Can secondary hemophagocytic lymphohistiocytosis (sHLH) occur in the context of bacterial sepsis?

Secondary Hemophagocytic Lymphohistiocytosis Can Occur in Bacterial Sepsis

Yes, secondary hemophagocytic lymphohistiocytosis (sHLH) can definitely occur in the context of bacterial sepsis, and sepsis can serve as a trigger for HLH. 1 This relationship is increasingly recognized but remains underdiagnosed in critical care settings.

Pathophysiological Connection Between Sepsis and sHLH

• HLH and sepsis share overlapping hyperinflammatory pathophysiologic characteristics, making them difficult to distinguish in some patients 2
• The Blood journal guidelines specifically note that "HLH, MODS (multiple organ dysfunction syndrome), and sepsis can coexist, with sepsis serving as the possible HLH trigger" 1
• This condition is sometimes referred to as "hyperinflammatory sepsis" or "MAS-like" sepsis 1

Evidence of Bacterial Triggers for sHLH

• Multiple case reports document bacterial sepsis as a trigger for sHLH:
  • Group B Streptococcus has been reported as a cause of fatal HLH 3
  • Escherichia coli has been identified as a common bacterial trigger, accounting for 30% of bacterial infections associated with HLH in one study 4
  • Serratia marcescens bacteremia has been documented as a potential trigger 5
  • Overall, bacterial infections were found to be the precipitating factor in 76% of patients with hemophagocytosis in the ICU 4

Clinical Presentation and Diagnostic Considerations

HLH should be suspected in critically ill patients with:

• Persistent fever unresponsive to antimicrobials
• Unexplained cytopenias (particularly progressive pancytopenia)
• Organomegaly (especially splenomegaly)
• Unresponsiveness to vasopressors
• Organ failure not responding to appropriate therapy 1, 2

Diagnostic Approach

In patients with suspected or confirmed sepsis who demonstrate disproportionate inflammatory response:

1. Screen using HLH-2004 criteria (need 5 of 8):

   • Fever
   • Splenomegaly
   • Cytopenias (affecting ≥2 cell lines)
   • Hypertriglyceridemia and/or hypofibrinogenemia
   • Hemophagocytosis in bone marrow, spleen, or lymph nodes
   • Low/absent NK cell activity
   • Ferritin ≥500 ng/mL
   • Elevated soluble CD25 1, 6

2. Pay particular attention to ferritin levels:

   • Serum ferritin >2,000 μg/L has been identified as a significant predictor of mortality in HLH patients 4
   • Dramatically rising serial ferritin measurements should raise suspicion for HLH 7

Management Considerations

• For bacterial sepsis-triggered HLH:

  • Focus on treating the underlying bacterial infection with appropriate antimicrobials 1
  • Avoid full immunosuppressive HLH-94 protocol in cases clearly triggered by bacterial pathogens 1
  • Consider short transient treatment of overt inflammation with corticosteroids in selected cases 1

• For refractory cases:

  • Reevaluate clinical condition frequently (at least every 12 hours) 1
  • Consider additional HLH-directed therapy if not responding to antimicrobial treatment and supportive care

Pitfalls and Caveats

• HLH is likely underdiagnosed in critical care settings, with many cases mislabeled as sepsis with MODS 7
• Fever, a key diagnostic criterion, may be masked in ICU patients due to antipyretics, continuous renal replacement therapy, or extracorporeal life support 1
• Bone marrow aspiration is a crucial diagnostic test but may yield false-negative results initially 2
• Without early recognition and treatment, mortality is extremely high, with >10% of patients dying within two months of diagnosis 6

The overlap between sepsis and HLH creates a diagnostic challenge, but recognition of this entity is crucial as the mortality rate remains high (43-57% in ICU settings) 7, 4. Early consideration of HLH in patients with sepsis who demonstrate disproportionate inflammatory responses can lead to more appropriate management strategies.