Syndromes Samin Alavi Pediatric hematologist oncologist PCHDRC Shahid Beheshti University of Medical Sciences TehranIran Kish Nov 2018 Diagnosis of HLH Diagnostic criteria for HLH were proposed by the Histiocyte Society in 1991 ID: 929980
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Slide1
Acquired Hemophagocytic Syndromes
Samin
Alavi
Pediatric hematologist oncologist
PCHD-RC,
Shahid
Beheshti
University of Medical Sciences
Tehran/Iran
Kish- Nov 2018
Slide2Diagnosis of HLHDiagnostic criteria for HLH were proposed by the Histiocyte Society in 1991
Five of the eight following criteria must be present to make the diagnosis:
Alternatively, identification of one of the known genetic defects associated with the disease
Ferritin is the most sensitive at discerning HLH from other disordersFerritin >10,000 ng/ml is >90% specific for HLH in childrenFerritin >50,000 ng/ml is less specific in adults, but still very sensitive
Fever
Cytopenias
in 2 of 3 lineages
Splenomegaly
Hypertriglyceridemia and/or
hypofibrinogenemia
Hemophagocytosis
Low or absent NK cell activity
Hyperferritinemia
Elevated plasma levels of soluble CD25
Slide3Cytokine Storm
Spectrum of Cytokine-Induced Disease
Normal response to infection
SIRS
Severe sepsis
Macrophage activation syndrome
Acquired HLH
Genetic HLH
Slide4Causes of HLHHLH
Perforin deficiency
Munc 13-4 deficiency
Syntaxin 11 deficiency
Munc 18-2 deficiency
Unknown gene mutations
Immune deficiencies
Malignancy
Autoimmune diseases
Viral infections
Bacterial infections
Fungal infections
Helminthic
infections
Medications
Slide5Subtypes of HLHGenetic HLH
D
isorders characterized by elevated risk for HLH
Includes Familial Hemophagocytic Lymphohistiocytosis (FHL) as well as certain immunodeficienciesCaused by defects in the cell-mediated cytotoxicity pathwaysAcquired HLH
Reactive Hemophagocytic
Lymphohistiocytosis
(RHL)
Varied group of disorders that result in hemophagocytic symptoms
Caused by dysregulated immune responses leading to lymphocyte and macrophage activation
Slide6Primary HLHFHL can be divided into 5 subtypes:
FHL1 – caused by unknown defect on chromosome 9
FHL2 – caused by deficiency of Perforin
FHL3 – caused by deficiency of Munc 13-4FHL4 – caused by deficiency of Syntaxin 11FHL5 – caused by deficiency of
Munc
18-2
Chediak
-Higashi &
Griscelli
II syndromes
are characterized by partial albinism and immune deficiency
XLP is characterized by massive
lymphoproliferation and immune deficiency (type 1 and 2)
Slide7Secondary HLH, currently more common than primary forms, affects older children or adults without known genetic cause. Infections may also represent the stimulus responsible for an acute exacerbation of primary forms of HLH or itself contributes to development of secondary HLH ‘
infection associated
hemophagocytic
syndrome’ (IAHS)Infections, mainly viral (EBV) , but also bacteria, fungi, and parasitic organisms, play a crucial role. ‘Virus associated
hemophagocytic
syndrome
’
Future Sci. OA
(2015) 1(4), FSO31
Secondary HLH
Slide8Infections promote HLH in the context of compromised immune system due to cytokines produced by the infected T lymphocytesHLH could also develop in patients with malignancies, mainly lymphoproliferative disorders
due to the interaction between
tumor cells and immune system or due to chemotherapy and release of cytokines from tumoral
cells.
Among hematological malignancies,
lymphomas or
leukemias
of T or NK cell lines
, which are frequently related to EBV infection, are most frequently associated with HLH.
Future
Sci. OA
(2015) 1(4), FSO31
Secondary HLH/RLH
Slide9Infection and HLH
Epstein-Barr virus
Escherichia coli
CMVSalmonella sp.
Varicella virus
Enterococcus
sp.
HHV6
Mycoplasma
sp.
Parvovirus B19
Tick-born bacteria
Hepatitis A
TuberculosisHIV
Visceral leishmaniasis
AdenovirusPlasmodium
sp.InfluenzaToxoplasma
sp.
Coxsackievirus
Pneumocystis jiroveci
Torovirus
Candida
sp.
Slide10HLH is associated with several disorders of the immune system, including autoimmune disorders, SLE , acquired immune deficiencies (such as AIDS) or immune disorders even after HSCT.HLH develope in context of
autoinflammatory
diseases, principally in
systemic JIA, as a complication.various metabolic disorders, including lysinuric protein intolerance, multiple
sulphatase
deficiency and alterations of propionate metabolism
are known to be potential triggers for HLH.
Acquired/RHL
Future
Sci. OA
(2015) 1(4), FSO31
Slide11Macrophage Activation Syndrome
Characteristic clinical features of MAS are high,
nonremitting
fever, hepatosplenomegaly, generalized lymphadenopathy, central nervous system dysfunction, and hemorrhagic manifestations. Typical laboratory abnormalities include
pancytopenia
,
hyperferritinemia
, increased liver
enzymesn
and LDH and TG,
D-dimers, and soluble IL-2 receptor [sCD25]), and
hypofibrinogenemia.A
typical histopathologic feature of MAS is hemophagocytic activity in bone marrow biopsy specimens or aspirates
Slide12In most cases, there is not an inherent impairment of lymphocyte cytotoxic activity, Although some heterozygous mutations in genes that regulate the innate immune response and the NK function have been correlated with secondary types of HLH.
Hazen
MM, Woodward AL, Hofmann I
et al. Mutations of the hemophagocytic lymphohistiocytosis
-associated
gene
UNC13D
in a patient with systemic juvenile
idiopathic arthritis
.
Arthritis Rheum. 58(2), 567–570 (2008
Slide13FHL/RHL OverlapAdult-onset HLH has been associated with homozygous and heterzygous mutations in multiple FHL genes
Striking number variants of FHL-associated genes have been identified in MAS patients
Current recommendation is to perform genetic analyses on
ALL patients suspected or confirmed to have HLH
Kaufman, et al.
Arthritis
Rheumatol
. 2014 Dec;66(12):3486-95.
Slide14MAS and AutoimmunityMAS can be associated with a wide variety of autoimmune diseases
The Strongest associations is with
sJIA
, clinically apparent MAS is reported in 7-13% of JIA Subclinical bone marrow evidence of MAS in >50% of sJIA patientsHowever, MAS also occurs with SLE and adult-onset Still’s disease, along with multiple other diseases
Slide15The 2004 diagnostic guidelines for HLH proposed by the Histiocyte Society are still the most widely used criteria to define and diagnose HLH in clinical
practice
.
Recently, alternative parameters have been evaluated to define a new diagnostic score: the H-score.
However, they have
only been validated
for the
diagnosis of reactive forms of HLH in an adult cohort
Slide16H Score for Diagnosing RHL
Included Parameters
Known underlying immunosuppressionTemperatureOrganomegaly
No.
of
cytopenias
Ferritin
Triglycerides
Fibrinogen
AST
Hemophagocytosis
on BM biopsy
Fardet
, et al.
Arthritis
Rheumatol. 2014 Sep;66(9):2613-20
Slide17Performances of the H-Score for Diagnosis of Hemophagocytic
Lymphohistiocytosis
in Adult
and Pediatric Patients, Am J Clin Pathol June 2016;145:862-870
Slide18HLH 2004 guideline vs H-score
At diagnostic
confirmation, 88
% of children and 90% of adults with HLH met at least four of the six diagnostic criteria of the HLH-2004
guidelines.
The
median (IQR) H-score was
205 (174-268
) for
children
with HLH and 270 (193-300) fo adults
with HLH.
Slide19MAS and Autoimmunity
Adult-onset
Still’s disease
Ankylosing spondylitisDermatomyositis
Inflammatory bowel disease
Kawasaki disease
Polyarticular
JIA , Systemic JIA
Sarcoidosis
Systemic lupus
erythematosus
Slide20Medication-Induced HLH
Aspirin
Morniflumate
NSAIDsMethotrexate
Sulfasalazine
Infliximab
Etanercept
Penicillamine
Anakinra
Vancomycin
Gold salts
Parenteral lipids
Autologous stem cell transplantation
Slide21Mediastinal germ cell tumorsPediatric neuroblastoma Rhabdomyosarcoma
Hepatocellular
carcinoma
Metastatic melanomaSCC of the neckLung cancerRenal cell carcinomaprostate cancer and colon cancer
Hemophagocytosis
and solid tumors
Future Sci. OA
(2015) 1(4), FSO31
Slide22Early-onset hemophagocytic lymphohistiocytosis after start of chemotherapy for advanced neuroblastoma.
A
3-year-old boy with stage 4 neuroblastoma complicated by HLH immediately after the start of chemotherapy. The patient developed high fever on the 2nd
day of chemo,
and was diagnosed as having HLH of the 7th day of
chemotherapy.
Massive
tumor cell destruction resulting from
chemotherapy
was thought to be a cause of systemic cytokine response and HLH.
Methylprednisolone
pulse therapy was effective for the HLH, which did not recur thereafter.
* Pediatr Hematol
Oncol 2012 Feb;29(1):99-103.
Slide23HLH secondary to or mimickinginborn errors of metabolism
Wolman disease
Biotinidase
deficiency Organic
acidemia
Gaucher
disease
Lysosomal
acid lipase deficiency
Galactosemia
Multiple
dulfatase
deficiency
Lysinuric
protein intolerance
These cases suggest that a careful metabolic workup should be performed, when facing to a pediatric patient with HLH especially if clinical features of the patient suggested a metabolic disorder including hypotonia
, irritability, or mild developmental delay.
Mediterr
J Hematol Infect Dis. 2017; 9; e2017057.
Mediterr
J
Hematol
Infect Dis. 2017; 9; e2017057.
Slide24FHLH and lysinuric protein intolerance-related HLH
A
nine-month-old-boy with
Atypical Hemophagocytic Lymphohistiocytosis
Mediterr
J
Hematol
Infect
Dis. 2017
; 9; e2017057.
Slide25As a severe condition, there should be no delay in starting therapy even in the setting of secondary cases
since we can not discriminate primary from secondary based on initial clinical and laboratory manifestations.
The
goal of treatment is to regulate the immune system dysfunction, suppressing the hyperinflammatory state.
It
is also important to treat the cause responsible for acquired
HLH.
*Jordan
MB, Allen CE, Weitzman S,
Filipovich
AH, McClain KL. How I treat
hemophagocyticlymphohistiocytosis. Blood 118(15), 4041–452 (2011).
Treatment of secondary/Acquired HLH
Slide26Corticosteroids alone, or in association with IVIG,
represent
the main therapy in patients with rheumatology-associated HLH
(MAS), but may be also active for others secondary forms of HLH.
*Jordan
MB, Allen CE, Weitzman S,
Filipovich
AH, McClain KL. How I treat
hemophagocytic
lymphohistiocytosis
. Blood 118(15), 4041–452 (2011).
Treatment of secondary/Acquired HLH
Slide27RHL/MAS TreatmentMutliple groups support
a graded-approach
, with corticosteroids alone as initial treatment
Initial
Therapy
High-dose corticosteroids (
prednisolon
e
30 mg/kg x3 days)
Elimination of suspected
triggers, infection control
Aggressive
supportive measures
Secondary Therapy
Intravenous immunoglobulin (1-3 g/kg)
Cyclosporine A, etoposide
Slide28Patients who can be weaned off dexamethasone and etoposide without recurrence and have no identified HLH-associated gene defects may stop therapy after 8-week
induction.
HCT
is generally recommended in patients with CNS involvement, recurrent/refractory disease or
proven
familial/genetic disease
Slide29Treatment of secondary/Acquired HLHUnfortunately, about 25% of patients fail to achieve complete remission with standard therapy.
At the moment, there are no standard salvage therapies.
No conclusive results are reported with the use of
infliximab, daclizumab, alemtuzumab, anakinra and other agents
* Jordan
MB, Allen CE, Weitzman S,
Filipovich
AH, McClain KL. How I treat
hemophagocytic
lymphohistiocytosis. Blood 118(15), 4041–452 (2011).
Slide30Treatment NotesRHL triggered by leishmaniasis may be treated solely with amphotericin.
Etoposide is crucial for EBV-associated RHL , inhibits activated T cells, plus EBV NA in infected cells
Multiple groups agree that
HLH 2004 should be initiated for relapses of RHL, despite etiologyHSCT has best overall outcome among all single treatment modalities across all patient populations
Slide31A 4-month-old girl infant was admitted to hematology deprtment due to pancytopenia and generalized maculopapular
rash whole over the body.
She was
febrile, generalized skin rash and splenomegaly.
Laboratory
tests showed
pancytopenia
and
serum
ferritin
of 1500 ng
/ml.A presumptive diagnosis of HLH was suggested for the patient.
Due to the presence of skin rashes, a specific array of tests including Ro/SSA and La/SSB antibodies
was performed which were positive with very high titers in two occasions. Mother serum was also highly positive for the anti-nuclear antibodies
.A course of corticosteroid was started for the baby, Skin lesions went away and she was discharged in good general condition. The mother was referred to rheumatology clinic for further follow-up.
Hemophagocytic lymphohistiocytosis complicating erythroleukemia
in a child with
monosomy 7The first
case of childhood
hemophagocytosis
following chemotherapy for AML-M6
in a child with
monosomy
7
is reported.
Prolonged pancytopenia
accompanied by persistent fever and huge hepatosplenomegaly
became evident after 2 courses of chemotherapy.On bone marrow aspiration, macrophages phagocytosing
erythroid
precursors were observed and diagnosis of HLH was established.
Case
Rep
Hematol
.
2013;2013:581073.
,
A
lavi
S
1
,
Ebadi
M
2
,
Jenabzadeh
A
1
,
Arzanian
MT
1
,
Shamsian