What is the approach to managing a patient with hyper eosinophilia, particularly in terms of evaluation, treatment, and prevention of potential organ damage?

Approach to Hypereosinophilia

The approach to hypereosinophilia prioritizes immediate exclusion of life-threatening organ damage, followed by systematic identification of secondary causes (especially parasitic infections), and then classification into primary neoplastic, secondary reactive, or idiopathic subtypes to guide targeted therapy that prevents irreversible morbidity and mortality. 1, 2

Immediate Assessment for Life-Threatening Complications

Any patient with hypereosinophilia presenting with cardiac symptoms (chest pain, dyspnea, heart failure, arrhythmias), pulmonary symptoms (persistent cough, wheezing, infiltrates), or neurological symptoms (altered mental status, focal deficits, peripheral neuropathy) requires urgent evaluation and consideration of emergency treatment before completing the full diagnostic workup. 2

• Obtain electrocardiogram, cardiac troponin, and NT-proBNP immediately in all patients with hypereosinophilia to screen for myocardial injury 2
• Perform echocardiography when cardiac troponin is elevated or clinical features suggest cardiac injury 2
• Cardiac MRI is indicated when elevated cardiac troponin or clinical features of cardiac injury are present to distinguish eosinophilic cardiac disease from other etiologies 2
• In cases of evolving life-threatening end-organ damage, initiate treatment immediately to avoid delay, even before completing the full diagnostic evaluation 1

Defining Hypereosinophilia and Risk Stratification

Hypereosinophilia is defined as peripheral blood eosinophil count ≥1.5 × 10⁹/L, with significant risk of organ damage requiring intervention. 1, 3

• Mild eosinophilia (0.5-1.5 × 10⁹/L) is most commonly caused by allergic disorders or medications in non-endemic areas, but helminth infections account for 19-80% of cases in returning travelers 2
• Moderate to severe eosinophilia (≥1.5 × 10⁹/L) requires hematology referral if it persists for more than 3 months after infectious causes have been excluded or treated 2, 4
• Absolute eosinophil count exceeding 5.0 × 10⁹/L at any time carries significant risk of morbidity and mortality 2

Systematic Evaluation Algorithm

Step 1: Exclude Secondary Causes (Highest Priority)

Helminth infections must be excluded first, as they account for 19-80% of eosinophilia cases in returning travelers and can cause fatal complications if missed, particularly Strongyloides in immunocompromised patients. 2, 4

Travel and Exposure History

• Document travel to helminth-endemic areas, focusing on fresh water exposure in Africa/tropical regions and raw/undercooked meat consumption 2
• Strongyloides stercoralis can persist lifelong and cause fatal hyperinfection syndrome in immunocompromised patients 2
• Schistosoma haematobium is associated with squamous cell bladder carcinoma and can cause spinal cord compression or portal hypertension in chronic cases 2

Parasitic Workup

• Obtain three separate concentrated stool specimens for ova and parasites 2, 4
• Send Strongyloides serology and culture immediately 2, 4
• Perform schistosomiasis serology if fresh water exposure in endemic areas 2
• Critical pitfall: Many helminth-infected patients do not have eosinophilia, so normal eosinophil counts do not exclude parasitic infection 2
• Critical warning for Loa loa: Do not use diethylcarbamazine if microfilariae are seen on blood film, as it may cause fatal encephalopathy; use corticosteroids with albendazole first to reduce microfilarial load to <1000/ml before definitive treatment 2

Medication Review

• Review all medications for drug-induced eosinophilia 2, 5
• Discontinue suspected offending agents when possible 5

Other Secondary Causes

• Evaluate for allergic disorders, asthma, and atopic conditions 2, 5
• Screen for malignancies, particularly lymphomas 5, 6
• Assess for Churg-Strauss syndrome vasculitis and other eosinophil-associated syndromes 5

Step 2: Assess for Organ Damage

Systematic evaluation of all potentially affected organ systems is mandatory to detect eosinophil-mediated injury before irreversible fibrosis develops. 1, 2

Cardiac Assessment (Highest Priority)

• Electrocardiogram, cardiac troponin, and NT-proBNP in all patients 2
• Echocardiography when biomarkers are elevated or symptoms present 2
• Cardiac MRI to distinguish eosinophilic cardiac disease from other etiologies 2

Pulmonary Assessment

• Pulmonary function tests in all patients with respiratory symptoms 2
• Chest X-ray to identify pulmonary infiltrates 2
• Bronchoscopy with bronchoalveolar lavage when imaging suggests parenchymal disease 2

Neurologic Assessment

• Electromyography to confirm eosinophil-induced peripheral neuropathy in patients with sensory or motor deficits 2
• Nerve biopsy confirms eosinophilic infiltration when EMG findings are consistent with neuropathy 2

Gastrointestinal Assessment

• Endoscopy with multiple biopsies (minimum 6 biopsies: 2-3 from proximal and 2-3 from distal esophagus) for patients with dysphagia or food impaction to evaluate for eosinophilic esophagitis 2, 4
• Peripheral eosinophilia occurs in only 10-50% of adults with eosinophilic esophagitis, so tissue diagnosis remains essential 2, 4
• Histological remission is defined as <15 eosinophils per 0.3 mm², and deep remission as <5 eosinophils per 0.3 mm² 2

Dermatologic Assessment

• Deep skin biopsy that includes fascia to confirm cutaneous involvement 2
• MRI to evaluate eosinophilic fasciitis when clinical suspicion is high 2

Tissue Confirmation Requirements

• Histopathologic confirmation of eosinophilic infiltration is the gold standard for documenting organ damage 2
• HE-related organ damage requires marked tissue eosinophil infiltrates and/or extensive deposition of eosinophil-derived proteins with at least one of the following: fibrosis (lung, heart, digestive tract, skin), thrombosis with or without thromboembolism, cutaneous manifestations (erythema, edema/angioedema, ulceration, pruritus, eczema), or peripheral/central neuropathy with chronic or recurrent neurologic deficit 1

Step 3: Classification of Hypereosinophilic Syndrome

Once secondary causes are excluded and organ damage is documented, classify into primary (neoplastic), secondary (reactive), or idiopathic HES to guide targeted therapy. 1, 4, 3

Mandatory Laboratory Testing

• CBC with differential, comprehensive metabolic panel, liver function tests 4, 3
• Serum tryptase levels and vitamin B12 levels 4, 3
• Serum immunoglobulins 4

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy with immunohistochemistry 3
• Reticulin/collagen stains to assess fibrosis 3
• Conventional cytogenetics 3
• FISH for CHIC2 deletion (surrogate marker for FIP1L1-PDGFRA fusion) 3
• RT-PCR for tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1) 1, 3

Flow Cytometry and T-Cell Clonality

• Flow immunocytometry to detect aberrant T-cell populations 6, 7
• T-cell receptor gene rearrangement studies to identify clonal T cells in lymphocyte-variant HES 6, 7

Classification Categories

Primary (Neoplastic) HES:

• Underlying myeloid or stem cell neoplasm with clonal eosinophils 1, 4
• Includes myeloid/lymphoid neoplasms with PDGFRA, PDGFRB, FGFR1, JAK2, or ABL1 rearrangements 1, 3
• Chronic eosinophilic leukemia, not otherwise specified (CEL-NOS) 6, 7

Secondary (Reactive) HES:

• Cytokine-driven eosinophilia with non-clonal eosinophils 1, 4
• Accounts for approximately 80% of cases 4
• Lymphocyte-variant HES is driven by an aberrant T-cell clone producing IL-5 4, 7

Idiopathic HES:

• Diagnosis of exclusion when no underlying cause is identified 1, 3
• No evidence of reactive or neoplastic condition underlying HE 1

Treatment Algorithm Based on Classification

Primary HES with PDGFRA or PDGFRB Rearrangements

Imatinib is first-line therapy due to exquisite responsiveness, with most patients achieving complete hematologic response. 1, 4, 6, 7

• Start imatinib at 100-400 mg daily (most patients with FIP1L1-PDGFRA respond to 100 mg daily, some require up to 400 mg daily) 1
• Monitor hematologic response, cytogenetic response (FISH), and molecular response (RT-qPCR if available) every 3 and 6 months 1
• For loss of response, evaluate patient compliance and drug interactions before escalating therapy 1
• Evaluate for cytogenetic/molecular clonal evolution to identify PDGFRA (T674I and D842V) or PDGFRB mutations conferring resistance to imatinib 1
• For PDGFRA D842V mutation resistant to imatinib, refer to clinical trial of avapritinib if available 1
• Consider clinical trial and/or early referral to allogeneic hematopoietic cell transplantation for patients with loss of response 1

Lymphocyte-Variant HES

Corticosteroids are first-line therapy for lymphocyte-variant HES, which is driven by an aberrant T-cell clone producing IL-5. 4, 6, 7, 8, 9

• Initiate prednisone 1 mg/kg/day (or equivalent) 6, 7
• Taper to lowest effective dose to maintain remission 6, 7
• For steroid-refractory cases, consider hydroxyurea or interferon-alpha 6, 7, 8, 9

Idiopathic HES

Corticosteroids are first-line therapy for idiopathic HES, particularly in the setting of acute, life-threatening organ damage. 4, 6, 7, 8, 9

• Initiate prednisone 1 mg/kg/day (or equivalent) for acute presentations 6, 7
• For corticosteroid-resistant cases, use hydroxyurea, interferon-alpha, or imatinib as second-line agents 4, 6, 7, 8, 9
• Second-line cytotoxic chemotherapy agents and hematopoietic cell transplant have been used for aggressive forms with limited reported outcomes 6, 7, 8, 9

Eosinophilic Esophagitis

Topical swallowed corticosteroids (fluticasone or budesonide) are first-line treatment, decreasing blood eosinophil counts in 88% of patients. 2, 4

• Initiate fluticasone 880-1760 mcg twice daily or budesonide 1-2 mg twice daily 2, 4
• Maintenance therapy is mandatory after achieving remission, as clinical relapse rates are high after topical steroid withdrawal 2
• Endoscopic dilation is safe and effective for fibrostenotic disease, but must be combined with anti-inflammatory therapy 2
• Repeat endoscopy with biopsies if symptoms recur during treatment 2

Tropical Pulmonary Eosinophilia

Diethylcarbamazine (DEC) must be initiated promptly to prevent irreversible pulmonary fibrosis, but only after excluding Loa loa co-infection. 2

• Obtain three separate concentrated stool specimens for ova and parasites before initiating corticosteroids 2
• Initiate DEC after confirming absence of Loa loa microfilariae 2
• Add adjunctive corticosteroids (prednisolone 20 mg/day for 5 days initially) for ongoing alveolitis 2
• 20% of patients relapse and require re-treatment with a second DEC course 2

Monitoring and Follow-Up

Serial monitoring is essential to detect treatment response, disease progression, and development of complications. 1, 4

• Monitor eosinophil counts regularly (frequency depends on severity and treatment) 4
• Serial cardiac imaging is necessary if cardiac involvement was present 4
• For patients on imatinib, monitor hematologic, cytogenetic, and molecular response every 3-6 months 1
• Monitor for treatment-related complications including corticosteroid side effects and imatinib hepatotoxicity 2
• For mild eosinophilia (<1.5 × 10⁹/L) without symptoms or signs of organ involvement, a watch-and-wait approach with close follow-up is appropriate 6, 7, 8, 9

Critical Pitfalls to Avoid

• Do not initiate corticosteroids before excluding Strongyloides, as immunosuppression can trigger fatal hyperinfection syndrome 2
• Do not assume eosinophilia alone is adequate screening for helminth infection, as many infected patients have normal eosinophil counts 2
• Do not wait for symptoms to develop before investigating persistent moderate-to-severe eosinophilia, as end-organ damage can be subclinical initially 2
• Do not fail to test for PDGFRA rearrangements with FISH, as this leads to missed diagnosis and treatment opportunities with imatinib 3
• Do not overlook cardiac assessment early, as this can result in irreversible heart failure and poor prognosis 3
• Do not rely solely on peripheral eosinophil counts to assess tissue eosinophilia in conditions like eosinophilic esophagitis, as tissue biopsy is the gold standard 2, 4