macrophage activation syndrome

1. MACROPHAGE
ACTIVATION
SYNDROME
& HLH

2. INTRODUCTION
 Life threatning disorder of chronic rheumatological
conditions like – systemic onset juvenile rheumatoid
arthritis, SLE, Adult onset stills disease, Kawasakis
disease.
 Rarely with SS, PAN, Sjogrens.
 Charecterised by activation and proliferation of T-
Lymphocytes and macrophages that infiltrate organs
resulting in cytokine production and widespread
hemophagocytosis.
 Proliferation of macrophages that demonstrate
phagocytosis of hematopoetic cells in bone marrow,
lymph node, spleen.

3. Pathogenesis-
 Mutation of PERFORIN gene
 Impairment in the NK Cell and Cytotoxic T-
Cell function.
 Hypersecretion of IFN ¥, IL6, IL10 are
implicated in pathogenesis.

4. Pathogenesis-

6. HLH
 It is a part of a broader spectrum ie
Haemophagocytic Lymphohistiocytosis (HLH)
AND INCLUDES-
 MAS
 INFECTION ASSOCIATED HLH
 FAMILIAL HLH.
 SECONDARY HLH associated with
rheumatological conditions.

7. TRIGGERS-
 Flare up of underlying diseases
 Aspirin
 NSAIDS
 VIRAL infections like EBV, CMV, Parvovirus.
 Rarely- Sulfasalazine and methotrexate
therapy in rheumatoligical conditions.

8. Classification-
 PRIMARY-
 FAMILIAL/ GENETIC-
 1) without immunodeficiency- includes FHLH
1,2,3,4,5
 2) with Immunodeficiency- Griscelli type 2, Chediak
Higashi.
 SECONDARY-
 Viral – EBV, HIV, CMV
 Bacterial
 Hematological Malignancies, lymphomas
 Fungal infections
 Malignancy
 MAS- SLE, AOSD, JRA

9. CLINICAL FEATURES-
 Acute presentation
 Sudden onset of non-remitting fever
 Profound Leukopenia
 Anaemia
 Thrombocytopenia
 Hepatospleenomegaly
 Lymphadenopathy

10.  Elevated liver enzymes
 High Triglycerides
 High LDH
 LOW Sodium
 CNS dysfunction occurs in form of lethargy,
irritabitlity, disorientation, headache, seizures
and coma.

11.  Significant deterioration In renal functions.
 Pathognomic feature- is
 Well differentiated macrophages actively
phagocytosing hematopoetic cells.found in
many organs and account for the systemic
flare of infections.
 In MAS , bone marrow does not always show
HP,and failure to reveal HP on bone
marrow doesn’t rule out MAS.

14. Contd…
 Coagulation profile is abnormal
 Prolongation of PT AND APTT
 HYPOFIBRINOGENEMIA
 Detectable FDPs
 IT may mimic SEPSIS AND ACUTE FLARE UP OF
INFECTIONS.
 Pattern of non remmiting high spiking fever is seen in
MAS whereas in sepsis patient does have remitting
fever patterns
 Moreover patients show a paradoxical improvement in
the underlying inflammatory disease at the onset of
MAS with a fall in ESR which reflects the degree of
hypofibrinogenemia with fibrinogen consumption
secondary to liver dysfunction

15. D/Ds
 Flare of Underlying Diseases
 Infections like brucellosis etc
 Sepsis

16. DIAGNOSTIC GUIDELINES
 Cytopneias involving atleast 2 CELL LINES.
 A precipitous fall in ESR despite a persistently rising high
CRP.
 Abnormal Serum Hepatic enzymes, Increased .bilirubin,
moderate hypoalbunemia
 Coagulopathy Fibrinogen < 250 mg/dl
 Platelets < 1,50, 000
 Elevated D- dimer
 Hypertriglyceridemia> 160 mg/dl
 Hyponatremia
 Hyperferritenemia >>>> 10000HALLMARK OF MAS.,
 Also related to prognosis and therapeutic response.

17. DIAGNOSTIC GUIDELINES
 HLH 2004 CRITERIA HENTER JI et al
 HLH is confirmed if either 1 or 2 is confirmed.
 A molecular diagnosis consistent
 Diagnositic criteria ( 5 out of 8 )

18. Initial diagnostic criteria
1. Fever > 38.5
2. Spleenomegaly
3. Cytopenias affecting atleast 2 cell lineages
4. Hypertriglyceridemia and hypofibrinogenemia >
265 and < 150
5. Haemophagocytosis in bone marrow , spleen or
ln with no evidence of malignancy
6. Low or absent NK cell activity
7. Ferritin > 500 ng/ ml
8. Soluble CD 25 > 2400 U/ ml

19. Criteria for MAS ( Ravelli et al)

20. MANAGEMENT
 Parenteral administration of high doses of
corticosteroids.
 Start with intravenous MPS pulse therapy 30
mg/ kg for 3 consecutive days.
 Followed by 2-3 mg/kg/day in four divided
doses
 Administration of IVIG, cyclophosphamide,
plasma xchange, etoposide, are conflicting.

21.  Use of cyclosporin A,
 Effective in steroid resistant or severe form of
MAS.
 Ifresponse to steroids is not evident within 24-
48 hours ,consider cyclosprine, as it can be life
saving.
 Parenteral iv dosing 207 mg/kg/ day.
 It exerts a “switch off effect” on disease
process, meaning fever, and laboratory
parameters improve within 12-24 hours.

22. FAILURE TO CONVENTIONAL
THERAPY
 High dose Dexamethasone 10 mg/ m2
 +
 Etoposide 150 mg/ m2
 +
 Cyclosporine A
 With intrathecal Methotrexate in patients with CNS
manifestations that do not remit after 2 weeks of
steroids.
 In refractory cases, hematopoetic stem cell
transplant.

23.  In place of etoposide, in patient with renal and
hepatic failure , anti-thymocyte globulin may
be safer alternative to etoposide.
 Depletes CD4 AND CD8 cells through
complement mediated lysis.
 In viral infection, if EBV derived one might
consider to Start Rituximab.
 It eliminates Bcell, which are the main harbour
of EBV.

24.  TNF α antagonist ETANERCEPT has been associated
with dramatic response.
 Dose is 0.4 MG TWICE WEKLY FOR 4 weeks.
 It should be considered only when systemic infections
are ruled out.
 Some cases have also responed dramatically to IL1
RECEPTOR ANTAGONIST-AANKAKINRA
 2mg /kg/ dy sc
 Dramatic response in 24 hours.
 Only for refractory MAS TO steroids and cyclosporin.

25. Supportive care-
 Blood transfusion, RBS platelet, and FFP
transfusions.
 Antibiotics
 Nutritional support.
 Require close monitoring as it may reoccur.
 Reported mortality is 15- 60%, but due to
increasing awareness, early diagnois and
treatment the outcome is improving.