How to differentiate between sepsis and Hemophagocytic Lymphohistiocytosis (HLH) in a patient with overlapping clinical presentations?

Differentiating Between Sepsis and Hemophagocytic Lymphohistiocytosis (HLH)

Sepsis and HLH have overlapping clinical presentations, but specific laboratory and clinical features can differentiate them, with ferritin levels >10,000 μg/L being highly suggestive of HLH, particularly when accompanied by cytopenias and organomegaly. 1

Key Distinguishing Features

Clinical Features That Suggest HLH

• Persistent fever unresponsive to antimicrobial therapy
• Disproportionate inflammatory response despite appropriate treatment
• Progressive pancytopenia (most distinctive feature in adults with presumed sepsis)
• Hepatosplenomegaly/organomegaly
• Unresponsiveness to vasopressors in critically ill patients 1, 2

Laboratory Parameters That Favor HLH

• Extreme hyperferritinemia (>10,000 μg/L highly specific for HLH)
• Hypofibrinogenemia (<150 mg/dL)
• Hypertriglyceridemia (particularly in adults)
• Low C-reactive protein (CRP) relative to the severity of illness
• Elevated soluble IL-2 receptor (sCD25) 1, 3

T-Cell Activation Profiles

• HLH shows distinctive T-cell activation patterns not seen in sepsis

• 7% CD38high/HLA-DR+ cells among CD8+ T cells has strong predictive value for distinguishing HLH from sepsis

• Activated T cells in HLH are CD38high/HLA-DR+ effector cells with CD8+ T cell activation being most pronounced 4

Diagnostic Algorithm

1. Initial Screening in patients with suspected sepsis who are deteriorating despite standard care:

   • Check ferritin levels (extreme elevation >10,000 μg/L strongly suggests HLH)
   • Evaluate complete blood count for progressive cytopenias
   • Assess liver function tests, triglycerides, and fibrinogen 1, 2

2. Apply HLH-2004 Diagnostic Criteria if initial screening suggests HLH:

   • Fever
   • Splenomegaly
   • Cytopenias affecting ≥2 cell lines
   • Hypertriglyceridemia and/or hypofibrinogenemia
   • Hemophagocytosis in bone marrow, spleen, or lymph nodes
   • Low or absent NK cell activity
   • Ferritin ≥500 μg/L
   • Elevated soluble CD25 1

3. Bone Marrow Examination:

   • Most useful diagnostic test in critically ill adults
   • May initially yield false-negative results; consider repeating if clinical suspicion remains high 5

4. Consider T-cell Activation Studies where available:

   • Evaluate CD38high/HLA-DR+ cells among CD8+ T cells 4

Important Caveats and Pitfalls

• HLH and sepsis can coexist, with sepsis potentially triggering HLH 1, 5
• Hemophagocytosis is neither specific nor sensitive for HLH diagnosis 3
• Fever may be masked in ICU patients due to antipyretics, continuous renal replacement therapy, or extracorporeal life support 1
• Frequent reevaluation (at least every 12 hours) is essential in critically ill patients 1
• Delayed diagnosis is associated with increased mortality 2

Treatment Implications

The distinction between sepsis and HLH is critical as treatment approaches differ fundamentally:

• Sepsis: Antimicrobial therapy and supportive care
• HLH: Immunosuppressive therapy (often including corticosteroids, cyclosporine, and sometimes etoposide) 1, 6

For patients with suspected HLH triggered by infection:

• Specific antimicrobial treatment should be initiated
• Immunosuppression may be necessary but should be tailored to the underlying trigger
• Consultation with an HLH reference center is strongly recommended 1, 6

Special Considerations for MAS-HLH

In patients with underlying rheumatic conditions (MAS-HLH):

• High-dose glucocorticoids (IV methylprednisolone 15-30 mg/kg/day) are first-line treatment
• IL-1 inhibitors (anakinra) or IL-6 inhibitors (tocilizumab) may be particularly effective
• JAK inhibitors (ruxolitinib, baricitinib) are emerging as effective therapeutic alternatives 6

Remember that early recognition and appropriate treatment are crucial for improving outcomes in both sepsis and HLH, with mortality being particularly high in adult HLH patients.