1. Management of Macrophage Activation Syndrome (MAS)
Vahid Ziaee MD
Children Medical Centre
Tehran University of Medical Sciences

2. Hemophagocytic Lympho- Histiocytosis
HLH a term that describes a spectrum of disease processes characterized by accumulations of well-differentiated mononuclear cells with a macrophage phenotype
Current classification of HLH:
Primary or familial HLH (FHLH)
Secondary or reactive HLH (ReHLH)
It may be difficult to distinguish one from the other.
Genetic variants may predispose patients to HLH at any age
1/13/2019
Dr V. Ziaee; Children’s Medical Center

3. Dr V. Ziaee; Children’s Medical Center
Primary HLH (FHLH)
FHLH Characteristics:
Autosomal recessive immune disorders
Genetic defects
Clinically presented within the first two months of life.
1/13/2019
Dr V. Ziaee; Children’s Medical Center

4. Dr V. Ziaee; Children’s Medical Center
Primary HLH
FHL 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 13-4
FHL4 – caused by deficiency of Syntaxin 11
FHL5 – 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 lympho-proliferation and immune deficiency.
Dr V. Ziaee; Children’s Medical Center

5. Dr V. Ziaee; Children’s Medical Center
Diagnostic Criteria 1 2 3 4 5 6 7 8
Dr V. Ziaee; Children’s Medical Center

6. Dr V. Ziaee; Children’s Medical Center
Diagnostic guideline  
Dr V. Ziaee; Children’s Medical Center

7. ≥ 3 cm below costal margin
Diagnosis of MAS
Laboratory Criteria
Value
Thrombocytopenia
≤ 262 x 106/l
Elevation in AST
> 59 U/L
Leukocytosis
≤ 4.0 x 106/l
Hypofibrinogenemia
≤ 250 mg/dL
Diagnosis requires:
>2 Laboratory criteria
>2 Lab + Clinical criteria
Clinical Criteria
Manifestation
CNS dysfunction
Irritability
Headache
Lethargy
Disorientation
Seizures
Coma
Hemorrhages
Ecchymosis
Purpura
Mucosal bleeding
Hepatomegaly
≥ 3 cm below costal margin
Addition of ferritin >500 ng/ml may better discriminate MAS vs systemic infection.
Adapted from: Davi, et al. Arthritis Rheumatol Oct;66(10):

8. New Diagnostic Criteria1 2 3 4
2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.
Ravelli A, t al; Ann Rheum Dis Mar;75(3):481-9.
2/29/2009
Dr V. Ziaee; Children’s Medical Center

9. Dr V. Ziaee; Children’s Medical Center
2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.
Ravelli A, t al; Ann Rheum Dis Mar;75(3):481-9.
2/29/2009
Dr V. Ziaee; Children’s Medical Center

10. Dr V. Ziaee; Children’s Medical Center
Dynamic Changes, Cut-Off Points, Sensitivity, and Specificity of Laboratory Data to Differentiate Macrophage Activation Syndrome from Active Disease.
Assari R, Ziaee V, Mirmohammadsadeghi A, Moradinejad MH. Dis Markers. 2015;2015:
2/29/2009
Dr V. Ziaee; Children’s Medical Center

11. Dr V. Ziaee; Children’s Medical Center
Comparison of Lab. Data
MAS
Sepsis
Flare up
Parameter or
Nl or
WBC
Hgb
or Nl
Plt Count
ESR
CRP Nl
Transaminases
Serum Ferritin
Nl or
Serum Fibrinogen
2/29/2009
Dr V. Ziaee; Children’s Medical Center

12. Dr V. Ziaee; Children’s Medical Center
Ferritin > 10,000 mg/L appear to be specific and sensitive for HLH.
In patients without a significant medical history and a new onset of febrile illness with highly elevated ferritin levels, the diagnosis of HLH should be evaluated.
3/1/2016
Dr V. Ziaee; Children’s Medical Center

13. Dr V. Ziaee; Children’s Medical Center
Treatment
Control of underlying disease
IV Ig
Supportive therapy with antibiotic profilaxy, G-CSF??, Electrolyte imbalance, ….
Immunosuppressive therapy is controversial
Blood products (Plt?, Packed cell?, FFP)
3/1/2016
Dr V. Ziaee; Children’s Medical Center

14. Treatment in Rheumatologic Disorders
Should be started as soon as possible.
IVIg
Corticosteroids (pulse therapy)
Cyclosporin A
Plasma­phoresis
Biologic agents (not clear)
Other immunosuppressive agents
3/1/2016
Dr V. Ziaee; Children’s Medical Center

15. Treatment in Rheumatologic Disorders
HLH protocol in persistent cases
Persistent cases to HLH Protocol:
Anti Thymo-Glubulin
Alemtuzumab (Anti-CD52)
Plasma exchange
Bone Marrow Transplantation
IFN-ᵞ ??
3/1/2016
Dr V. Ziaee; Children’s Medical Center

16. Treatment protocol Overview for HLH (HLH-2004)
3/3/2016
Dr V. Ziaee; Children’s Medical Center

17. Dr V. Ziaee; Children’s Medical Center
Systemic Therapy
Dexamethasone
Etoposide
Cyclosporine
Week 1
10 mg/m2 daily
150 mg/m2 IV biw
3 mg/kg bid
Week 2
To Trough 200 g/L
Week 3
5 mg/m2 daily
150 mg/m2 IV qwk
Week 4
Week 5
2.5 mg/m2 daily
Week 6
Week 7
1.25 mg/m2 daily
Week 8
Taper and d/c
2/29/2009
Dr V. Ziaee; Children’s Medical Center

18. Dr V. Ziaee; Children’s Medical Center
ReHLH / MAS Treatment
Applicability of HLH 04 protocol to Re-HLH syndromes (e.g., MAS) and to adult populations is not been established
Mutliple groups support a graded-approach, with corticosteroids alone as initial treatment
Initial Therapy
High-dose corticosteroids (prednisolone 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
Dr V. Ziaee; Children’s Medical Center

19. MAS Treatment Options
Proposed Treatments for Autoimmune-Associated HLH
Cyclosporine A
Plasmaphoresis
Etanercept
Abatacept
Anakinra
Antithymocyte globulin
Intravenous immunoglobulin
Corticosteroids
Etoposide
Naproxen
Splenectomy
Dr V. Ziaee; Children’s Medical Center

20. Dr V. Ziaee; Children’s Medical Center
Summary of Treatment
Suppression of Inflammation:
Corticosteroids, IVIg, Cyclosporin, Anticytotoxic agants
Elimination of achived immune cells and (infected) APCs:
Corticosteroids, Etoposide, T-cell antibodies (ATG, Rituximab, Abetecept)
Elimination of trigger:
Anti-infectious therapy
Supportive therapy (neutropenia, coagulopathy):
Antifungals, antibiotics, FFP
Replacement of defective immune system:
Bone marrow transplantation
Dr V. Ziaee; Children’s Medical Center

21. Dr V. Ziaee; Children’s Medical Center
Treatment Notes
Several series suggest outcomes are poor in Re- HLH if infection control measures are used alone.
Re-HLH triggered by leishmaniasis may be treated solely with amphotericin
Multiple groups agree that HLH 2004 should be initiated for relapses of Re-HLH, despite etiology.
HSCT has best overall outcome among all single treatment modalities across all patient populations
Dr V. Ziaee; Children’s Medical Center

22. Dr V. Ziaee; Children’s Medical Center
2/29/2009
Dr V. Ziaee; Children’s Medical Center

23. Dr V. Ziaee; Children’s Medical Center

24. Prognosis Without therapy, mortality of patients with HLH is high
Those with an inherited mutation in an HLH gene have a survival of approximately two months without treatment.
Patients treated on the HLH-2004 protocol had a median survival of 54 percent at 6.2 years (249 patients, median age eight months).

25. Dr V. Ziaee; Children’s Medical Center
2/29/2009
Dr V. Ziaee; Children’s Medical Center