Hypereosinophilic syndrome (HES) represents a rare and complex group of disorders defined by persistently elevated levels of eosinophils—a type of white blood cell involved in immune defense and inflammation.

This unchecked proliferation and activation of eosinophils can lead to widespread damage in tissues.

Defining Hypereosinophilic Syndrome

Eosinophils are normally present in small numbers in the bloodstream, playing a critical role in combating parasitic infections, modulating immune responses, and contributing to allergic reactions. Hypereosinophilia, the hallmark of HES, is characterized by an eosinophil count exceeding 1,500 cells per microliter of blood sustained over six months or longer without a clear identifiable cause.

Causes and Classification

HES is a heterogeneous disorder with multifactorial etiologies. It can be broadly classified into several subtypes based on underlying mechanisms:

Primary (myeloproliferative) HES: Caused by clonal proliferation of eosinophils originating in the bones marrow, often linked to genetic abnormalities such as the FIP1L1-PDGFRA fusion gene.

Secondary (reactive) HES: Results from excessive eosinophil production triggered by external factors like parasitic infections, allergic diseases, autoimmune disorders, or malignancies outside of the eosinophil lineage.

Idiopathic HES: Diagnosed when no underlying cause for eosinophilia or damage can be identified despite exhaustive evaluations.

Familial HES: An inherited form marked by persistent eosinophilia across generations, though it is exceedingly rare.

Clinical Manifestations

Cardiac complications: Present in over 70% of cases, including myocarditis, restrictive cardiomyopathy, mural thrombi formation, and ultimately heart failure. Cardiac involvement constitutes a leading cause of morbidity and mortality.

Dermatologic signs: Occur in more than half of patients, featuring rashes, pruritus, urticaria, angioedema, and dermatitis, often resembling eczema or hives.

Respiratory symptoms: Include chronic cough, wheezing, dyspnea, and pleural effusions caused by pulmonary eosinophilic infiltration.

Neurological deficits: May manifest as peripheral neuropathy, cognitive impairments, or encephalopathy linked to cerebral emboli originating from cardiac thrombi.

Gastrointestinal distress: Encompassing abdominal pain, nausea, vomiting, and diarrhea, due to eosinophilic infiltration of the digestive tract.

Hematologic findings: Such as anemia, thrombocytopenia, lymphadenopathy, and splenomegaly, are common and correlate with underlying marrow abnormalities.

Diagnostic Approach

Accurate diagnosis involves a combination of hematologic tests, imaging, biopsies, and molecular analyses. Confirmatory criteria include persistently high eosinophil counts, tissue infiltration evidenced by biopsy, exclusion of secondary causes, and detection of genetic mutations or clonal markers where applicable.

Measurement of serum tryptase and vitamin B12 levels, along with bones marrow examination, helps differentiate myeloproliferative forms. Imaging modalities such as echocardiography, MRI, and CT scans identify damage or thrombi. Neurologic and gastrointestinal assessments complement a multidisciplinary diagnostic evaluation.

Treatment Modalities

Therapeutic strategies are tailored to the HES subtype and severity of involvement. Corticosteroids remain the first-line treatment for symptom control and eosinophil reduction. However, long-term steroid use poses risks of adverse effects, necessitating steroid-sparing agents.

Targeted therapies have revolutionized HES management, especially for myeloproliferative forms harboring the FIP1L1-PDGFRA fusion gene, where tyrosine kinase inhibitors like imatinib achieve remarkable remission rates.

Prognosis and Future Directions

Prognosis varies substantially based on disease subtype, involvement, and treatment responsiveness. Indolent cases can achieve near-normal life expectancy with appropriate management, while aggressive disease forms carry significant morbidity and mortality. Ongoing research focuses on elucidating molecular pathways driving eosinophil proliferation, refining diagnostic markers, and developing safer, more effective targeted therapies.

Florence E. Roufosse emphasized the importance of early diagnosis and a multidisciplinary approach in managing HES "Early recognition is critical, yet many patients experience years of delay before receiving a diagnosis."

Hypereosinophilic syndrome is a rare but potentially life-threatening disorder characterized by excessive eosinophil proliferation leading to multi damage. Its diverse clinical spectrum requires high suspicion and comprehensive diagnostics to differentiate subtypes and exclude secondary causes. Treatment includes corticosteroids, targeted molecular therapies, and supportive care, aimed at reducing eosinophil levels and preventing complications.