2. Case presentation
Dr. Neda Ashayeri

3. 2.5 m full term boy presented with nausea and vomiting and pallor
History of GE reflux
Drug history: ranitidine, omeprazol
V/S: BP: 9/5 PR: 100/s,
RR: 40/s AT: 36.5
P/E: Hepatosplenomegaly

4. 1/ 22
1/23
1/25
1/28
2/1
2/10
2/17
2/26
3/2
3/7
3/16
WBC
8.5
8.2
9.9
15.1
16.1
12.6
9.5
17.3
11.3
10.3
RBC
1.48
3.45
2.64
1.99
2.32
2.97
3.04
2.23
2.5
3.16
4.02 Hb
4.5
9.4
6.9 6
7.2
8.6
8.8
6.3
7.9
10.1
MCV
87.2
86.7
88.3 95
100
91.2
88.2 91
99.2
99.4
95.5
MCH
30.4
27.2
26.1 30 31 29
28.9
28.3
31.6 32
31.3
PLT 10
<10
141 98
302
150
319
341
145

5. Retic: 3%
Direct Coombs: anti IgG 3+
Screen Ab: -
Auto Ab: 2+
CMV Ab: IgG: 45 IgM: 37
Toxo Ab: Neg
EBV: Neg
CMV PCR:
Ophthalmology study: Nl
Brain Sono: Nl

6. Diagnosis
Evans

7. How I manage Evans Syndrome and AIHA cases in children
Maurizio Miano British Journal of Haematology, 2016, 172, 524–534

8. Evans Initially described: AIHA and ITP with unknown etiology
New definition: Destruction of at least two blood cell lineages in the absence of other diagnoses

9. Incidence and prevalence
Iincidence of AIHA: 0.4 cases/ children per year
13% - 73% of patients with AIHA: have multi-lineage involvement

10. Pathogenesis
Auto-reactive Ig G binds RBC antigens mainly extravascular destruction
More rarely, both IgA and IgM can target the RBCs as well.

11. Pathogenesis In a minority of children (25–30%),
IgM destroys RBCs by activating the complement cascade
mainly in the intra-vascular compartment
when exposed to cold temperatures (cold antibodies)

12. Secondary forms Infections: Epstein-Barr virus Cytomegalovirus
Human Immunodeficiency Virus
Helicobacter Pylorii
Hepatitis C virus
Mycoplasma pneumoniae
Parvovirus B19

13. Immunodeficiencies and Lymphoproliferative disorders:
CVID
SCID
Di George syndrome
Selective IgA deficiency
Autoimmune lymphoproliferative syndrome (ALPS), …

14. Autoimmune and Rheumatology disorders:
Systemic lupus erythematosus
Anti-phospholipid syndrome
Rheumatoid arthritis
Giant-cell hepatitis

15. Malignancies: Other: Lymphoma Leukemia Myelodysplasia Drugs
Vaccination
Stem cell transplantation

16. Key Signs and Symptoms
Anaemia is usually normocytic or macrocytic, often hyperchromic
Hepato-splenomegaly, jaundice
and haematuria/hemoglobinuria
The association may either develop concomitantly or separately after a median interval of 3 years

17. Diagnosis
Patient and family history of malignancies, infections and immunological
Recent exposure to drugs or vaccinations

18. Lab Data DAT positivity reticulocytosis Indirect hyperbilirubinaemia
Increased LDH
Reduced serum haptoglobin

19. PBS Spherocytes  extravascular hemolysis
Aggregations of RBC in long chains (‘rouleaux’).
Artifactual macrocytosis due to RBC agglutination

20. DAT WA-AIHA: DAT is usually IgG+ or IgG/C3d+
CA-AIHA usually: negative or C3d+ DAT
Negative DAT: should not exclude the
diagnosis of WA-AIHA
1. 10% of patients may have an undetectably low number of Ab
2. ‘warm’ IgM or IgA,

21. immunological work-up
IG with subclasses
Screening for other auto-immune diseases
Lymphocytes subset count with double-negative T-cells

23. First-line treatment Steroids are the first-choice treatment
Prednisolone at a dose of1–6 mg/kg/d
Remission: 80–85%
Risk of relapse is high, especially during the tapering off
a full dose of steroid should be given for at least 3–4 weeks.

24. Evaluation of Response to Prednisolone
Response after 3W +
Continue full dosage for another week then slowly taper over 6 months
Partial
Continue full dosage for another 2 weeks _
Anothr treatment

25. Packed red blood cell (PRBC)
Only for very symptomatic patients, who may suffer from life-threatening events
Small (3 ml/kg) amounts of leucodepleted PRBC should be given slowly under careful supervision

26. plasma-exchange
In the case of life-threatening events not responding to transfusions
Its optimal role is not established for WA-AHIA even if it may have some efficacy in cold-AHIA

27. Second and further-line treatment
Indication:
relapsing
resistant cytopenia
chronic disease that often requiring prolonged treatment with steroids

28. Attack Therapy: (Fast Response)
Monoclonal antibodies
Chemotherapy
Splenectomy
Maintenance:
Immunosuppressive agents, such as:
Mycophenolate mofetil (MMF)
Sirolimus
Cyclosporin

29. Rituximab Monoclonal antibody against the CD20 molecule
Causes B-cell depletion and is usually given at a dose of 375 mg/m2 on days 1, 8, 15 and 22.
Overall response rates between 77–93%

30. Rituximab Is preferred to splenectomy
Time to response: 3–6 weeks but also after up to 12 weeks
ALPS patients have lower response rates, higher risk of infection and prolonged hypogammaglobulinaemia

31. Mycophenolate mofetil
Response: 62-82%
Dose: 600 mg/m2 twice a day (maintaining serum levels between 1–3.5 microgram/ml)
Evaluation: after 3 months
In responding children:
full dose for a total of 2 years
tapered off over 6 months

32. Sirolimus Successful results in posttransplant AIHA
Dose: 2–3 mg/m2 once a day, maintaining serum levels between 4–12 ng/m2
Evaluation: after 3 months
For a total of 2 years followed by another 6 months of tapering off

33. Cyclosporin
5 mg/kg
Due to the side effects and the need for frequent clinical and serum level monitoring only after the failure of newer and more tolerable agents

34. IVIG Controversial and little data
Dose of 0.4–0.5 g/kg for 4–5 d, concomitantly with steroids or after their failure
Response: 55% in children
Only in patients with severe disease
Symptomatic thrombocytopenia

35. Splenectomy
Complication
Sepsis

36. Alemtuzumab humanized anti-CD52
Dose of 10 mg/m2/d for 10 d, or of 0.2 mg/kg for 5 d

37. Thrombopoietin receptor agonists
Romiplostim and eltrombopag have been increasingly used in some haematological disorders.
Reports of sustained remission after thrombopoietin receptor agonist discontinuation

38. Bortezomib Inhibitor of 26S proteasome
that has been successfully used in AC following SCT
A clinical trial is on-going in the setting of post-transplant AC

39. Stem cell transplantation
There is little data, and mainly from small series/case reports
Overall, these studies reported complete remission of around 50%

42. Treatment options for relapsed or refractory warm AIHA

43. Treatment options for relapsed or refractory cold agglutinin disease

44. In this Case:
CMV Gancyclovir+IVIG PLT
Then CMV Pred+IVIG HB

45. IVIG
1/ 22
1/23
1/25
1/28
2/1
2/10
2/17
2/26
3/2
3/7
3/16
WBC
8.5
8.2
9.9
15.1
16.1
12.6
9.5
17.3
11.3
10.3
RBC
1.48
3.45
2.64
1.99
2.32
2.97
3.04
2.23
2.5
3.16
4.02 Hb
4.5
9.4
6.9 6
7.2
8.6
8.8
6.3
7.9
10.1
MCV
87.2
86.7
88.3 95
100
91.2
88.2 91
99.2
99.4
95.5
MCH
30.4
27.2
26.1 30 31 29
28.9
28.3
31.6 32
31.3
PLT 10
<10
141 98
302
150
319
341
145