Persistent hypereosinophilia requires a systematic evaluation to distinguish reactive causes from clonal hematological disorders. Although allergic diseases, parasitic infections, and drug reactions account for the majority of cases, failure to identify the underlying etiology may delay appropriate treatment and predispose to irreversible organ damage.
We report a 35-year-old male who presented with chronic cough, significant weight loss, marked eosinophilia, and significant splenomegaly. The patient had initially received corticosteroid therapy elsewhere with only partial improvement. Further evaluation excluded secondary causes of eosinophilia. Bone marrow examination demonstrated marked eosinophilic proliferation, and molecular testing identified FIP1L1–PDGFRA fusion, establishing the diagnosis of a clonal eosinophilic disorder. Low-dose imatinib therapy resulted in rapid normalization of eosinophil counts, complete hematologic remission, and marked reduction in splenic size.
This case highlights the importance of a structured diagnostic approach to persistent hypereosinophilia and emphasizes the role of molecular testing in identifying highly treatable eosinophilic disorders.
Eosinophilia is defined as an absolute eosinophil count (AEC) greater than 500 cells/µL, while hypereosinophilia refers to an AEC of ≥1500 cells/µL. Persistent hypereosinophilia presents a diagnostic challenge because it encompasses a broad spectrum of disorders ranging from benign reactive conditions to clonal hematological neoplasms.
Common secondary causes include allergic diseases, parasitic infections, drug hypersensitivity, autoimmune disorders, and certain malignancies. When eosinophilia persists despite exclusion of these conditions, evaluation should focus on identifying clonal disorders through bone marrow examination and molecular studies.
Next-generation sequencing (NGS) plays an important role in persistent unexplained hypereosinophilia by identifying clinically relevant molecular abnormalities and guiding targeted therapy. In our patient, detection of the FIP1L1–PDGFRA fusion established the molecular diagnosis and enabled treatment with low-dose imatinib, resulting in rapid hematological remission.
Among the molecular abnormalities associated with clonal eosinophilia, FIP1L1–PDGFRA fusion is particularly important because it predicts an excellent response to low-dose imatinib. Early recognition prevents eosinophil-mediated cardiac, pulmonary, neurological, and thromboembolic complications while allowing targeted therapy.
We report a patient with persistent hypereosinophilia in whom molecular testing established the diagnosis after initial empirical treatment with corticosteroids.
A 35-year-old gentleman presented with complaints of persistent cough and progressive weight loss of approximately 10 kg over the preceding two years. There was no history of fever, wheeze, allergic rhinitis, bronchial asthma, skin rash, recent drug exposure, or travel to areas endemic for parasitic infections.
The patient had initially been treated with systemic corticosteroids at an outside facility; however, persistent hypereosinophilia prompted further evaluation.
On examination, he was afebrile and hemodynamically stable. Abdominal examination revealed significant splenomegaly without hepatomegaly or lymphadenopathy. Cardiovascular, respiratory, and neurological examinations were unremarkable.
Initial laboratory investigations revealed:
* Hemoglobin – 12.8 g/dL
* Total leukocyte count – 15,430/mm³
* Eosinophils – 67%
* Absolute eosinophil count – 10,338/µL
* Mild thrombocytopenia
Peripheral smear demonstrated leukocytosis with marked eosinophilia and macrocytic red blood cells without blasts or atypical cells.
Evaluation for secondary eosinophilia included:
* Stool examination for ova and parasites – Negative
* ANA – Negative
* No clinical evidence of allergic disease or parasitic infestation
* No significant drug exposure
Echocardiography revealed no evidence of eosinophilic cardiac involvement.
Ultrasonography of the abdomen demonstrated massive splenomegaly measuring 18 cm.
Bone marrow aspiration showed normocellular marrow with marked eosinophilia and increased iron stores.
Trephine biopsy demonstrated hypercellular marrow with trilineage hematopoiesis and prominent eosinophilic proliferation.
Molecular analysis by next-generation sequencing identified FIP1L1–PDGFRA fusion, confirming a clonal eosinophilic disorder.
Following confirmation of the molecular diagnosis, corticosteroids were discontinued and the patient was started on Imatinib 100 mg once daily.
Serial blood counts and clinical assessments were performed to monitor therapeutic response.
The patient showed remarkable clinical and hematological improvement at 6 month follow-up after initiating imatinib.
Repeat investigations demonstrated:
* Hemoglobin – 15.6 g/dL
* Total leukocyte count – 8,510/mm³
* Eosinophils – 4%
* Platelet count – 150,000/mm³
Peripheral smear normalized without atypical cells.
Repeat ultrasonography showed regression of splenomegaly from 18 cm to 13.5 cm, and the spleen was no longer palpable clinically.
The patient continues on maintenance low-dose imatinib with sustained hematologic remission.
Persistent hypereosinophilia should never be regarded as a diagnosis in itself but rather as a manifestation of an underlying disorder. The initial step in evaluation is distinguishing reactive eosinophilia from clonal eosinophilic disorders.
Reactive eosinophilia is commonly associated with allergic diseases, parasitic infections, drug reactions, connective tissue diseases, eosinophilic gastrointestinal disorders, and vasculitides. A detailed history, physical examination, and directed laboratory investigations usually identify these causes.
In patients with persistent hypereosinophilia (AEC ≥1500/µL), particularly those with constitutional symptoms, splenomegaly, or unexplained hematologic abnormalities, evaluation should extend to bone marrow examination and molecular studies. The British Society for Haematology recommends testing for FIP1L1–PDGFRA in patients with an eosinophil count ≥1.5 × 10⁹/L when no obvious underlying cause is identified.
Our patient demonstrated several features suggestive of a clonal disorder, including marked persistent hypereosinophilia, constitutional symptoms, leukocytosis, and massive splenomegaly. Despite empirical corticosteroid therapy, eosinophilia persisted, emphasizing that transient steroid responsiveness does not exclude a clonal etiology.
The FIP1L1–PDGFRA fusion results from a cryptic interstitial deletion on chromosome 4q12, leading to constitutive activation of the platelet-derived growth factor receptor alpha tyrosine kinase. This molecular alteration drives eosinophilic proliferation and is highly sensitive to imatinib.
Unlike chronic myeloid leukemia, patients harboring this fusion generally achieve complete hematologic and molecular remission with low-dose imatinib (100 mg daily). The dramatic normalization of eosinophil counts and regression of splenomegaly observed in our patient illustrate the importance of recognizing this entity early.
Delayed diagnosis may result in irreversible eosinophil-mediated end-organ damage involving the heart, lungs, nervous system, gastrointestinal tract, and thromboembolic complications. Therefore, molecular testing should be considered early in patients with persistent hypereosinophilia after exclusion of common secondary causes.
This case demonstrates that persistent hypereosinophilia should prompt a systematic evaluation rather than prolonged empirical treatment. Early molecular testing with Next Generation Sequencing not only establishes the diagnosis but also identifies patients who can achieve excellent outcomes with targeted therapy. Recognition of FIP1L1–PDGFRA rearrangement transforms the management of these patients, converting a potentially progressive disease into one with an excellent prognosis.
* Persistent hypereosinophilia (AEC ≥1500/µL) warrants systematic evaluation.
* Reactive causes including parasitic infections, allergy, drugs, and autoimmune diseases should be excluded before considering clonal disorders.
* Constitutional symptoms and splenomegaly should raise suspicion for an underlying hematologic disorder.
* Bone marrow examination and molecular testing are essential when secondary causes are excluded.
* NGS can uncover actionable molecular drivers such as FIP1L1–PDGFRA, transforming diagnosis and enabling effective targeted therapy.
* FIP1L1–PDGFRA rearrangement predicts an excellent response to low-dose imatinib.
* Empirical corticosteroid therapy may transiently improve eosinophilia but should not delay definitive diagnosis.
* Early molecular diagnosis prevents irreversible eosinophil-mediated organ damage and significantly improves patient outcomes.
Dr. S. Akash Kumar, MBBS DNB Resident, Department of General Medicine Kauvery Hospital, Chennai.
Dr. Arshad Raja, MBBS, MD, PDF Consultant Hematologist Kauvery Hospital, Chennai.
