blood chemistries, including liver function tests, electrolytes, troponin, blood urea nitrogen, and creatinine
• •Stools for ova and parasites ×3
• •Serologic blood tests for parasitic infections (e.g., Strongyloides)
• •Serum immunoglobulins, particularly IgE
• •Serum levels of vitamin B₁₂
• •Serum levels of tryptase
• •Tissue biopsies as indicated
• Hematologic evaluation:
• •Fluorescence in situ hybridization (FISH) for CHIC2 deletion
• •RT-PCR for FIP1L1-PDGFRA mutation
• •Flow cytometry staining and analysis for specific T-lymphocyte phenotypes
• •Molecular studies for fusion genes such as FGFR1 and PDGFRB, as well as other mutations, including BCR-ABL1, JAK2 V617F, KIT D816V, and clonal T-cell receptor arrangements
• •Bone marrow aspirate and biopsy (Fig. E2)

• •ECG
• •Chest radiograph may be clear or show infiltrates, effusions, or fibrotic scarring
• •Computed tomography scan of chest, abdomen, and pelvis
• •Echocardiogram (or cardiac MRI for early cardiac involvement) can assess for ventricular function and valvular pathology including regurgitation and thrombi formation
• •Pulmonary function tests

All patients, including those who are asymptomatic, should be re-evaluated every 3 mo for the first 1 to 2 yr after diagnosis. Serial ECG and echocardiograms, complete blood counts, blood chemistries, and pulmonary evaluations (PFTs and CT scans) are recommended at each visit.

• •In patients with extremely elevated eosinophile levels (e.g., AEC above 100 ×10⁹/L), leukostasis, or potentially life-threatening complications like heart failure, thromboemboli, or pulmonary decompensations, high-dose intravenous glucocorticoid therapy is indicated. The initial therapy is prednisone 1 mg/kg/day or 1 g methylprednisolone. Meanwhile, prophylaxis with ivermectin at 200 mcg/kg/daily for 2 days in patients with potential Strongyloides exposure is recommended.
• •In response to high-dose glucocorticoids, the eosinophil count typically either drops dramatically (e.g., by more than 50% of the original value) within 24 h or remains the same (no response).
• •Doses may be tapered to alternate-day prednisone use in patients whose eosinophil counts have been suppressed.
• •If there is no response to steroid treatment, patients with features of EGPA (e.g., asthma, sinus disease, pulmonary infiltrates) are preferably treated with either cyclophosphamide or rituximab. Other interventions, such as imatinib mesylate, vincristine, and hydroxyurea, have been used in a small number of cases.

• •In cases of clinically stable HES, symptomatic patients and those with evidence of end-organ damage should be initiated on therapy. Systemic glucocorticoids remain the initial line of therapy for most HES variants before a steroid-sparing agent can be initiated.
• •For all patients with the FIP1L1::PDGFRA mutation, first-line therapy is the tyrosine kinase inhibitor imatinib mesylate at the recommended daily dosage of 400 mg.
• •For patients with myeloproliferative features, treatment with imatinib is generally recommended. Additionally, ruxolitinib is approved for several myeloid disorders typically associated with JAK2 mutations.
• •Mepolizumab, an IL-5 inhibitor, is approved for the treatment of HES and EGPA at a dose of 300 mg monthly. It offers better efficacy and lower toxicity compared to systemic steroids, but it is expensive and not available in all countries.
• •As conventional second-line therapy, hydroxyurea is generally preferred over interferon alfa for individuals who are unresponsive to glucocorticoid monotherapy with neither L-HES nor myeloid features or if they are not eligible for mepolizumab.
• •Clinical trials in HES patients have investigated treatment with anti-IL-5 (reslizumab) and anti-IL-5 receptor (benralizumab) antibodies and a small molecule of unknown target (dexpramipexole).
• •Anticoagulation and/or antiplatelet agents are often used in patients with HES.
• •If all else fails, bone marrow transplantation may be considered in severe cases.

• •Before the use of cardiac imaging (echo) and cardiac surgeries (valve replacement), patients with HES had a poor prognosis with a mean survival time of 9 mo and a 3-yr survival rate of 12%.¹
• •Deaths usually result from CHF, endocarditis, and systemic emboli.
• •Over time, earlier diagnosis of HES, close clinical and echocardiographic monitoring for heart disease, and improved medical and surgical management of cardiac complications have improved the longevity of HES patients.
• •Currently, the 5-yr and 15-yr survival rates are 80% and 42%, respectively.³

HES is a rare and complicated disorder and referral to allergy and immunology and/or hematology should be considered.