What is the diagnostic approach for a child presenting with lethargy, pallor, low-grade fever, and lymphadenopathy for 2 months?

Diagnostic Approach for a Child with Lethargy, Pallor, Low-Grade Fever, and Lymphadenopathy for 2 Months

Begin with a peripheral blood film immediately, followed by complete blood count with differential and inflammatory markers; if these reveal cytopenias, abnormal cells, or blasts, proceed directly to bone marrow examination to rule out acute lymphoblastic leukemia—the most critical diagnosis to exclude in this presentation. 1, 2, 3

Initial Laboratory Testing Priority

1. Blood Film and Complete Blood Count (First-Line)

• Perform peripheral blood film examination first as 95% of children with acute lymphoblastic leukemia (ALL) present with enlargement of lymph nodes, liver, and/or spleen, and the characteristic laboratory constellation includes mono-, bi-, or trilinear pathology of the blood count with blasts in the blood smear 3
• Look specifically for:
  • Cytopenias (anemia, thrombocytopenia, leukopenia) 4, 3
  • Abnormal white blood cell morphology or circulating blasts 3
  • Lymphocytosis with atypical lymphocytes 5
• The blood film is more diagnostically valuable than elaborate laboratory investigations in detecting ALL, as the alertness to clinical findings and pathologic blood count is paramount 3

2. Additional Initial Laboratory Studies

• Complete blood count with manual differential 1, 2
• Inflammatory markers: ESR, CRP, procalcitonin 1, 2
• Comprehensive metabolic panel including liver function tests 1, 2
• Lactate dehydrogenase (LDH) - elevated in lymphoproliferative disorders 5
• Urinalysis and urine culture (catheterized specimen) to exclude urinary tract infection 1, 2

When to Proceed to Bone Marrow Examination

Indications for Urgent Bone Marrow Aspiration/Biopsy

Proceed immediately to bone marrow examination if:

• Blasts are present on peripheral blood film 3
• Unexplained cytopenias (anemia, thrombocytopenia, or leukopenia) persist 4, 3
• Lymph nodes are larger than 2 cm, hard, or matted/fused to surrounding structures 6
• Hepatosplenomegaly is present with cytopenias 5
• Clinical suspicion for leukemia remains high despite normal or subtle blood findings, as blood examinations can sometimes be within normal limits in early leukemia 4

What Bone Marrow Examination Reveals

• Definitive diagnosis of acute lymphoblastic leukemia through identification of lymphoblasts 3
• Hemophagocytic lymphohistiocytosis (HLH) - shows hemophagocytosis and lymphoproliferation 5
• Bone marrow infiltration patterns 4
• Exclusion of aplastic anemia 7

Virology Screening (Secondary Priority)

When to Perform Virology Testing

Virology screening should be performed concurrently with initial blood work but should NOT delay bone marrow examination if malignancy is suspected:

• Epstein-Barr virus (EBV) serology and PCR - can cause hemophagocytic lymphohistiocytosis with fever, lymphadenopathy, hepatosplenomegaly, and cytopenias 5
• Influenza A and B testing - influenza B can mimic hematologic malignancies with severe cytopenias and pallor 7
• HIV testing if risk factors present 1
• Cytomegalovirus (CMV) serology 1
• SARS-CoV-2 testing (PCR and serology) to exclude MIS-C, which presents 2-6 weeks post-exposure with prolonged fever, lymphadenopathy, and significantly elevated inflammatory markers 8, 1

Critical Caveat

The presence of one viral infection does not preclude coexisting bacterial infection or malignancy - do not stop the diagnostic workup if viral testing is positive 1

Algorithmic Approach

Step 1: Immediate Actions (Day 1)

1. Peripheral blood film examination 3
2. CBC with manual differential 1, 2
3. Inflammatory markers (ESR, CRP) 1, 2
4. Comprehensive metabolic panel 1, 2
5. Blood culture 1, 2
6. Urinalysis and urine culture 1, 2

Step 2: Risk Stratification Based on Initial Results

If blood film shows blasts OR significant cytopenias:

• Urgent hematology/oncology consultation 3
• Proceed directly to bone marrow examination 3
• Do NOT delay for virology results 3

If blood film is normal but clinical suspicion remains high:

• Obtain virology screening (EBV, CMV, influenza, SARS-CoV-2) 1, 7, 5
• Consider imaging if lymph nodes >2 cm or matted 6
• Close follow-up examination within 24-48 hours, as ALL may unmask itself over time and will likely be stratified in the low-risk group if caught early 3

Step 3: Additional Considerations

• Tuberculosis testing should be performed given the 2-month duration of symptoms and lymphadenopathy 6
• Chest radiograph if respiratory symptoms or mediastinal lymphadenopathy suspected 8
• Echocardiography only if Kawasaki disease criteria met (fever ≥5 days plus 4 of 5 principal features), which is unlikely given the low-grade fever and 2-month duration 8, 1, 2

Common Pitfalls to Avoid

• Do not assume viral infection explains all findings - influenza B can present with life-threatening cytopenias mimicking leukemia, but true leukemia must be excluded first 7
• Do not delay bone marrow examination waiting for virology results if blood film or CBC suggests malignancy 3
• Do not dismiss normal initial blood counts - 5% of ALL patients are diagnosed accidentally without symptoms, and blood examinations can be subtle or within normal limits initially 4, 3
• Do not attribute lymphadenopathy solely to reactive causes without excluding malignancy, especially if nodes are >2 cm, hard, or matted 6
• Do not perform bone marrow examination if rapid hematologic recovery occurs with supportive treatment for confirmed viral infection 7