What is hypereosinophilic syndrome?

What is Hypereosinophilic Syndrome?

Hypereosinophilic syndrome (HES) is a rare group of disorders characterized by persistent peripheral blood eosinophilia (>1,500 cells/μL on two examinations at least one month apart) combined with organ damage or dysfunction directly attributable to eosinophilic tissue infiltration, after excluding other causes of eosinophilia. 1, 2

Diagnostic Criteria

HES requires three essential components to be present 2, 3:

• Persistent peripheral blood eosinophilia >1.5 × 10⁹/L (>1,500 cells/μL) documented on two separate examinations at least one month apart 1, 3
• Organ damage and/or dysfunction directly attributable to tissue eosinophilic infiltration with marked tissue eosinophil infiltrates and/or extensive deposition of eosinophil-derived proteins 1
• Exclusion of other disorders as the primary cause of eosinophilia and organ damage, including allergic disorders (most common cause, ~80% of cases), parasitic infections (especially Strongyloides), drug reactions, solid tumors, and lymphoid malignancies 1, 2

Important caveat: In cases of evolving life-threatening end-organ damage, diagnosis can be made immediately without waiting for the one-month interval to avoid treatment delay 1, 3

Classification of HES Variants

HES is classified into distinct subtypes based on underlying pathophysiology 1, 3:

Primary (Neoplastic) HES (HESN)

• Underlying myeloid or stem cell neoplasm where eosinophils are clonal (neoplastic) cells 1
• Often associated with tyrosine kinase fusion genes, particularly the FIP1L1-PDGFRA fusion gene on chromosome 4q12 4, 5
• Characterized by elevated serum tryptase and vitamin B12 levels 2
• Predominantly affects males (4-9:1 ratio in historic series) 4

Secondary (Reactive) HES (HESR)

• Eosinophils are non-clonal cells driven by cytokine overproduction, particularly interleukin-5 (IL-5) 1, 6
• Includes lymphoid variant HES (L-HES) with clonal T-cell populations (typically CD3-CD4+ phenotype) producing excess IL-5 1, 4
• Associated with underlying conditions where eosinophils respond to cytokine signals 1

Idiopathic HES

• No identifiable underlying cause of hypereosinophilia 1
• No evidence of reactive or neoplastic condition underlying the eosinophilia 1
• Diagnosis of exclusion after comprehensive workup 3

Organ Systems Affected

The most commonly involved organ systems include 1, 2:

Cardiovascular (Most Critical Prognostically)

• Endomyocardial thrombosis and fibrosis are frequently documented, particularly in primary (neoplastic) HES variants 1, 2
• Cardiac involvement represents the most critical prognostic factor and leading cause of morbidity and mortality 2, 7, 4
• Valvular damage and heart failure can develop 7

Gastrointestinal

• Up to 38% of HES patients develop GI symptoms 1, 2
• Esophageal involvement can mimic eosinophilic esophagitis with dysphagia and food impaction 1, 2
• Eosinophilic gastroenteritis with ulcerations (as seen in sigmoid colon) 4, 8

Dermatologic

• Cutaneous manifestations including erythema, edema/angioedema, ulceration, pruritus, and eczema 1
• Skin involvement occurs in >50% of cases 4

Pulmonary

• Cough, dyspnea, and infiltrative lung disease 1, 4
• Pleural effusions and pneumonia 8
• Lung involvement in >50% of cases 4

Neurologic

• Peripheral and central neuropathy with chronic or recurrent neurologic deficits 1
• Seizures (including complex partial seizures) 8
• Stroke and encephalopathy 7
• Central and peripheral nervous system involvement in >50% of cases 4

Other Systems

• Hepatosplenomegaly 4
• Thromboembolic events due to hypercoagulability 7
• Coagulation disorders 4

Distinguishing HES from Other Conditions

HES can be distinguished from isolated eosinophilic esophagitis (EoE) by the presence of peripheral eosinophilia (absolute eosinophil count >1,500 cells/μL), which is rare in isolated EoE. 1, 3 However, other eosinophilic gastrointestinal diseases (eosinophilic gastritis, enteritis) may present with peripheral eosinophilia and esophageal involvement 1.

Patients presenting with esophageal symptoms and hypereosinophilia require screening of the entire upper and lower GI tract plus monitoring for involvement of other organ systems (skin, lung, heart, neurologic) consistent with multisystem HES or eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) 1, 2, 7.

Clinical Presentation

Common presenting symptoms include 1, 4, 8:

• Weakness and fatigue
• Cough and dyspnea
• Myalgias or angioedema
• Rash or fever
• Rhinitis
• Blood count abnormalities (neutrophilia, basophilia, thrombocytosis, monocytosis, myeloid immaturity)

Critical timing consideration: The level and timing of eosinophilia and organ damage are often discordant—organ damage may occur before, during, or after peak eosinophilia 8.