Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled inflammation caused by excessive activation of T cells and macrophages. It can be primary, caused by genetic defects, or secondary to infections, malignancies, or rheumatologic conditions. The key features include fever, cytopenias, hepatosplenomegaly, and hyperferritinemia. Treatment involves controlling triggers, immunosuppression with steroids, and definitive therapy with bone marrow transplant or etoposide in severe cases. Anakinra and emapalumab show promise for macrophage-associated syndrome in systemic juvenile idiopathic arthritis.

1. MAS the 4th be with you
MAS and HLH
No conflicts of interest to disclose.
Devanshu Verma
May 4, 2022

2. What is HLH?
• Hemophagocytic lymphohistiocytosis
= Lots of lymphocytes that eat red blood cells
Macrophage with
ingested RBCs

3. Not a single disease but a syndrome
• Clinical manifestations of various conditions
• Manifest with uncontrolled systemic inflammation due to excessive
activation and proliferation of T cells and well-differentiated non-
neoplastic macrophages
• Mostly CD8+ T cells
• Mostly CD163+ macrophages
• CD163 = Macrophage hemoglobin scavenger receptor
• Hyperinflammation causes tissue damage

4. COVID inspired many articles

5. HLH can be Primary or Secondary
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315691/pdf/296_2020_Article_4636.pdf

6. Summary of Triggers
• Infections – EBV
• Flare of underlying inflammatory condition (sJIA, SLE, Kawasaki)
• Developing malignancy
• Defects of perforin gene (among others) in cytosolic secretory
pathway  HLH

7. Familial HLH – Perforin protein perforates
infected cells
Defect in Perforin gene
Defective cytotoxicity
Familial HLH type 2

8. Immune
Synapse –
Perforin/
granzyme

9. Familial Hemophagocytic Lymphohistiocytosis
(FHL)

10. Immunodeficiency Associated HLH

11. Chediak-Higashi = microtubule dysfunction
Albinism because
defective LYST gene 
cannot traffic
melanocytes 
albinism
https://creativemeddoses.com/topics-list/chediak-higashi-syndrome-visual-maps/

12. X-linked Lymphoproliferative Disorder 1
• Deficiency of SAP (SLAM
Associated Protein)
• Gene SH2D1A on X chromosome
• Catastrophic EBV infection  HLH
• Intestinal lymphoma
• Vasculitic lesions in lungs, brain

13. Medium & Small Vessel Vasculitis in XLP1
Case of HLH in 13-month-old boy treated and stable
until age 10 that progressed to low IgG on IVIG, leg
atrophy from denervation neuropathy, negative
ANCA, ANA progressed to resp failure requiring
intubation and passed after 1 month. Autopsy
revealed widespread microscopic necrotizing arteritis
resembling PAN including in CNS, cardiac, renal, testes
and pancreas, and chorioretinitis. Found to have
altered SAP gene and diagnosed with XLP.
https://pubmed.ncbi.nlm.nih.gov/11133747/

14. X-linked Lymphoproliferative Disorder 2
• Deficiency of XIAP
• T cells deficient in XIAP are
defective in pathogen clearance
• Loss of inflammasome clearance
• Deficient XIAP = dysregulated gut
innate immunity = 30% boys
develop IBD

15. North American Consortium for Histiocytosis
(NACHO) - 2019
https://pubmed.ncbi.nlm.nih.gov/31339233/

16. Life Threatening Complication of sJIA
• Macrophage activation syndrome (MAS) = form of HLH
• 10% of sJIA patients
• Subclinical MAS may be in 30-40% of active sJIA
https://juvenilearthritisnews.com/2020/02/14/actemra-can-mask-
macrophage-activation-syndrome-systemic-jia-study-reports/

17. Simple Video of HLH
https://vimeo.com/406196004
https://vimeo.com/gamifant?embedded=true&source=owner_name&owner=110035876

18. Consider MAS in any sJIA patient if:
• Decreasing fibrinogen  decreasing ESR
• Increasing CRP and D-dimers
• Decreasing WBC and platelet counts
• Increasing LFTs
• Increasing triglycerides
• Ferritin > 3000 to 10000 ng/mL
• Increasing soluble alpha chain of IL-2 receptor (sCD25)
• Increasing CD163. Because CD163 = Macrophage hemoglobin
scavenger receptor

19. Common Manifestations
• High fevers
• Hepatosplenomegaly
• Lymphadenopathy
• Severe cytopenias
• Liver dysfunction
• Coagulopathy  decreasing fibrinogen + increasing PT, PTT  DIC
• Hypertriglyceredemia
• CNS involvement = seizures

20. Less likely MAS in sJIA if:
• Normal sIL-2R
• High WBC
• No cytopenias
• High fibrinogen
• Lymphadenopathy (may be malignancy)
• Normal LFTs

21. Symptoms in Relation to Cytokines
• Fever  IL-1 & IL-6
• Pancytopenia  TNFa and IFNy
• Hypertriglyceridemia  TNFa inhibits LPL
• Hypofibrinogenemia  Macrophages activate
plasminogen  hyperfibrinolysis
• Elevates sIL-2  Activated lymphocytes
• High LFTs, organ Sx  Organ infiltration by lymphocytes

22. Why is Ferritin High?
https://pubmed.ncbi.nlm.nih.gov/17968951/
Macrophage surface 
Enzyme activation to
break down heme 
RBCs take up by
macrophages 
 Need more ferritin to
transport excess iron to
bone marrow

23. CD8 T Cells
Cycle of activation and
recruitment of more
macrophages
Negative feedback when
antigenic stimulation is
eliminated (via clearance
of infected cells)

24. Lack of negative feedback in HLH
Self damaging cycle of
proliferation

26. HLH Diagnostic
Criteria came
from research
inclusion criteria

27. Newer MAS Guidelines in sJIA in 2016 from
ACR/EULAR
Febrile patient with known/suspected sJIA
• Ferritin > 684
AND At least 2 of:
• Platelets < 181
• AST > 48
• Triglycerides > 156
• Fibrinogen < 360
https://pubmed.ncbi.nlm.nih.gov/26314788/

28. Various
Diagnostic
Criteria

30. General Approach
• Identify that there is hyperinflammation (ferritin, CD25)
• Find and treat any triggers (infection, flares)
• Treat the hyperinflammation (steroids)
• Rule out any immune system defects
• Immunoreplacement if needed

31. Find Triggers
• HLH is not occur spontaneously
• Each flare may have the same or separate trigger
• In addition to infections, look for malignancy  consider PET-CT
• May have underlying immune defect  check perforin (FHL2), SAP (X-
linked lymphoproliferative 1), XIAP ((X-linked lymphoproliferative 2)

32. NACHO Strategy

33. Review of Pathway for HLH

34. Biopsy
• May not be positive early in disease course
• Activated macrophages staining with CD163+ (Heme scavengers
receptor) showing hemophagocytosis in bone marrow

35. Treatment Phase 1: Induction
• Acutely reign-in out of control immune activation
• Treat underlying infectious triggers
• Limit organ damage
1) Supportive care
1) Antibiotics/fungals/virals
2) Transfusions  RBC, platelets, FFP, cryoprecipitate
2) Immunosuppression
1) Steroids: dexamethasone 10 mg/m2/day over 4 weeks or IV SoluMedrol
pulse (30 mg/kg) x 3 days
1) Dexamethasone has better CNS penetration in case of seizures, etc
2) DMARDs

36. Treatment Phase 2: Definitive Therapy
• Prevent future recurrences
• Correct underlying immune defect, if possible, with bone marrow
transplant

37. Treatment Options
Canakinumab and tocilizumab
are NOT effective

38. HLH-94 Protocol
• Etoposide = 150 mg/m2 per dose
• If CNS involvement  weekly intrathecal methotrexate (6 – 12 mg
depending on age) and hydrocortisone until 1 week after resultion
of CNS symptoms

39. Give Enough Treatment to Control Disease
and Prevent Damage
• May not need full HLH-94 based induction
• May be able to treat with less aggressive therapy with steroids +/-
anakinra alone

40. Survival

41. IFN-gamma higher in MAS than active sJIA
https://ard.bmj.com/content/76/1/166.long

42. No correlation with IL-6 and TNFa in MAS vs
active sJIA
https://ard.bmj.com/content/76/1/166.long
Canakinumab and tocilizumab
are NOT effective

43. Tocilizumab not really effective for MAS
• Study compared 12 patients on Actemra (age 8.5 years average) with
18 untreated participants (average age 5.5 years).
• Of patients on TCZ, two were diagnosed with full-blown MAS
• Remaining 10 individuals were diagnosed with possible MAS
• Of 18 untreated patients, 10 had full-blown MAS and eight possible
MAS
• Full-blown MAS was defined as the time of most severe MAS.
• Possible MAS referred to characteristic laboratory features without
clinical features of MAS

44. Uncertain validity in using 2016 classification criteria in TCZ
treated patients – absence of fever or insufficient increases in
ferritin compared to untreated patients

45. Anakinra
https://www.thelancet.com/journals/lanrhe/article/PIIS2665-9913(20)30096-5/fulltext

46. Simplified
Algorithm

47. Even
Simpler
Algorithm
https://www.histiocytosisuk.org/wp-content/uploads/2020/01/Anakinra-protocol-UCLH.pdf
https://pubmed.ncbi.nlm.nih.gov/29481673/
Etoposide 150mg/m2 twice weekly for two weeks then
weekly for 6 doses
IV SoluMedrol 1g daily for 3-5 days
IVIG 1g/kg daily for 2 days, repeat in 14 days
1-2mg/kg daily, max 8mg/kg/day

48. Treatment Options

49. Emapalumab – IFNy monoclonal Ab
https://vimeo.com/406195638

50. Ruxolitinib

51. Ruxolitinib in HLH

52. References
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315691/pdf/296_2
020_Article_4636.pdf
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334831/
• https://www.jni-journal.com/article/S0165-5728(17)30114-5/fulltext
• https://www.thelancet.com/journals/lanrhe/article/PIIS2665-
9913(20)30096-5/fulltext
• https://pubmed.ncbi.nlm.nih.gov/17968951/
• https://pubmed.ncbi.nlm.nih.gov/26314788/

53. References
• https://pubmed.ncbi.nlm.nih.gov/29481673/
• https://pubmed.ncbi.nlm.nih.gov/31732958/

54. MAS