What is the diagnosis and treatment approach for a patient with suspected Hypereosinophilic Syndrome (HES)?

Hypereosinophilic Syndrome: Diagnosis and Treatment

Diagnostic Criteria

HES requires three essential components: peripheral blood eosinophil count >1.5 × 10⁹/L on two examinations at least one month apart, organ damage and/or dysfunction attributable to tissue eosinophilic infiltration, and exclusion of secondary causes. 1

• Hypereosinophilia is defined as peripheral blood eosinophil count >0.5 × 10⁹/L, with significant hypereosinophilia at ≥1.5 × 10⁹/L 2
• The most commonly affected organs include skin, gastrointestinal tract, heart, lungs, and nervous system 1

Initial Diagnostic Workup

The National Comprehensive Cancer Network recommends that the diagnostic workup include CBC with differential, serum chemistries, vitamin B12 and serum tryptase, and serum immunoglobulins. 1

Essential Laboratory Testing

• Perform stool examination for ova and parasites, Strongyloides serology, and comprehensive medication review to exclude secondary causes 1
• Obtain bone marrow aspirate and biopsy with immunohistochemistry, conventional cytogenetics and FISH for tyrosine kinase fusion genes, and flow cytometry with T-cell immunophenotyping 1
• Elevated serum tryptase and vitamin B12 levels suggest primary (neoplastic) HES 1

Cardiac Evaluation - Critical Priority

Any patient with end-organ damage requires urgent medical assessment and emergency treatment regardless of eosinophil count, with cardiac involvement being the most life-threatening complication. 3

• Perform echocardiogram and serum troponin testing in all HES patients 3
• Myocardial biopsy remains the gold standard for diagnosis of eosinophilic myocarditis 3
• Cardiac involvement (Löeffler endocarditis) presents with myocardial fibrosis, systemic thromboembolism, and acute heart failure—the primary cause of mortality in HES 2
• In patients with hypereosinophilic syndrome with occult infiltration of HES cells within the myocardium, cardiogenic shock/left ventricular dysfunction can occur upon initiation of imatinib therapy due to HES cell degranulation 4

Gastrointestinal Assessment

• Up to 38% of HES patients develop gastrointestinal symptoms, including esophageal involvement that mimics eosinophilic esophagitis with dysphagia and food impaction 1
• The American Gastroenterological Association recommends screening of upper and lower GI tract plus monitoring for other organ involvement in patients with esophageal symptoms and hypereosinophilia 1

Classification of HES Variants

Primary (Neoplastic) HES

• Characterized by an underlying myeloid or stem cell neoplasm where eosinophils are clonal cells 1
• Accurate molecular/genetic diagnosis is essential as it dictates therapy, with identification of PDGFRA or PDGFRB rearrangements being critical for treatment with imatinib 3
• The 2022 WHO classification includes "myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions" (MLN-eo-TK) as a major category 5

Secondary (Reactive) HES

• Characterized by cytokine-driven eosinophilia with non-clonal eosinophils 1
• Secondary eosinophilia accounts for approximately 80% of cases, with allergic disorders being most common, followed by parasitic infections 3
• Helminths are the most common identifiable cause of eosinophilia in returning travelers or migrants, with diagnosis rates of 19-80% 2

Lymphocyte-Variant HES (L-HES)

• Driven by an aberrant T-cell clone producing IL-5 5
• Most frequently characterized by a CD3-CD4+ phenotype 6
• First-line therapy is corticosteroids, with flow cytometry and molecular analysis required for diagnosis 3

Critical Exclusions Before Diagnosing HES

Before diagnosing HES, systematically exclude secondary causes including allergic disorders, parasitic infections, medications, and malignancies. 1

Parasitic Infections - Highest Priority

• Strongyloides stercoralis can persist lifelong and present as hyperinfection syndrome with high mortality in immunocompromised patients 2
• Schistosoma haematobium is associated with squamous cell bladder carcinoma 2
• Testing for eosinophilia alone is not adequate screening for helminth infection—many infected patients do not have eosinophilia 2

Treatment Algorithm

Step 1: Assess for Life-Threatening Complications

Do not delay treatment in patients with end-organ damage—this is a medical emergency requiring prompt aggressive therapy to reduce morbidity and mortality. 2

• If cardiac involvement is suspected, consider prophylactic systemic steroids (1-2 mg/kg) for 1-2 weeks concomitantly with imatinib at initiation of therapy to prevent cardiogenic shock from HES cell degranulation 4

Step 2: Treatment Based on Molecular Classification

PDGFRA/PDGFRB-Rearranged HES

Imatinib is first-line therapy for patients with PDGFRA or PDGFRB rearrangements due to exquisite responsiveness. 5

• Failing to test for PDGFRA rearrangements can lead to missed treatment opportunities with imatinib therapy 3
• PDGFRA/B-rearranged patients usually manifest as imatinib-sensitive myeloproliferative neoplasms 7

FGFR1-Rearranged Neoplasms

• Pemigatinib was recently approved for patients with relapsed or refractory FGFR1-rearranged neoplasms 5
• FGFR1-rearranged cases may manifest as MPNs or aggressive lymphomas/leukemias and historically have had a dismal prognosis 7

Lymphocyte-Variant HES

Corticosteroids are first-line therapy for lymphocyte-variant HES. 3, 5

• Corticosteroids remain the mainstay of initial therapy in the setting of acute, life-threatening PDGFR mutation-negative HES 8

Idiopathic HES (Diagnosis of Exclusion)

For idiopathic HES, corticosteroids are generally administered initially, followed by agents such as hydroxycarbamide, interferon-alpha, and imatinib for corticosteroid-resistant cases. 6

• Mepolizumab, an IL-5 antagonist monoclonal antibody, is approved by the FDA for patients with idiopathic HES 5
• Mepolizumab is an effective corticosteroid-sparing agent for F/P-negative patients 6
• Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES 5

Step 3: Treatment of Secondary Eosinophilia

Parasitic Infections

• For asymptomatic eosinophilia in patients aged >24 months: albendazole 400 mg single dose plus ivermectin 200 μg/kg single dose 2
• For strongyloidiasis, ivermectin is the treatment of choice 3
• For schistosomiasis, praziquantel is recommended 3
• Overlooking Strongyloides in travelers can lead to fatal hyperinfection syndrome in immunocompromised patients 3

Monitoring Strategy

• Refer to hematology if eosinophilia ≥1.5 × 10⁹/L persists for >3 months after treating infectious causes 2
• Serial cardiac imaging is necessary if cardiac involvement was present 2
• Follow-up eosinophil counts and serial cardiac imaging are necessary for monitoring 3

Special Considerations

Hematopoietic Stem Cell Transplantation

• HSCT should be considered for both type 1 (autosomal dominant) and type 2 (DOCK8 deficiency) HIES 9
• Successful HSCT for patients with type 2 HIES has been reported with restoration of immune function and resolution of eosinophilia 9
• Cytotoxic chemotherapy agents and HSCT have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients 5

Immunoglobulin Replacement

• Patients with DOCK8 deficiency and poor antibody production should receive IgG replacement therapy 9

Growth Monitoring in Children

• Growth retardation has been reported in children and pre-adolescents receiving imatinib 4
• Monitor growth in children under imatinib treatment as the long-term effects of prolonged treatment on growth are unknown 4

Tumor Lysis Syndrome Prevention

• Cases of tumor lysis syndrome, including fatal cases, have been reported in patients with CML, GIST, ALL, and eosinophilic leukemia receiving imatinib 4
• Correct clinically significant dehydration and treat high uric acid levels prior to initiation of imatinib 4
• Monitor patients with high proliferative rate or high tumor burden closely 4

Critical Pitfalls to Avoid

• Delaying treatment in patients with end-organ damage can lead to irreversible heart failure and mortality 3
• Failing to test for PDGFRA rearrangements leads to missed treatment opportunities with imatinib therapy 3
• Overlooking Strongyloides in travelers can lead to fatal hyperinfection syndrome in immunocompromised patients 3
• Testing for eosinophilia alone is inadequate screening for helminth infection, as many infected patients do not have eosinophilia 3, 2
• Imatinib should be taken with food and a large glass of water to minimize GI irritation 4
• Advise patients that they may experience dizziness, blurred vision, or somnolence during treatment with imatinib, and recommend caution when driving or operating machinery 4