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seminar on MAS
1. WELCOME TO SEMINAR
Dr. S. M. Zakaria Hossain,
Resident, General Paediatrics
Dr. Md. Aurangozeb,
Resident, Nephrology
BSMMU
2. Macrophage activation syndrome (MAS)
Severe, potentially fatal condition
excessive activation and expansion of
macrophages and T cells
Overwhelming inflammatory reaction.
3. Hemophagocytic Lymphohistiocytosis (HLH):
Hyperinflammatory syndrome
Severe hypercytokinemia
Highly stimulated but ineffective immune process
accumulation of well differentiated mononuclear cells with a
macrophase phenotype
HLH has two types- Primary/Genetic and Secondary/Acquired.
Macrophage activation syndrome is the resemblance of
secondary HLH
5. History
In the early 1980s, several report described that patients with
systemic JIA developed severe coagulopathy often associated with
mental status changes, hepatosplenomegaly, ↑ liver enzymes and a
sharp fall in blood cell counts and ESR.
In 1985, A study linked these symptoms to massive proliferation of
activated non-neoplastic macrophagic histiocytes with prominent
hemophagocytic activity. The term “macrophage activation
syndrome” was eventually introduced in 1993 by a follow up
report originating from the same center.
6. Epidemiology
MAS has been reported in association with almost any
rheumatic disease like Systemic juvenile idiopathic arthritis,
systemic lupus erythematosus, Kawasaki disease, Juvenile
dermatomyositis
By far, most common in systemic JIA
-7-17% patient with sJIA develop MAS
Mild subclinical MAS may be seen in as many as 1/3rd
patient with active sJIA
No gender and racial predilection.
Youngest MAS patient reported was < 12 months.
8. Genetic predisposition to macrophage hyperresponsiveness / infection /flare
Failure of cytolytic function of NK cell and CTL
Persistent antigenic stimulation
Uncontrolled T cell proliferation
Failure to provide apoptotic signal- delay in contraction stage of immune
response
9. Persistent expansion of T cell and macrophage
Escalating cytokine production (IFN-γ ) , M-CSF by CD8 T Cell
Prolonged stimulation of monocytes with cytokines leads to their excessive
activation and differentiation into macrophages
↑↑ production of
proinflammatory
cytokines (TNF-α,IL-6
,IL-1 ,IL-18) and
chemokines
hemophagocytic activity
11. continuous secretion of cytokines( cytokine strom)
Infiltration of hemophagocytic macrophage in bone marrow
• Nonremitting fever
• Endothelial cell activation
• CNS demyelination
•Phagocytosis of blood elements
•Cytopenias
Hepatic lipogenesis &
inhibit synthesis of
lipoprotein lipase
activity
↑triglyceride
12. •Hepatic Dysfunction
•Elevated liver enzyme
Hypofibrinogenemia
Activated macrophage
the conversion of plasminogen to
secret hemostatic tissue factor
Secretion of plasminogen activator
Coagulopathy
infiltration of macrophage , histiocyte and lymphocytes into the liver +
extramedullary erytropoiesis
plasmin
Consumption of
clotting factors
14. Breakdown of RBC
Release of Hemoglobin Heme + globin
Free heme is a source of redox-active
iron
To prevent cell damage caused by iron-
derived reactive oxygen species,
haptoglobin forms a complex
with free hemoglobin
The hemophagocytic macrophages in
MAS express the scavenger
receptor CD163
The haptoglobin-hemoglobin (Hp-Hb)
complexes then bind to CD163 and are
internalized by the macrophage
Endocytosis of Hp-Hb complexes leads to
upregulation of HO enzymatic activity
heme degrades into biliverdin, CO,
and free iron
Most of the free iron is sequestered with ferritin
↑uptake of Hp-Hb complexes by
macrophages leads to
increased synthesis of
ferritin
15. Clinical features
Symptom
persistent fever, easy
bruising, and mucosal bleeding
Mental status changes,
seizures, and coma are the
most common manifestations
of CNS disease
Respiratory distress , oliguria
may occur
Pt may present with shock
Sign
Anemia
jaundice
Lymphadenopathy
hepatosplenomegaly,
Ascites , pleural effusion
Petechiae , pupura ,
ecchimoses
Bleeding from multiple sites
Features of shock
16.
17. Diagnostic Criteria for MAS in sJIA
Histopathological Criterion
Evidence of macrophage hemophagocytosis in the bone
marrow aspirate
Diagnostic rule
The diagnosis of MAS requires the presence of any two or
more clinical criteria with two or more labortory criteria.
A bone maroow aspirate for the demonstration of
haemophagocytosis may be required only in doubtful cases
18. Proposed Criteria for MAS in sJIA
(Classification criteria for MAS complicating sJIA: a
EULAR/ ACR/ PRINTO collaborative
initiative)Ravelli A et al. 2016
S. Ferritin level: >684 ng/ml and
Any 2 of the following:
a. Thrombocytopenia (≤ 181×109/L)
b. Elevated liver enzymes (aspartate transaminase > 48 U/L)
c. Hypertriglyceridemia(>156 mg/dl)
d. Hypofibrinogenemia (≤ 360 mg/dl)
19. Proposed Criteria for MAS in sJIA (contd)
These criteria apply to a febrile patient suspected of sJIA
and in the absence of disorders such as –
Immune-mediated thrombocytopenia.
Infectious hepatitis.
Familial hypertriglyceridemia.
Visceral Leishmaniasis.
20. A 12 year old boy diagnosed case of SJIA since his 3 yrs of age was
on CRM, suddenly developed - non remitting fever, abdominal pain,
vomiting, jaundice. O/E- deeply icteric, edematous
,hepatosplenomegaly , ascites present.
Inv- suggestive of MAS with Anti HAV IgM (+ve)
21.
22.
23. Investigations for MAS
1. CBC: Cytopenia (affecting at least two lineages in the peripheral blood).
(Platelet Count: ≤ 181×109/L)
2. ESR: Decreased.
3. S. Ferritin level: >684 ng/ml. (Often above 10,000 ng/ml)
4. Abnormal liver function test:
S. AST (aspartate transaminase > 48 U/L)
24. Investigations for MAS
5. S. Fibrinogen level: Decreased (≤ 360 mg/dl)
6. S. Triglyceride level (>156 mg/dl)
7. S. Electrolytes: Hyponatremia.
8. S. Albumin level: Hypoalbuminemia.
9. Elevated sCD25 and sCD163.
10. S. LDH is usually highly elevated.
25. Investigations for MAS (contd)
PT & APTT - prolonged
S. Fibrinogen level - marked hypofibrinogenemia
Vitamin K–dependent clotting factors- moderate deficiency.
Factor V levels is usually mildly low.
Fibrin degradation products are usually present as well.
26. Histopathologic Features (Ravelli A et
al. 2012)
1. Macrophage hemophagocytosis in the bone marrow aspirate.
2. Increased CD163 staining of the bone marrow.
27. Neutrophilic band forms
and metamyelocyte
within an activated
macrophage. Nuclei of
band forms appear
condensed, a result of
destruction
29. Investigations for MAS (contd)
In normal physiological conditions, serum ferritin is usually
60% to 80% glycosylated, while intracellular ferritin is not
glycosylated.
It has been shown that the percentage of glycosylated ferritin in
the serum of patients with hemophagocytic syndromes is very
low (below 20%).
So assessment of the glycosylated ferritin may be a useful tool
for the diagnosis of hemophagocytic syndromes.
30. Investigations for MAS (contd)
In some reports, additional biopsies were performed due
to the initial failure to detect hemophagocytosis in the
bone marrow, and hemophagocytic macrophages were
found in organs, such as the liver, lymph nodes, or the
lungs.
31. Investigations for MAS (contd)
Soluble IL2Rα receptors and soluble CD163 are now
increasingly recognized as important biomarkers of
MAS. Because they shed off the surface of activated T
cells and macrophages respectively, their levels are
likely to increase in the serum regardless of the tissue
localization of the cells.
32. Laboratory Feature SJIA MAS
WBC,PMN ↑↑ ↓
Haemoglobin Normal/↓ ↓
Platelet ↑↑ ↓
ESR ↑↑ ↓
ALT/AST Normal/↑ ↑↑
PT Normal ↑
APTT Normal ↑
D-Dimer ↑ ↑↑
Fibrinogen ↑ ↓
Ferritin Normal/↑ ↑↑
HPS in BM _ +
33. Treatment
Intravenous Methylprednisolone pulse therapy (30 mg/Kg
for 3-7 consecutive days) followed by 2-3 mg/Kg/day in four
divided doses.
Normalization of haematological abnormality and
resolution of coagulopathy – slow tapering of steroid
34. Corticosteroid resistant MAS
Cyclosporine A, I/V or Oral, 2-7 mg/Kg/D
Effects
- T cell suppression
Benefit
-Rapid control of symptoms
-Allows for avoiding excessive steroid
Etoposide
35. Other Treatment Options
Antithymocyte Globulin (ATG)
Cyclophosphamide
Biological agent
-Anakinra (IL-1)
-Canakinumab (IL-1β)
-Tocillizumab (IL-6)
IVIG (virus associated reactive HLH)
Rituximab (EBV infection)
HSCT- who experience a relapse after initial response to HLH 2004 protocol
therapy for resistant MAS.
36. Prognosis
MAS is a life-threatening condition. Its prognosis depends upon the
underlying disease of patient, age, duration of presentation, delay in
diagnosing the condition.
Mortality rate varies in sJIA patients- 8%-23% and in SLE patients-
5%-35%.
Mortality is higher in older age.
37. Take home message
MAS is a serious complication of systemic inflammatory
disorders that is probably underdiagnosed
Prompt recognition and treatment of MAS are critical and
can be life-saving
Platelet count, ferritin and AST are the lab tests whose
change over time is most useful for timely detection of
MAS
IL-1 inhibitors represent a promising adjunctive therapy
for MAS, particularly in refractory cases
