What is the differential diagnosis (ddx) for a patient with elevated red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), platelets, lymphocytes, and eosinophils?

Differential Diagnosis for Elevated RBC, Hemoglobin, Hematocrit, Platelets, Lymphocytes, and Eosinophils

The combination of elevated RBC parameters with thrombocytosis, lymphocytosis, and eosinophilia most critically suggests a myeloproliferative neoplasm with tyrosine kinase gene fusion, particularly BCR::ABL1-positive chronic myeloid leukemia (CML), which can present with this exact constellation of findings including characteristic basophilia. 1, 2

Primary (Clonal/Neoplastic) Disorders - Most Critical to Rule Out

Myeloproliferative Neoplasms with Tyrosine Kinase Fusions

• BCR::ABL1-positive CML is the leading diagnosis when you see pancytosis with elevated RBC, platelets, lymphocytes, and eosinophils together, especially if basophilia is also present 1, 2
• Myeloid/lymphoid neoplasms with PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, or FLT3 rearrangements must be excluded because they respond to tyrosine kinase inhibitors and represent highly treatable causes 3, 1, 2
• These disorders commonly present with elevated serum tryptase and vitamin B12 levels, which serve as important diagnostic clues 3, 2

Polycythemia Vera (PV)

• PV should be considered when RBC, hemoglobin, and hematocrit are elevated above the 95th percentile for sex and race, particularly when accompanied by thrombocytosis and leukocytosis 3
• Serum erythropoietin (EPO) levels are characteristically low in PV (>90% specificity), though sensitivity is only approximately 70% 3
• Splenomegaly, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels support this diagnosis 3

Chronic Eosinophilic Leukemia (CEL-NOS)

• CEL-NOS is diagnosed when cytogenetic or molecular abnormalities (such as trisomy 8 or isochromosome 17) are present, or when blast cells are increased (>2% in peripheral blood or >5% in bone marrow, but <20% in both) 3
• This diagnosis requires exclusion of specific tyrosine kinase fusion genes 3

Lymphocyte-Variant Hypereosinophilic Syndrome (L-HES)

• L-HES is characterized by clonal T-cells with aberrant immunophenotype (CD3-, CD4+, CD8- or CD3+, CD4-, CD7-) producing IL-4, IL-5, and IL-13 that drive reactive eosinophilia 3
• Elevated serum TARC and IgE levels are common but neither sensitive nor specific 3
• Approximately 10-20% of cases evolve to T-cell lymphoma or Sézary syndrome 3

Mandatory Initial Workup

History and Physical Examination

• Travel history (parasitic infections, especially Strongyloides), new medications, recurrent infections, and family history of eosinophilia or autoimmune disease are critical historical elements 3, 2, 4
• Physical examination must assess spleen and liver size (measured in cm below costal margin), skin manifestations, and signs of immunodeficiency 3, 2

Essential Laboratory Testing

• Complete blood count with manual differential to determine absolute eosinophil count, basophil percentage, blast percentage, and promyelocyte count 3, 1, 2
• Serum tryptase and vitamin B12 levels are elevated in myeloproliferative variants and provide crucial diagnostic information 3, 2
• Serum erythropoietin level to evaluate for polycythemia vera (low in PV, normal or high in secondary causes) 3
• Comprehensive metabolic panel, liver function tests, lactate dehydrogenase, and uric acid 3, 2
• Quantitative immunoglobulin levels including IgE (elevated in allergic conditions, L-HES, and ABPA) 3, 2

Peripheral Blood Studies

• Peripheral blood smear review for dysplasia, monocytosis, circulating blasts, and left-shifted myeloid maturation 3
• Flow cytometry to define myeloid versus lymphoid phenotype and identify aberrant T-cell populations 3, 1

Bone Marrow Evaluation - Mandatory for Definitive Diagnosis

• Bone marrow aspirate and biopsy with morphology assessment for hypercellularity, blast percentage, and focal "nests of blasts" 3, 1
• Immunohistochemistry for CD117, CD25, and tryptase 3, 2
• Reticulin/collagen stains to assess for fibrosis 3
• Conventional cytogenetics with minimum of 15 metaphases analyzed 3, 2
• FISH for CHIC2 deletion (indicates cryptic FIP1L1-PDGFRA fusion) 1, 4
• RT-PCR for tyrosine kinase fusion genes (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, FLT3, BCR::ABL1) 3, 1, 2
• Next-generation sequencing via myeloid mutation panels to establish clonality when no TK fusion genes are detected 3

Additional Testing Based on Clinical Context

• Serology for parasitic infections, particularly Strongyloides, with stool ova and parasites test and GI PCR 3, 2
• Antineutrophil cytoplasmic antibodies (ANCA) and antinuclear antibodies to evaluate for eosinophilic granulomatosis with polyangiitis (EGPA) 2
• Aspergillus-specific IgE if allergic bronchopulmonary aspergillosis (ABPA) is suspected 3

Secondary (Reactive) Causes to Exclude

Parasitic Infections

• Tissue-invasive helminth infections are the most common cause of marked eosinophilia worldwide, but rarely cause the full constellation of findings described 2, 5
• Strongyloides serology is mandatory, especially with travel history 3, 2

Allergic/Inflammatory Disorders

• Allergic disorders account for 80% of eosinophilia cases but cause only mild elevations (typically <1500/μL) and would not explain the pancytosis 1, 6
• EGPA can cause eosinophilia but typically presents with asthma, sinusitis, and vasculitis 2

Drug Reactions

• Medication-induced eosinophilia should be considered, but the combination with elevated RBC parameters and thrombocytosis makes this less likely 3, 4

Malignancies

• Solid tumors and lymphoid malignancies (particularly T-cell lymphomas) can cause secondary eosinophilia, but the elevated RBC parameters point toward a primary myeloid process 3

Critical Diagnostic Pitfalls to Avoid

• Failing to test for PDGFRA/PDGFRB rearrangements leads to missed opportunities for highly effective imatinib therapy, which can be curative in these disorders 1, 4
• Not performing BCR::ABL1 testing misses CML, which is the most likely diagnosis given the specific combination of findings 1, 2
• Attributing severe leukocytosis with this constellation to allergic disease is a dangerous error, as allergic disorders cause only mild eosinophilia 1
• Overlooking cardiac evaluation is potentially fatal, as persistent hypereosinophilia causes irreversible endomyocardial fibrosis; ECG, echocardiogram, and troponin are mandatory 1, 4
• Not assessing for organ damage early (cardiac, pulmonary, neurologic, dermatologic) can result in irreversible complications 4
• Relying solely on RBC mass measurement is costly and often unnecessary when hematocrit exceeds 60% without obvious hemoconcentration 3

Diagnostic Algorithm

1. Confirm absolute values for all cell lines and calculate absolute eosinophil count 3, 1
2. Measure serum tryptase, vitamin B12, and EPO levels immediately 3, 2
3. Perform peripheral blood flow cytometry and review smear 3, 1
4. Proceed directly to bone marrow evaluation with comprehensive cytogenetic and molecular testing for tyrosine kinase fusions 3, 1, 2
5. Obtain cardiac evaluation (ECG, echo, troponin) urgently 1, 4
6. Test for parasitic infections and review medication history 3, 2
7. If tyrosine kinase fusion is identified, initiate targeted therapy immediately and refer to hematology 1, 2