3. A 21–year-old man presented with a 10–day history of
fever, headache and jaundice. He was previously healthy
and taking no regular medications. His family history was
unremarkable. The physical exam revealed a
temperature of 40.7 °C, jaundice and
hepatosplenomegaly but was otherwise normal.
3
4. White blood cells 2.7 x 109/L
Neutrophils 1.8 x 109/L
Hemoglobin 110 g/L
Platelets 60 x 109/L
Coag normal
PBM unremarkable
Lab:
4
5. • ALT 103 U/L
• AST 144
• ALP 226 U/L
• GGT 478 U/L
• LDH 783 U/L
• Total Bilirubin 68 U/L
• INR 1.2 PTT 65 s Fibrinogen 0.8 g/L
• Creatinine 124 µmol/L
5
7. • Blood , urine and secretions culture: negative
Viral studies:
• CMV IgM positive
CMV IgG negative
• PCR multiplex for respiratory viruses(Corona, influenza, A and B and ……) came
negative, but H1N1. strongly positive,
• CMV PCR < 1000 copies/mL
• Hepatitis serology for hep A,B, and C negative
7
8. • Patient put on Oseltmevir but continue to
deteriorate, shifted to ICU, continue to be febrile.
• CT cap after 7 days of admission done came with
HSM and ARDS
• Start to have decrease level of consciousness then
seizures
• MRI of the brain and lumbar puncture with
cerebrospinal fluid analysis showed no evidence CNS
disease.
8
9. • CBC still pancytopenia
• PBM pancytopenia, no abnormal cells,
Neutrophil TG, atypical lymphocytes
• Blood , urine and secretions culture: still
negative
• ? What to do ?
9
10. • CRP 240
• Pro cal high
• Ferritin > 40000
• cholesterol 5.25 Triglycerides 4.04
mmol/L
10
20. definition
• Hemophagocytic lymphohistiocytosis (HLH) is an
aggressive and life-threatening syndrome of excessive
immune activation.
• It most frequently affects infants from birth to 18
months of age, but the disease is also observed in
children and adults of all ages.
• HLH can occur as a familial or sporadic disorder, and it
can be triggered by a variety of events that disrupt
immune homeostasis.
• Infection is a common trigger both in those with a
genetic predisposition and in sporadic cases.
20
21. HISTIOCYTOSES
The term "histiocyte" refers to large white blood cells resident in tissues,
including Langerhans
cells, monocytes/macrophages, and dermal/interstitial/dendritic cells
Two major types of diseases
– 1. Dendritic cell-related disorders
• Langerhans Cell Histiocytosis (LCH) (Histiocytosis X)
• Erdheim-Chester Disease.
– 2. Macrophage-related disorders
• histiocytosis with massive lymphadenopathy (Rosai-Dorfman
disease
• Hemophagocytic Lymphohistiocytosis (HLH)
Familial hemophagocytic lymphohistiocytosis (FHL)
Secondary hemophagocytic lymphohistiocytosis
21
24. Primary HLH
• Primary HLH, (familial) hemophagocytic
lymphohistiocytosis (FHL), refers to HLH
caused by a gene mutation, either at one of
the FLH loci or in a gene responsible for one of
several immunodeficiency syndromes.
24
25. Mutations at FLH loci
• Several of the gene mutations in HLH map to familial
hemophagocytic lymphohistiocytosis (FLH) loci.
• ●PRF1/Perforin – FHL2 results from mutations in the PRF1
gene,
• ●UNC13D/Munc13-4 – FHL3 results from mutations in the
UNC13D gene
• ●STX11/Syntaxin 11 – FHL4
• ●STXBP2/Munc18-2 – FHL5
25
26. Immunodeficiency syndromes
• — Several mutations that cause congenital
immunodeficiency syndromes are also associated with an
increased incidence of HLH. These include the following:
• ●Griscelli syndrome –(GS) type 2 is caused by mutations in
RAB27A, is characterized by hypopigmentation, immune deficiency,
thrombocytopenia, and/or neurologic defects. ●Chediak-Higashi
syndrome – (CHS) is caused by mutations
in CHS1/LYST, characterized by partial oculocutaneous albinism,
neutrophil defects, neutropenia, and neurologic abnormalities.
• ●X-linked lymphoproliferative disease – X-linked
lymphoproliferative disease type 1 , caused by mutations in
SH2 domain protein 1A (SH2D1
26
27. Secondary (sporadic, acquired) HLH
• Secondary (sporadic, acquired) HLH has
generally been used to describe those without
a known familial mutation; adults; and those
for whom a clear trigger of the HLH episode
has been identified (eg, viral illness,
autoimmune disease, lymphoma)
27
28. Macrophage activation syndrome
• – Macrophage activation syndrome (MAS) is a form
of HLH that occurs primarily in patients with juvenile
idiopathic arthritis or other rheumatologic diseases.
Some authors call this "reactive hemophagocytic
syndrome
• MAS should be thought of as HLH in the setting of a
rheumatologic disorder rather than as a separate
syndrome.
28
29. PATHOPHYSIOLOGY
• Immunologic abnormalities — HLH is not a
malignancy; it is a syndrome of excessive
inflammation and tissue destruction due to
abnormal immune activation and excessive
inflammation. In general, the excessive
inflammation is thought to be caused by a lack
of normal downregulation of activated
macrophages and lymphocytes
29
30. • Hemophagocytosis refers to the engulfment
(eating) of host blood cells by macrophages.
Hemophagocytosis is characterized by the
presence of red blood cells, platelets, or white
blood cells (or fragments of these cells) within
the cytoplasm of macrophages
30
37. CLINICAL FEATURES
Initial presentation —
• HLH presents as a febrile illness associated with multiple
organ involvement.
• Most patients with HLH are acutely ill.
• Common findings include fever, hepatosplenomegaly, rash,
lymphadenopathy, neurologic symptoms, cytopenias, high
serum ferritin, and liver function abnormalities
• Thus, initial signs and symptoms of HLH can mimic common
infections, fever of unknown origin, hepatitis, or encephalitis.
• Patients may have already experienced a prolonged
hospitalization or clinical deterioration without a clear
diagnosis before the possibility of HLH is raised
37
38. CLINICAL FEATURES
In the HLH-94 study of 249 patients, which is one of the largest cohorts
described, prominent clinical signs included the following
●Hepatomegaly – 95 percent
●Lymphadenopathy – 33 percent
●Neurologic symptoms – 33 percent
●Rash – 31 percent
38
39. Familial HLH (FHL)
• Typically during infancy, or early childhood
• Also during adolescence and in (young) adults
• (Typically rapidly fatal if untreated - in infants
– Median survival = 1-2 months after diagnosis
• Course in adolescents and adults = less explosive bomb
39
42. Diagnostic criteria (HLH-2004)
The diagnosis of HLH is made by one of:
1. Molecular identification of an HLH-associated gene mutation
(eg, PRF1, UNC13D, STX11, STXBP2, Rab27A, SH2D1A, BIRC4, LYST, ITK, SLC7A7, X
MEN, HPS)
2. Clinical and laboratory criteria (5/8 criteria)
• Fever
• Splenomegaly
• Cytopenia = > 2 cell lines
Hemoglobin < 90 g/l (
Platelets < 100 · 109/l
Neutrophils < 1 · 109/l
• Hypertriglyceridemia and/or hypofibrinogenemia
Fasting triglycerides = > 3 mmol/l
Fibrinogen < 1.5 g/l
• Ferritin > 500 microg/l
• sCD25 = > 2400 U/ml (Soluble IL-2 receptor alpha (sCD25 or sIL-2R)
• Decreased or absent NK-cell activity
• Hemophagocytosis in bone marrow, CSF or lymph nodes
Henter et al Pediatr Blood Cancer 2007;48:124–131
42
43. Q. A 21–year-old man presented with a 10–day history
of fever, headache and jaundice. He was previously
healthy and taking no regular medications. His family
history was unremarkable. The physical exam revealed a
temperature of 40.7 °C, jaundice and
hepatosplenomegaly but was otherwise normal.
43
44. Helpful tests-Ferritin
Sickkids study compared rheumatology patients with and without
HLH
>20,000 ferritin most HLH
>30,000 all HLH
(Ramananan et al, 2006)
Texas children’s >10,000 suggests HLH
Allen C et al, Pediatr Blood Cancer,2008)
>500 100% sensitivity
>10,000 90% sensitivity and 96% specificity
44
45. Helpful tests-HLH cytokine storm
Increased sCD25 (sIL2R) =activated T-cells
Increased sCD163 = activated macrophages
Combination may be very useful in diagnosis and follow-up to assess
activity
45
46. Helpful tests-Hemphagocytosis
• Hemophagocytosis ( in BM or tissue biopsy)is neither sensitive nor specific for
HLH.
• Seen after transfusion reactions, surgery, IVIG
• The less important diagnostic criteria.
• It is late finding in most of the occaisons.
• Diagnosis should not be delayed looking for this single
feature.
46
50. • Patients with HLH who are clinically stable can
undergo treatment for a triggering condition (eg,
infection, macrophage activation syndrome, other
rheumatologic condition) or continued search for a
triggering condition.
• Rarely, these patients may be able to avoid cytotoxic
therapy.
50
51. chemotherapy
• Patients who are acutely ill or deteriorating,
we suggest HLH-specific therapy based on the
HLH-94 protocol (HLH-94-based therapy
includes etoposide and dexamethasone given at tapering doses over eight
weeks, with intrathecal methotrexate
• The response to initial therapy is a major factor in
determining the need for additional therapy
including HCT.
51
54. HLH Survival in 1983 vs HLH-94
Time after diagnosis (years)
109876543210
1,0
,9
,8
,7
,6
,5
,4
,3
,2
,1
0,0
1983: 3% alive >5yr
2002: 55% alive >5yr
1983-data: Janka, Eur J Pediatr 1983; 140: 221-230
HLH-94: Henter et al. Blood 2002; 100: 2367-2373 54
55. Median survival
for patients with HLH is approximately 50 percent with HLH-94-
based treatment.
Poor prognostic factors include
• younger age,
• CNS involvement,
• failure of therapy to induce a remission prior to HCT
55
59. allogeneic Stem cell Transplantation
For those with
• HLH gene mutations,
• refractory disease,
• CNS involvement,
• and hematologic malignancies that cannot be cured,
we suggest allogeneic HCT following induction therapy
59
60. Stem Cell Transplantation for HLH
HLH-94
1994-2003
N= 124
F/U till Oct 2008
TRM
23 %
Graft failure
7%
Myeloablative
Conditioning
BU / CY / VP-16
. Trottestam et al; Blood 2011;118: 4577-4584. 60
61. Take home massage 1
Residents should consider HLH in DD of:
• Pancytopenia
• FOU
• Hepatosplenomegaly
• febrile illness associated with multiple organ involvement.
HLH can mimic:
• common infections,
• fever of unknown origin,
• hepatitis,
• or encephalitis
61
62. Take home massage 2
1. Clinical and laboratory
criteria (5/8 criteria)
• Fever
• Splenomegaly
• Cytopenia
• Hypertriglyceridemia and/or
hypofibrinogenemia
• Ferritin > 500 microg/l
• sCD25 = > 2400 U/ml)
• Decreased or absent NK-cell
activity
• Hemophagocytosis in bone
marrow, CSF or lymph nodes
62
