Case presentation Dr. Neda Ashayeri

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

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

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: 46212 Ophthalmology study: Nl Brain Sono: Nl

Diagnosis Evans

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

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

Incidence and prevalence Iincidence of AIHA: 0.4 cases/100 000 children per year 13% - 73% of patients with AIHA: have multi-lineage involvement

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

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)

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

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

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

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

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

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

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

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

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,

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

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.

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

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

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

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

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

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%

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

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

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

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

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

Splenectomy Complication Sepsis

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

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

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

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

Treatment options for relapsed or refractory warm AIHA

Treatment options for relapsed or refractory cold agglutinin disease

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

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