What are the complications of Hemophagocytic Lymphohistiocytosis (HLH)?

Complications of Hemophagocytic Lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) can lead to rapid multi-organ failure and death without prompt recognition and treatment, with more than 10% of patients dying within two months of diagnosis due to severe complications including visceral organ hemorrhage, opportunistic infections, and multi-organ dysfunction. 1

Major Complications

Hematologic Complications

• Coagulation disorders (68% of critically ill HLH patients) 2
  • Hypofibrinogenemia (<1.5 g/L) in 52% of patients
  • Prolonged prothrombin time in 44% of patients
  • Disseminated intravascular coagulation (DIC) in 50% of patients
• Severe bleeding (22% of patients) 2
  • Fibrinogen levels <2 g/L significantly associated with severe bleeding
  • Can progress to hemorrhagic shock (fatal in some cases)
• Cytopenias (universal finding) 3, 1
  • Thrombocytopenia (present in all patients)
  • Neutropenia leading to increased risk of opportunistic infections

Organ System Failure

• Liver dysfunction 3, 1
  • Elevated liver enzymes (grade ≥3 increases in bilirubin, AST, ALT)
  • Hepatic failure
• Renal dysfunction 3
  • Oliguria
  • Elevated serum creatinine
  • Need for renal replacement therapy
• Respiratory failure 3, 1
  • Pulmonary edema
  • Acute respiratory distress syndrome
  • Need for mechanical ventilation
• Cardiovascular complications 1, 2
  • Shock requiring vasopressors
  • Myocardial dysfunction

Neurological Complications

• Central nervous system involvement 1, 4
  • Headaches
  • Vision disturbances
  • Gait abnormalities
  • Seizures
  • Altered mental status
  • Potential for long-term neurological sequelae

Risk Factors for Poor Outcomes

The following factors are associated with higher mortality in HLH patients 2:

• Fibrinogen level <2 g/L (OR 2.42 [1.08-5.41])
• SOFA score >6 (OR 3.04 [1.32-6.98])
• Age >46 years (OR 2.26 [1.02-5.04])

Clinical Course and Mortality

• HLH presents as a sepsis-like syndrome that may rapidly progress to terminal multiple organ failure 3
• Hospital mortality rate is approximately 44% in critically ill patients 2
• Patients with coagulation disorders require more life support measures and have higher mortality rates 2
• Delayed diagnosis and treatment significantly worsen prognosis 1

Special Considerations

HLH Following CAR T-cell Therapy

• Occurs in approximately 3.5% of patients treated with CAR T-cell therapy 3
• May present with features overlapping with cytokine release syndrome (CRS)
• Can be tocilizumab-refractory, particularly in late-onset cases 3

Primary vs. Secondary HLH

• Primary (genetic) HLH is more common in children but can occur in adolescents and young adults 3
• Secondary (acquired) HLH is more common in adults and is typically triggered by:
  • Infections
  • Malignancies (particularly lymphomas)
  • Autoimmune disorders
  • Therapeutic interventions (e.g., CAR T-cell therapy) 3, 1

Clinical Pitfalls

1. Diagnostic challenges: HLH can mimic sepsis or multiple organ dysfunction syndrome, leading to delayed diagnosis 3
2. Laboratory interpretation: While ferritin >10,000 μg/L is highly specific for HLH in children, hyperferritinemia is less specific in adults 1
3. Treatment considerations: Pediatric protocols (HLH-94, HLH-2004) may result in overtreatment and unnecessary toxicity in adults 3
4. Bleeding risk assessment: Monitoring fibrinogen levels is crucial, as levels <2 g/L significantly increase bleeding risk 2

Early recognition and aggressive management are essential to prevent irreversible organ damage and improve survival in patients with HLH.