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Law: Hemophagocytic Lymphohistiocytosis, a critical care conundrum!

Today we welcome Jennie Y. Law, M.D., Assistant Professor of Medicine here at the University of Maryland. Dr. Law is a true home grown talent, doing both her medical school and medicine residency here at the University of Maryland before leaving to do her fellowship in Hematology/Oncology at UT Southwestern down in Dallas, Texas. Today she is here to talk about Hemophagocytic Lymphohistiocytosis (HLH), a topic that has puzzled internists, intensivists, and hematologists alike. Review the pathophysiology, learn the criteria for diagnosis – both the HLH 2004 criteria and the newer HSCORE – and go through her treatment algorithms. See why and how you may be overlooking this important diagnosis in your patients!


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

hlh

        • 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

Suggested Reading

  1. Halacli B, Unver N, Halacli SO, Canpinar H, Ersoy EO, Ocal S, Guc D, Buyukasik Y, Topeli A. Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care. 2016 Oct;35:185-90. [Pubmed Link]
  2. Nikiforow S, Berliner N. The unique aspects of presentation and diagnosis of hemophagocytic lymphohistiocytosis in adults. Hematology Am Soc Hematol Educ Program. 2015;2015:183-9. [Pubmed Link]
About the Author

Jim Lantry

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Just your average critical care doc: Wandering the ED and ICUs for the USAF down in the San Antonio Military Medical Center, traveling the globe to cannulate for ECLS wherever the need arises, and trying to keep up with great minds of today. E: JlantryMD@gmail.com

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