What is the management approach for a patient with lymphocytosis and refusal to feed?

Management of Lymphocytosis with Refusal to Feed

In a patient presenting with lymphocytosis and refusal to feed, immediate evaluation for life-threatening conditions is essential, with particular attention to hemophagocytic lymphohistiocytosis (HLH), viral encephalitis, and acute T-cell leukemia/lymphoma (ATL), as these conditions require urgent intervention and have high mortality if diagnosis is delayed.

Immediate Diagnostic Priorities

Rule Out Hemophagocytic Lymphohistiocytosis First

• Test ferritin immediately in any patient with the triad of fever, cytopenia, and organomegaly who refuses to feed 1
• HLH presents with a sepsis-like phenotype including fever, cytopenia, organomegaly, and deterioration despite standard care 2, 1
• Initiate HLH-2004 diagnostic criteria testing promptly: fever, splenomegaly, cytopenias affecting ≥2 cell lines, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low/absent NK cell activity, ferritin ≥500 μg/L, and elevated soluble CD25 1
• Meeting 5 or more of 8 criteria confirms HLH diagnosis 1
• Do not delay steroid treatment if HLH is suspected, particularly if organ dysfunction is present 1

Evaluate for Viral Encephalitis

• Consider NMDA receptor antibody-associated encephalitis in patients with refusal to feed, particularly if accompanied by confusion, seizures, or behavioral changes 3
• CSF lymphocytosis (up to 500 cells/μL) is frequently present in the first phase 3
• Refusal of feeding may represent persistent explicit refusal requiring interpretation of the patient's values and previous statements 3
• Serum and CSF antibody testing should be performed; CSF is not essential as antibodies are present in serum 3

Screen for Adult T-Cell Leukemia/Lymphoma

• Evaluate for HTLV-1 infection if lymphocytosis is present with hypercalcemia, elevated LDH, or gastrointestinal symptoms 3
• Gastrointestinal involvement is frequent in ATL and may cause refusal to feed 3
• Upper gastrointestinal endoscopy is recommended in all ATL patients due to frequent GI involvement 3

Systematic Diagnostic Workup

Essential Laboratory Evaluation

• Complete blood count with differential to confirm sustained lymphocytosis >5 x 10^9 cells/L 4
• Blood smear examination for morphology: small mature lymphocytes suggest CLL; atypical lymphocytes suggest reactive process 4, 5
• Immunophenotyping to distinguish CLL (CD5+, CD23+, CD20 dim+, sIg dim+, FMC7-) from other lymphoproliferative disorders 4
• Chemistry panel including calcium, LDH, ferritin, triglycerides, and fibrinogen 3, 1
• Direct antiglobulin test to evaluate for autoimmune hemolytic anemia 3

Physical Examination Focus

• Palpate all lymph node regions; nodes >2 cm, hard, or matted suggest malignancy or granulomatous disease 6
• Epitrochlear or supraclavicular lymphadenopathy specifically indicates higher risk of malignancy 6
• Assess for hepatosplenomegaly (spleen ≥6 cm below left costal margin is massive) 3
• Evaluate for skin lesions, particularly in ATL where skin involvement is common 3

Imaging and Additional Studies

• CT scans of neck, thorax, abdomen, and pelvis if lymphoma or ATL suspected 3
• Brain MRI if encephalitis suspected (though initially normal in 90% of NMDA receptor encephalitis) 3
• Lymph node biopsy (excisional preferred) when accessible nodes are present and diagnosis unclear 3, 4

Treatment Algorithm Based on Diagnosis

If HLH Confirmed or Highly Suspected

• Begin high-dose corticosteroids immediately; do not delay for diagnostic confirmation if organ dysfunction present 1
• Add individualized, age-adjusted etoposide for severe, persistent, or relapsing disease 1
• Aggressive critical care support for multisystem organ failure 1
• Investigate underlying triggers: infections, malignancies, autoimmune diseases 1

If Viral Encephalitis Confirmed

• High-dose oral corticosteroids (0.5 mg/kg/day) combined with either IVIg (0.4 g/kg/day) or plasma exchange 3
• For NMDA receptor encephalitis, two immunosuppressive agents in combination are important 3
• Consider rituximab or cyclophosphamide for non-responders 3

If ATL Diagnosed

• For acute ATL: initiate AZT (1 g/d orally) and IFN-α (6-10 million units/day) as first-line therapy 3
• This regimen shows improved survival compared to first-line chemotherapy 3
• Treatment should never be interrupted in responding patients 3
• Response expected within 1-2 months; discontinue if no response at 2 months 3
• Antimicrobial prophylaxis with trimethoprim-sulfamethoxazole and strongyloidosis prophylaxis required 3

If CLL Diagnosed

• Watch and wait strategy with blood count monitoring every 3 months for early-stage disease (Binet A, Rai 0) 3, 4
• Treatment indicated only if: progressive marrow failure, massive/progressive splenomegaly or lymphadenopathy, progressive lymphocytosis with >50% increase over 2 months, autoimmune cytopenias, or constitutional symptoms 3
• Absolute lymphocyte count alone is NOT an indication for treatment 3, 4

Critical Pitfalls to Avoid

• Never dismiss lymphocytosis with refusal to feed as benign without excluding HLH, as missed or late diagnosis causes high mortality 2, 1
• Do not use corticosteroids empirically without considering lymphoma, as they can mask histologic diagnosis 6
• In patients unable to consent who persistently refuse feeding, establish whether this represents true refusal of life-preserving nutrition versus discomfort from a foreign object 3
• Do not delay biopsy in adults with lymphocytosis and villous atrophy on duodenal biopsy, as serology alone cannot replace tissue diagnosis for celiac disease 3
• Transient lymphocytosis in trauma patients may indicate higher injury severity and mortality risk, requiring heightened vigilance 7