Vol 41 # 3 September 2009 - Kma.org.kw

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September 2009 KUWAIT MEDICAL JOURNAL 257 Case Report Rituximab in Severe Refractory Autoimmune Hemolytic Anemia in Children Ravishankar Nagaraj 1 , Sundus Alsherida 1 , Adekunle Adekile 2 1 Department of Pediatrics, Mubarak Al-Kabeer Hospital, and 2 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait ABSTRACT Kuwait Medical Journal 2009; 41 (3): 257-260 Rituximab, an anti-CD20 monoclonal antibody, is a relatively new drug for autoimmune diseases, and its use in childhood autoimmune hemolytic anemia (AIHA) is still limited. We report our experience with two children who presented with acute severe AIHA not responding to standard treatment modalities. The first patient was a 4- month-old infant with severe AIHA who did not respond to steroids, intravenous immune gammaglobulin (IVIG), cyclophosphamide and plasmapheresis, but responded well to rituximab. The second patient was an 8-year-old with a similar presentation who did not respond to all modalities of treatment including rituximab. He eventually required a splenectomy to control his hemolysis. While rituximab is a useful addition to the treatment regime in AIHA, it is not always effective and the occasional patient may still require splenectomy. KEY WORDS: autoimmune hemolytic anemia, children, plasmapheresis, rituximab INTRODUCTION Autoimmune hemolytic anemia (AIHA) is a rare disorder in children in whom the most common variant is the warm antibody type characterized by IgG auto-antibodies (mainly IgG1) directed against most red cell antigens (pan-agglutinins). The disorder is acute in the majority of children with hemolysis developing over hours to days [1-3] . Most cases are associated with viral (cytomegalovirus, parvovirus B19) or bacterial infection and, less frequently, with malignancy (Hodgkin disease) or immunodeficiency states (HIV infection, common variable immunodeficiency). Although the disorder generally responds well to corticosteroid therapy, patients with a severe and refractory course may require intravenous immunoglobulin (IVIG), cytotoxic drugs or splenectomy [1-3] . Recently, rituximab, an anti-CD 20 monoclonal antibody, has emerged as a promising agent in refractory cases of AIHA in children [4] . Here we discuss the management of two children with severe AIHA who showed different responses to rituximab. CLINICAL PRESENTATION Patient 1 A 4-month-old Egyptian female infant was admitted with a 2-day history of pallor, lethargy, and difficulty in feeding. Her parents had noted red- brown staining of the diaper from urine. She had recently recovered from an upper respiratory tract infection and was otherwise well. On admission, she was febrile and irritable with marked pallor and jaundice. Physical examination revealed an enlarged spleen with a normal liver span and there was no skin rash, lymphadenopathy or bone tenderness. Initial investigations showed: hemoglobin 28 g/l, hematocrit 0.095, white blood cells 10.4 x 10 9 /l, platelets 163 x 10 9 /l, reticulocyte count of 28.4%, MCV 109.7 fl and MCH 37 pg. Total serum bilirubin (94 μmol/l), conjugated bilirubin (8 μmol/l) and serum LDH (543 IU/l) were elevated. The peripheral blood film showed severe anisopoikilocytosis with macro-ovalocytes, polychromasia, nucleated red cells, increased rouleaux formation and a few spherocytes. Occasional activated and atypical lymphocytes were also seen. Urine examination showed hemoglobinuria. The direct antiglobulin test (Coombs’ test) was positive; sickling test was negative and glucose-6-phosphate dehydrogenase was normal. Antibody studies confirmed the diagnosis of warm antibody-type hemolytic anemia with panreactive IgG antibodies. Computed tomography scan of abdomen and chest showed no lymphadenopathy, thymic hyperplasia or other masses. Address correspondence to: Prof. Adekunle D. Adekile, Department of Pediatrics, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait . Tel: +965 531-9486, Fax: +965 533-8940, E-mail: adekile@hsc.edu.kw
258 Rituximab in Severe Refractory Autoimmune Hemolytic Anemia in Children She received washed filtered packed red cell transfusions cross-matched against the mother’s serum. Initial treatment was started with oral prednisolone, 2 mg/kg/day. She did not require another transfusion in the first week of treatment. However hemolysis worsened over the next two weeks, with hemodynamic instability, requiring repeated transfusions and ICU care. IVIG was added at 1 g/kg at weekly intervals but she remained transfusion dependent. Therefore methylprednisolone pulse therapy, 30 mg/kg/day for three days, was given with poor response. High dose cyclophosphamide, 50 mg/kg/day over five days, was added to control the persistent hemolysis. She subsequently developed severe febrile neutropenia and enterocolitis, which were treated with antibiotics and granulocyte-colony stimulating factor (G-CSF), (Neupogen, Filgrastim ® , Hoffmanla-Roche, Ltd., Basel, Switzerland) at a dose of 6 mcg/kg subcutaneously 12 hourly for six days. Her renal function remained normal throughout this period. As transfusion requirements persisted, rituximab (at a weekly dose of 375 mg/m 2 ) was commenced with plasmapheresis (using a Prisma 4 hemodialysis machine fitted with a Gambro membrane filter) as additional supportive treatment. Prednisolone was gradually tapered and withdrawn. Hemolysis abated after three doses of rituximab with the hemoglobin rising to 60-80 g/l and no further transfusions were required. Plasmapheresis had to be discontinued after two sessions because of technical difficulties. However, the patient’s improvement was rather slow and rituximab was continued for a total of eight weeks after which the hemoglobin increased to 120 g/l, the spleen regressed and there were no adverse effects from the drug. Although there was an initial drop in immunoglobulin levels (especially IgG) requiring monthly IVIG infusions, subsequently they rose to normal levels. During this period of drug-induced hypogammaglobulinemia she suffered no infections. She is well one year after the acute illness. Patient 2 An 8-year-old boy was admitted with a 3- day history of fever, abdominal pain, jaundice, vomiting and passing dark urine. The stool color was normal. He had a positive family history for AIHA with his maternal uncle undergoing splenectomy and subsequently requiring steroid therapy for two years after surgery. On examination he was ill looking, febrile, pale, icteric and dehydrated. His abdomen was distended with right upper quadrant tenderness, with an enlarged spleen and liver. There were no skin rashes or lymphadenopathy, and his joints were normal. September 2009 Laboratory investigations revealed a hemoglobin of 73 g/l, reticulocyte count of 3.7%, normal platelet count (289 X 10 9 /l) with direct hyperbilirubinemia and elevated LDH (593 U/l). His direct Coombs’ test was positive with panreactive anti-erythrocyte antibodies. An abdominal ultrasound examination showed enlarged liver and spleen with no signs of cholecystitis or gallstones. Treatment was started with oral prednisolone at 2 mg/kg/day but hemolysis persisted (with a drop in hemoglobin to 32 g/l over 72 h) and he required almost daily transfusion to keep his Hb at about 40g/l in the first week of presentation. At this time his blood film showed macrocytosis with numerous target cells and activated lymphocytes. Due to his unstable clinical condition, methylprednisolone pulse therapy was added and repeated in the second week but with no clinical response. He remained transfusion dependent in spite of adding IVIG to his treatment. At this point, rituximab infusion was started at a weekly dose of 375 mg/m 2 . Hemolysis abated after the first dose with his hemoglobin stabilizing at about 70g/l. However, hemolysis started afresh soon after the third weekly dose of rituximab with Hb dipping again below 40 g/l. This time he underwent three sessions of plasmapheresis with only partial response. Transfusion requirements increased and finally at about six weeks after the initial presentation, splenectomy was carried out and steroid therapy was gradually withdrawn. His hemoglobin stabilized at about 110 g/l and he has suffered no recurrences in the subsequent ninemonth follow up period. There was only slight fall in his serum IgG, which normalized after six months. He did not have any infections. DISCUSSION AIHA has an estimated annual incidence of 0.2 per 100,000 individuals below 20 years of age. The highest incidence is seen in children below four years of age [1,2] . In about half of these patients the disorder has an acute presentation with hemolysis worsening over days. Among young children it can be frequently life-threatening, with a mortality rate of approximately 10% [3] . When it occurs in infants, as in our first patient, the disorder tends to be severe and refractory to treatment and often results in transfusion dependency [1,2] . Rare familial variants of AIHA present with similar acute hemolysis [1] . Most cases of AIHA in children are due to the warm IgG autoantibodies directed against almost all red cell surface antigens. These antibodies are bound to the red cell membrane and have a variable capacity to fix complement. Most of the hemolysis occurs in the spleen as the IgG-coated red cells are bound to the Fcγ receptors of the splenic macrophages with
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