Vol 41 # 3 September 2009 - Kma.org.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gradually tapered and withdrawn.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