Law: Hemophagocytic Lymphohistiocytosis, a critical care conundrum!

Clinical Pearls (thanks to Meagan Pate)

• Clinical syndrome of excessive immune activation
  • Manifests with signs/symptoms of extreme inflammation
• Diagnostic dilemma
  • Rare entity with variable clinical presentations
  • Unique pattern of often non-specific clinical findings
  • Can encompass a wide spectrum of clinical conditions which converge to cause extreme pathological inflammation
  • Normal physiologic mechanisms unable to dampen immune response leads to end-organ damage
• 2 broad groups
  • Primary or familial HLH
    • Infants with pre-disponsing immune dysfunction
    • Autosomal recessive
      • Fixed defect of cytotoxic function
      • Usually requires infectious trigger to manifest symptoms
    • Incidence
      • Swedish population studies: 1.2 cases per 1M (1991), but hard to extrapolate
      • Texas study: 1 per 100k – higher than previously reported (2010)
        • Increased in various ethnic groups
      • Important to identify a possible genetic mutation
        • Impacts likelihood of recurrence
        • Determines need for hematopoietic stem cell transplant
        • Anticipates risk of HLH in other family members
      • Diagnosis
        • Typically infants in first 2 yrs of life
        • However, increasing number of case reports of adult onset primary HLH
          • Retrospective review with hypomorphic mutations in familial HLH-causing genes
            • Altered gene leads to residual level of activity
            • Thus, later onset of clinical symptoms and more indolent course
        • Importantly, older age no longer excludes diagnosis of primary HLH
  • Secondary HLH
    • Older patients
    • Significant immune activation due to variety of antigen challenges
      • Infection
        • Infection doesn’t help distinguish between primary or secondary – infection is predominant trigger in both
        • Viruses most common infectious cause
          • EBV most frequent
          • CMV
          • HSV
          • In patients with HIV, HLH can be associated with initiation of HAART (IRIS)
            • Also, histoplasmosis, PCP, pneumococcal
        • Malignancy, especially hematologic
          • Malignancy is the most common etiology in adults with acquired HLH
          • Can occur before or during treatment of malignancy
        • Rheumatologic/autoimmune disease
        • Idiopathic
      • No family history or known genetic cause
      • Most common cause of death is multisystem organ failure
    • Specific categorization as primary vs secondary in acute setting is not clinically imperative
• Diagnosis
  • Scoring systems
    • HLH-2004

• Developed to standardize clinical trial enrollment
• Incorporates known pathologic mutations
  • Limitations
    • Sensitivity and specificity not prospectively validated
    • Criteria derived solely from pediatric population
    • Doesn’t capture clinical features of HLH, e.g. liver failure, DIC
• HSCORE
  • Developed in response to limitations of HLH-2004
  • First validated score for diagnosis of secondary HLH
    • Easy online scoring system found here
    • Additional prospective validation still needed
• Bone marrow biopsy
  • Finding hemophagocytosis is not pathognomonic
    • Not required for diagnosis
    • Often not detected at initial presentation
  • Important not to make treatment decision solely on bone marrow result
• Ferritin
  • Physiologic role
    • Manages iron stores
    • Positively regulates transcription in response to oxidative stress
    • Pro-inflammatory signaling
  • Multiple studies looking at various ferritin levels
    • Allen et al (2008)
      • Ferritin > 500: 100% sensitive but less specific
      • Ferritin > 10,000: 90% sensitivity, 96% specificity
      • Study only in pediatrics
    • Schram et al (2015)
      • Ferritin > 50,000 seen in a variety of conditions, e.g. renal failure, hepatocellular injury, infection, hematologic malignancies in the adult population
      • However, it does have a high negative predictive value in both adults and children
    • Grange et al (2016)
      • Ferritin > 4780 significantly predicted ICU mortality
      • Did not use HLH-2004 criteria; broadly defined population “MICU patients with hemophagocytosis”
• Treatment of primary HLH
  • Mainstay is chemo-immunotherapy
  • HLH-94
    • Etoposide + steroids + intrathecal MTX to induce remission
      • All primary HLH patients relapsed and died
      • Cure only achieved through allogeneic bone marrow transplantation
      • Improvement in survivial with combination of chemo-immunotherapy and transplant for primary
        • Benefit for patients with secondary HLH – no transplant needed
  • HLH-2004
    • Ongoing trial designed to improve initial control of HLH
      • Still only pediatric patients
    • Initial therapy
      • Cyclosporine added to improve treatment intensity without inducing additional myelotoxicity
      • HLH-94 didn’t answer whether or not IT therapy beneficial
    • Still pending results; until then, HLH-94 recommended for treatment
  • Alternative regimens
    • Antithymocyte globulin
      • Used in combination with cyclosporine, steroids, and intrathecal MTX
      • Mahlaoui et al (2007): overall survival 55%, earlier relapses more common
      • No RCT comparing ATG versus HLH-94
    • Alemtuzumab (salvage therapy)
      • Paucity of validated studies examining choice of therapy in refractory HLH
      • Monoclonal antibody against CD52
• Treatment of secondary HLH
  • Insufficient clinical data to determine which patients with secondary HLH need “full” treatment protocol
  • Clinically stable patients with identifiable underlying condition:
    • May respond to treatment of underlying condition alone
      • g. EBV-triggered HLH -> successfully treated with weekly Rituximab
    • May only require treatment with steroids
    • But, clinical deterioration should prompt initiation of HLH-specific therapy immediately
  • Initiation of treatment often clinically counterintuitive
    • Starting potent immunosuppression in setting of uncontrolled infection/inflammatory process
• Future directions
  • Ongoing clinical trials recruiting patients with acquired HLH
    • Tocilizumab to reduce high cytokine levels
  • German adult HLH registry
    • Offers consultations for physicians caring for adult HLH patients