In a 12‑year‑old boy with a 20‑day fever, markedly elevated C‑reactive protein, elevated erythrocyte sedimentation rate, normal procalcitonin, mild leukocytosis and anemia, does the finding of increased alpha‑1 and alpha‑2 globulin fractions on serum protein electrophoresis reflect an acute‑phase response rather than a monoclonal protein disorder?

Elevated Alpha-1 and Alpha-2 Globulins Reflect Acute-Phase Response

In this 12-year-old boy with prolonged fever, markedly elevated CRP, elevated ESR, and normal procalcitonin, the increased alpha-1 and alpha-2 globulin fractions on serum protein electrophoresis represent an acute-phase inflammatory response, not a monoclonal protein disorder. 1, 2

Understanding the Electrophoretic Pattern

Acute-Phase Response Characteristics

• Alpha-1 and alpha-2 globulins are positive acute-phase proteins that increase during inflammation, including C-reactive protein, α1-acid glycoprotein (orosomucoid), α1-antitrypsin, haptoglobin, fibrinogen, and ceruloplasmin. 3, 4, 5

• These proteins display predictable elevations in response to acute inflammation, malignancy, trauma, necrosis, infarction, burns, and chemical injury—creating a polyclonal pattern on electrophoresis. 2

• In pediatric patients, acute and chronic inflammatory responses produce specific pathological electrophoretic patterns characterized by elevated alpha-1 and alpha-2 fractions without monoclonal spikes. 1

Distinguishing From Monoclonal Disorders

• A monoclonal gammopathy produces a homogeneous spike-like peak in the gamma-globulin zone, not elevations in the alpha fractions. 2

• Monoclonal gammopathies (multiple myeloma, Waldenström's macroglobulinemia) are exceedingly rare in children and would not present with this clinical picture of acute inflammation. 6, 2

• The presence of markedly elevated CRP alongside elevated ESR confirms active inflammation, which is the expected driver of alpha globulin elevation. 6, 4

Clinical Context Supporting Inflammatory Etiology

Laboratory Pattern Analysis

• Normal procalcitonin with elevated CRP and ESR suggests a non-bacterial inflammatory process rather than acute bacterial sepsis. 6

• The 20-day fever duration with persistent inflammatory markers indicates either subacute bacterial infection, viral infection with prolonged inflammatory response, or autoimmune/autoinflammatory disease. 6, 1

• Mild leukocytosis and anemia are consistent with chronic inflammation, where anemia represents the anemia of chronic disease. 6

Differential Diagnosis Considerations

• Kawasaki disease should be strongly considered in this age group with prolonged fever and markedly elevated inflammatory markers (ESR commonly ≥100 mm/h). 6, 7

• Infective endocarditis must be excluded given the prolonged fever—blood cultures and echocardiography are essential. 6

• Multisystem inflammatory syndrome in children (MIS-C) should be screened for if there is recent SARS-CoV-2 exposure. 7

• Juvenile idiopathic arthritis or other autoinflammatory conditions demonstrate ESR elevation in 95-98% of cases and can present with fever as the predominant symptom. 8

Recommended Diagnostic Approach

Immediate Evaluation

• Obtain blood cultures (if not already done) to exclude bacterial endocarditis or occult bacteremia, especially given the prolonged fever. 6, 8

• Perform echocardiography to evaluate for vegetations (endocarditis) or coronary artery abnormalities (Kawasaki disease). 6

• Assess for Kawasaki disease criteria: conjunctival injection, oral changes, rash, extremity changes, and cervical lymphadenopathy. 6

Additional Laboratory Testing

• Complete metabolic panel to assess for renal involvement, liver dysfunction, or azotemia that could affect inflammatory marker interpretation. 7, 8

• Serum ferritin if Still's disease (systemic juvenile idiopathic arthritis) is suspected, as it is markedly elevated in this condition. 8

• Rheumatoid factor and anti-CCP antibodies only if joint symptoms develop, as these are not indicated in isolated fever. 8

Follow-Up Strategy

• Repeat inflammatory markers (CRP, ESR) in 2-4 weeks if no diagnosis is established and symptoms persist, to determine if elevation is transitory or persistent. 7, 8

• Do not pursue monoclonal protein workup (immunofixation, serum free light chains) in this clinical context, as the electrophoretic pattern and clinical presentation are inconsistent with monoclonal gammopathy. 6, 2

Critical Pitfalls to Avoid

• Do not misinterpret polyclonal alpha globulin elevation as a monoclonal disorder—monoclonal proteins produce sharp spikes in the gamma region, not broad-based elevations in alpha fractions. 2

• Do not delay evaluation for serious infections (endocarditis, osteomyelitis) or Kawasaki disease while pursuing unnecessary monoclonal protein studies. 6

• Remember that anemia and hypergammaglobulinemia can artificially elevate ESR, but in this case, the markedly elevated CRP confirms true inflammation. 7, 4

• CRP rises and falls more rapidly than ESR, making it the superior marker for monitoring acute inflammatory changes and treatment response. 6, 8, 4