What is the differential diagnosis for a patient with elevated Immunoglobulin G (IgG), elevated Immunoglobulin E (IgE), eosinophilia, normal to high basophil and monocyte counts, thrombocytosis, microcytic anemia, and low Unbound Iron-Binding Capacity (UIBC)?

Differential Diagnosis for This Laboratory Pattern

This constellation of findings—elevated IgG and IgE, eosinophilia, microcytic anemia with low UIBC and normal/high iron—most strongly suggests a myeloproliferative hypereosinophilic syndrome (particularly myeloid/lymphoid neoplasms with tyrosine kinase fusion genes) or eosinophilic granulomatosis with polyangiitis (EGPA), with parasitic infection and allergic disorders as critical secondary causes to exclude. 1

Primary (Neoplastic) Eosinophilic Disorders

Myeloid/lymphoid neoplasms with tyrosine kinase (TK) fusion genes should be the first consideration given the combination of eosinophilia with thrombocytosis, basophilia, and monocytosis—this myeloproliferative pattern is characteristic. 1

• These neoplasms commonly present with neutrophilia, basophilia, thrombocytosis, monocytosis, and both mature and immature eosinophils with varying degrees of dysplasia. 1
• Elevated serum tryptase and/or vitamin B12 levels are commonly observed in myeloproliferative variants, particularly in myeloid neoplasms with PDGFRA fusion genes. 1
• Bone marrow evaluation with immunohistochemistry for CD117, CD25, tryptase, conventional cytogenetics, FISH for CHIC2 deletion, and RT-PCR for tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1) is mandatory to confirm or exclude this diagnosis. 1, 2

Chronic eosinophilic leukemia-NOS remains in the differential when morphologic and cytogenetic evidence suggests clonal hematopoiesis but no TK fusion gene is identified. 1

Vasculitic/Autoimmune Disorders

Eosinophilic granulomatosis with polyangiitis (EGPA) is a critical consideration, particularly if there is any history of asthma, rhinosinusitis, or systemic symptoms. 1

• Elevated IgE is a nonspecific finding in EGPA and other allergic/reactive conditions. 1
• ANCA testing (specifically MPO-ANCA) should be performed in all suspected cases; 30-40% of EGPA patients are ANCA-positive, and these patients more frequently show vasculitis features like glomerulonephritis, neuropathy, and purpura. 1
• ANCA-negative EGPA patients more frequently manifest cardiomyopathy and lung involvement. 1
• Cardiac evaluation with troponin, NT-proBNP, ECG, and echocardiogram is essential as endomyocardial involvement can cause irreversible damage. 1, 2

Secondary (Reactive) Eosinophilic Disorders

Parasitic infections must be rigorously excluded, as they represent the second most common cause of hypereosinophilia after allergic disorders. 3, 4

• Strongyloides stercoralis is the most common parasitic cause and can persist lifelong, causing fatal hyperinfection syndrome in immunocompromised patients. 3, 4
• Hookworm (Ancylostoma duodenale, Necator americanus) and schistosomiasis are other important causes. 3, 4
• Obtain detailed travel history, three separate concentrated stool specimens for ova and parasites, Strongyloides serology and culture, and schistosomiasis serology if freshwater exposure in endemic areas. 4
• Serological tests may not become positive until 4-12 weeks after infection, so temporal patterns must be considered. 3

Allergic and atopic disorders account for approximately 80% of secondary reactive hypereosinophilia cases. 3, 4

• Allergic bronchopulmonary aspergillosis (ABPA) presents with Aspergillus-specific immunoglobulins and increased serum IgE. 1
• Drug reactions (NSAIDs, beta-lactam antibiotics, nitrofurantoin) typically occur within days to weeks of medication initiation. 4

Microcytic Anemia Component

The microcytic anemia with low UIBC and normal/high iron is atypical for simple iron deficiency and suggests either:

• Anemia of chronic disease/inflammation associated with the underlying eosinophilic disorder, characterized by low iron levels and decreased total iron-binding capacity. 5
• Thalassemia trait as a concurrent condition, which would show elevated hemoglobin A2 on electrophoresis. 5, 6
• Iron overload states or functional iron deficiency related to chronic inflammation. 6

Low UIBC with normal/high iron is inconsistent with iron deficiency anemia (which shows high UIBC and low iron), making this pattern more consistent with anemia of chronic disease in the context of a chronic inflammatory or neoplastic eosinophilic disorder. 7, 8, 5

Critical Diagnostic Algorithm

1. Immediately assess for organ damage (cardiac troponin, NT-proBNP, ECG, echocardiogram, pulmonary function tests) as persistent eosinophilia >1.5 × 10⁹/L can cause irreversible damage to heart, lungs, GI tract, nervous system, and skin. 1, 3, 2

2. Exclude parasitic infections with comprehensive stool studies, Strongyloides serology, and travel/exposure history. 3, 4, 2

3. Perform bone marrow evaluation with cytogenetics, FISH, and RT-PCR for TK fusion genes to identify myeloid/lymphoid neoplasms. 1, 2

4. Check ANCA (MPO-ANCA) and consider tissue biopsy if EGPA is suspected based on clinical phenotype. 1

5. Measure serum tryptase and vitamin B12 as elevated levels support myeloproliferative variants. 1

6. Evaluate iron studies comprehensively (serum ferritin, iron, TIBC, transferrin saturation) and consider hemoglobin electrophoresis to differentiate causes of microcytosis. 5, 6

Common Pitfalls

• Failing to test for PDGFRA rearrangements can miss a highly treatable neoplasm responsive to imatinib. 2
• Overlooking Strongyloides in travelers can lead to fatal hyperinfection syndrome if immunosuppression is initiated. 3, 4, 2
• Not assessing cardiac involvement early can result in irreversible heart failure. 2
• Assuming iron deficiency based solely on microcytosis without checking ferritin and TIBC leads to inappropriate iron supplementation. 7, 5