Hemophagocytic lymphohistiocytosis hlh presentation Hemophagocytic lymphohistiocytosis presentation hlh

1. Hemophagocytic
lymphohistiocytosis
Ranya H Albar PGY3

2. Outlines
Introduction
Terminology
Etiology
Pathophysiology
Epidemiology
Clinical features
Investigation
Diagnostic criteria
Differential diagnosis
Treatment
Summary
Reference

3. Introduction
Hemophagocytosis:
• Phagocytosis by macrophages of erythrocytes, leukocytes,
platelets & their precursors in BM & other tissues
Uncommon
Aggressive & life threatening
Hyperinflammatory syndrome➝ high stimulated but ineffective immune
process
MC* 0-18 month, but can present in all ages
Familial, sporadic & environmental

4. Terminology
In 1952 Farquhar & Claireaux:
• Familial hemophagocytic reticulosis
Other terms:
• Primary
• Secondary
• Macrophage activation syndrome

5. Etiology
Secondary (acquired, sporadic)
Infectious
Autoimmune
Malignant disease
Immunosuppression/Organ transplant
Primary (genetic)
Familial: (known/unknown gene defect)
Immune deficiency syndrome
Genes
FHL 1-5
GS2
HSP2
XLP1
BLOC1S6
CD27
ITK
LYST
MAGT1
SLC7A7
XIAP

6. Primary VS. secondary
Points Primary Secondary
Age < 1 yr > 1 yr
Hx Similar Similar
Labs Similar Similar

7. Primary
Young age
1.2/1,000,000 per year
Median survival < 2 month if
untreated
Trigger 1ry ➝ infection
Divided:
• Mutations at FHL loci
• Immunodeficiency
syndromes

8. Continue
primary
Mutations at FHL loci
Several HLH gene mutations map to loci that
code for elements of the cytotoxic granule
formation & release pathway
Labeled familial hemophagocytic
lymphohistiocytosis (FHL) loci.

9. Continue primary
FHL1 ➝ Gene not yet described ( 9q21.3-22)
FHL2 ➝ Perfoin (PRF1, 10q21-22)
FHL3 ➝ Munc 13-4 (UNC13D, 17q25)
FHL4 ➝ Syntaxin 11 (STX11, 17q24)
FHL5 ➝ Munc 18-2 (STXBP2, 19p13)

10. Continue
primary
Immunodeficiency syndromes
Several mutations that cause congenital
immunodeficiency syndromes are also
associated with ⇈ incidence of HLH.

11. Continue primary
Griscelli syndrome 2 ➝ RAB27A
Chediak-Higashi syndrome ➝ LYST
X-Linked proliferative syndrome. ➝ SAP
XMEN disease ➝ MAGT1
Hermanski-pudlak syndrome 1 ➝ HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6,
DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN)
Lysinuric protein intolerance ➝ LPI; MIM 222700
Interleukin-2-inducible T cell kinase (ITK) deficiency
CD27 (TNFRSF7) deficiency
Chronic granulomatous disease

12. Griscelli syndrome 2
Partial
albinism
AR
Immunodeficienc
y
Malnutritio
n

13. Chediak-Higashi
syndrome
Albinis
m
Immunodeficiency Neuropathy
AR

14. Continue primary
Genotype-phenotype correlations
• Patients with HLH gene mutations tend to present at a younger age than
those without mutations.
• The affected gene & specific type & site of mutation may affect the age of
presentation and clinical features
• But there is controversy regarding the contribution of hypomorphic
mutations to development of HLH

15. Secondary
SECONDARY EXAMPLE
Infection Viral, Bacterial, Parasites, Fungi
Autoimmune AKA: macrophage activation syndrome (SLE,RA)
Malignant Leukemias, Lymphoma
Immunosuppression/ organ
transplant
Post chemotherapy, post transplant,
immunosuppresent

16. Pathophysiology
 Immunologic abnormalities
 Excessive inflammation & tissue destruction ➝ abnormal
immune activation.
 The hyperinflammatory/dysregulated immune state ➝
absence of normal downregulation by activated
macrophages & lymphocytes

17. Continue pathophysiology
Cell Action
Macrophages  professional antigen
 Derived ➝ circulating monocytes
 Present foreign antigens to lymphocytes
 In HLH:
• Activated & secrete ➝ ⇈ cytokines
• Severe tissue damage. ➝ organ failure
Hemophagocytosis  Engulfment. ➝ host blood cells by macrophages
 Characterized ➝ RBC, PLT, or WBC (fragments of these cells)
 Observed in biopsies of immune tissues (lymph nodes, spleen, liver,
BM)
 A marker of excessive macrophage activation & supports the diagnosis
 Alone its neither pathognomonic nor required for the diagnosis of HLH.

18. Continue pathophysiology
Cell Action
Cytokine storm  Persistent activation of macrophages, NK cells, & CTLs
➝⇈ cytokine production (cytokine storm)
 Responsible for multiorgan failure & ⇈ mortality
 ⇈ Cytokines found in plasma include:
• Interferon gamma (IFNˠ)
• Tumor necrosis factor alpha (TNF𝛼)
• Interleukins (IL) : IL-6, IL-10, IL-12 &
soluble IL-2 receptor (CD25)

19. Continue pathophysiology
Cell Action
Natural killer
Cytotoxic lymphocytes
 10-15 % lymphocytes.
 Eliminate damaged, stressed, or infected host cells ➝ macrophages
 Typically in response to viral infection or malignancy
 Activated T lymphocytes that lyse autologous cells such as macrophages
 Most CTLs express CD8
 Both fail to eliminate activated macrophages
 ⇈ macrophage activity & highly elevated levels of interferon gamma & other
cytokines.
Toll-like receptor  Non-antigen-specific receptors on the surface of NK cells that are activated
➝ bacteria, fungi, viruses, or mycoplasma.
 Genes associated with TLR/interleukin 1 receptor (IL-1R) signaling are
upregulated ➝ juvenile idiopathic arthritis & MAS

20. Continue
pathophysiolog
y
Triggers
Immune
activation
Infection (EBV, Kawasaki disease)
Immune
inhibitors
Nivolumab & ipilimumab may be linked
But the incidence has not been defined
Excessive
cytokine
release
Chronic granulomatous disease 3/17
Immune
deficiency
Inherited syndromes
Malignancy
Rheumatologic disorders
Infection (HIV)

21. Epidemiology
PEDIATRIC
SYNDROME
INFANTS MC ♂ = ♀ IN ADULTS
♂>♀
1/3000
ADMITTED
TERTIARY
CARE
¼ FAMILIAL

22. Continue
epidemiology
A review of 224 North American
patients with HLH mutations
found the following distribution
of specific mutations according
to ethnicity:
Ethnicity Mutation
Whites UNC13D (47 %), STXBP2 (22
PRF1 (20 %)
Blacks PRF1 (98 %)
Hispanics PRF1 (71 %), UNC13D (17 %)
Arabs PRF1 (36 %), UNC13D (27 %),
STXBP2 (18 %)
Turkish origin PRF1, UNC13D, STX11
Japanese PRF1 mutations
Saudi Arabia, United Arab Emirates
&Turkey
STXBP2 mutations

23. Clinical
presentation
Febrile illness associated
with multiple organ
involvement
Initial S&S can mimic
common infections
Clinical features are similar
regardless of whether an
underlying genetic defect
has been identified
Common Less common
Prolonged fever Lymphadenopathy
Hepatosplenomegaly Rash
Neurological Sx: seizure, CN
palsies
Jaundice

24. Investigatio
n
Initial tests
CBC with differential, chemistry
Coagulation
Serum ferritin
LFT, RFT
Serum triglycerides
Full septic
Serology & PCR
BM evaluation
ECG, EEG & CXR
MRI, CT & abdomen US

25. Continue
investigation
Specialized tests
Immunological profile
Genetic testing
Human leukocyte antigen testing

26. Diagnostic
criteria
In HLH-94, diagnosis was
based on 5 criteria
In 2004 added 3
additional criteria, total 8
The HLH-2004 study, which included 369 patients, reported the
following clinical finding:
Soluble CD25 evaluation 97%
Fever 95%
Ferritin >500 mcg/L 94%
Bicytopenia 92%
Hypertriglyceridemia or hypofibrinogenemia 90%
Splenomegaly 89%
Hemophagocytosis 82%
Low/absent NK cell activity 71%

27. Continue Diagnostic criteria
Fever >38.5 for ≳ 7 D
Splenomegaly > 3 cm LCM
Cytopenia -Hb < 9.0 g/dL
-PLT < 100,000/ µL
-ANC < 1000/ µL
Ferritin > 500µg/L
Hypertriglyceridemia/hypofibrinogenemia -Fasting triglycride > 2mmol/L or >3SD above normal to age
-Fibrinogen <1.5g/L or >3SD below normal to age
Hemophagocytosis Demonstrated in BM, spleen, LN no evidence for malignancy
sCD25 Soluble CD25 (sIL-2 receptor)>2400 U/mL
NK cell activity Low/absent

28. Continue
If 4/8 criteria & clinical suspicion is high, initiate appropriate
Tx
HLH
 5/8 criteria
fulfilled
 Molecular Dx :
• PRF
mutation
• SAP
mutation

29. Differential diagnosis
Macrophage activation syndrome (MAS)
Infection/sepsis
Liver disease/liver failure
Multiple organ dysfunction syndrome
Encephalitis
Autoimmune lymphoproliferative syndrome (ALPS)
Drug reaction with eosinophilia and systemic symptoms (DRESS)

30. Continue Differential diagnosis
Child abuse
Kawasaki disease
Cytophagic histiocytic panniculitis
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Drug-induced thrombotic microangiopathy (DITMA)
Transfusion-associated graft-versus-host disease (ta-GVHD)

31. Treatment
HLH-94:
• Tx ineffective, 90% fatalities
• 1st international study on Tx
• Combination of (chemotherapy, immunotherapy,
steroids, Abx, antiviral followed by stem cell
transplant)
• Two phases:
o Initial phase (8wks)
o Continuation phase
• Survival rate 55%, median F/U 3 yrs
HLH-2004:
• Cyclosporine A started at the onset of therapy
instead of week 9

32. Continue Treatment
IMMEDIATE GOALS LONG TERM GOALS

33. Continue Treatment
IMMEDIATE GOALS
 Suppress the severe inflammation
• Steroids ➝ Dexamethasone
• Cyclosporine A
• Intrathecal methotrexate, hydrocortisone (persistent active CNS disease)
 Kill the over-stimulated antigen-presenting cells
• Etoposide (VP-16)
 Treat the triggering agent (infection, neoplasm..etc)
• Abx
• Antivirals
 Supportive therapy
• Prophylactic ➝ Trimethoprim/sulfamethoxazole, oral anti-mycotic
• Gastroprotection ➝ Ranitidine

34. Continue Treatment
LONG TERM GOALS
 Replace the defective system
 Allogenic hematopoietic stem cell transplantation
• Best overall cure rate
• Needed for patients with:
I. Genetic mutations or family Hx
II. Poor response with initial 8 wks of chemo
III. CNS disease
 Non-myeloablative or reduced intensity transplantation
• Use of fludarabine, melphalan & alemtuzumab (anti-CD25 antibody) prior to transplantation improves survival rates

35. Other treatment approaches
Anti-thymocyte
globulin
IVIG Rituximab (EBV
HLH)
HIT-HLH trial
Combined use of ATG,
Etoposide, Intrathecal
methotrexate &
hydrocortisone

36. Summary
Aggressive & life-threatening syndrome of excessive immune activation. It is most
common in infants and young children but can affect patients of any age.
Most patients are acutely ill with multiorgan involvement.
Patients may have already experienced a prolonged hospitalization or clinical
deterioration without a clear diagnosis
Many patients have a predisposing genetic defect, and/or an immunologic trigger

37. Summary
The initial/specialized evaluation
Those with a high clinical suspicion, specialized testing of immunologic parameters and
genetic testing are also indicated
The diagnosis made by identifying a mutation in an HLH gene, or by fulfilling five of eight
diagnostic criteria.
The differential diagnosis is important, We consider macrophage activation syndrome to
be a form of HLH associated with a rheumatologic condition rather than a distinct entity.

38. References
THE AMERICAN ACADEMY
OF PEDIATRICS.
UPTO DATE PEDIATRICS IN REVIEW