Abstract
Compliment activation has been implicated in Delayed Hemolytic
Transfusion Reaction (DHTR) in patients with sickle cell disease, and
eculizumab has been reported as an effective treatment for patients with
DHTR. Previously reported patients with SCD and DHTR responded well
after few doses of eculizumab. We report on the long-term use of
eculizumab in a pediatric sickle cell patient with DHTR who had a slow
and less sustained response. Long-term use of eculizumab in this SCD
patient was effective and well tolerated.
Introduction
DHTR is a rare but serious complication of red cell transfusion,
occurring in 3-8% of transfused sickle cell
paints.1 The majority of DHTR in patients with SCD are
mediated by antibodies2 and treatment of
DHTR includes immune regulation with steroids, IVIG and rituximab.3 Dysregulated compliment activation has been
implicated in DHTR and may be a particularly important component of
pathophysiology in cases where no antibody is
identified.1 There is a growing body of literature
demonstrating the efficacy of eculizumab for the treatment of DHTR in
patients with sickle cell disease, especially those who may not respond
to more conventional therapy. 3 We report on a
pediatric patient with SCD and DHTR unresponsive to therapy, who
responded when eculizumab was added. Unlike other patients described in
the literature she did not tolerate weaning of her multi-agent
treatment, leading to 22 total months of treatment for the DHTR. This is
the first report of long-term use of eculizumab in a patient with sickle
cell disease for disorders of immune dysregulation. We report that long
term use of eculizumab is effective and well tolerated in this
setting.
Results
The patient is a 16-year-old female with homozygous SCD on a chronic
transfusion protocol. She was admitted to the hospital
for VOC associated with an acute viral gastroenteritis. Prior to
discharge, she received a RBC transfusion as part of her regularly
scheduled transfusion protocol once she had returned to clinical
baseline. Pre-transfusion hemoglobin was 9.3 g/dL. Ten days following
transfusion, she presented to the emergency department with jaundice,
tachycardia, fatigue and a hemoglobin of 4.9 g/dL. The DAT was negative,
she was diagnosed with presumed DHTR and admitted to the hospital for
management. She was started on intravenous methylprednisolone 2 mg/kg
and IVIG 1 g/kg every 2 weeks with stabilization but no improvement of
hemoglobin. Rituximab was added without benefit after four doses.
Her hemoglobin dropped to a nadir of 3.3 g/dL. At that time,
her CH50 was significantly elevated (>60)
suggesting ongoing compliment activation contributing to
sustained hemolysis. She received first dose of eculizumab on day 46,
with day zero being the day of her initial transfusion. With the
addition of eculizumab to multi-agent therapy, her hemoglobin increased
for the first time during hospitalization. Additionally, her CH50
returned to normal. Upon stabilization of her hemoglobin, attempts were
made to wean her multimodal therapy. Because of the side effect
profile, steroids were chosen as the first intervention to be weaned.
She had transient decreases in her hemoglobin with each wean in her
steroid dosing which led to a very protracted wean. She continued IVIG
and eculizumab during the wean; a strategy that was continued into the
outpatient setting. In total, her steroids were weaned over 16
months, then transitioned to hydrocortisone at physiologic replacement
doses. Once she had a stable hemoglobin independent of steroids, her
IVIG was weaned while continuing her eculizumab. Her eculizumab was then
spaced from every 2 weeks to every 3 weeks, then every 4 weeks, and then
stopped. In total, she received 22 months of therapy for her DHTR with
eculizumab. Hydroxyurea was reinstituted during her initial
hospitalization and dose escalated to maximum tolerated dose.
Discussion
Eculizumab is a humanized monoclonal antibody that binds to complement
protein C5 and prevents the cleavage of C5 to C5b preventing
the formation of terminal complex C5b-9. 10 The role
of compliment activation is incompletely understood in the setting of
DHTR, but both classic compliment activation as well as alternate
pathways of compliment activation have been implicated as important
components of the pathophysiology.1 This is supported
by published reports that eculizumab is an effective treatment of DHTR
in SCD. 6,7,4 In each of these case reports, adults
with SDC and DHTR were treated with 1-6 total doses of eculizumab in
addition to multiagent therapy. Each of the patients had an increase in
hemoglobin after a short course of eculizumab with a rapid wean of
therapy after the patient returned to baseline.
In contrast to previously reported experience, the pediatric patient we
report had improvement in hemoglobin after eculizumab but did not return
to baseline hemoglobin until day 128 after initial blood transfusion.
This was accomplished after nine doses of eculizumab, five doses of
IVIG, high dose steroids, and a blood transfusion on day 86 of
hospitalization. Our patient did not tolerate
discontinuation of DHTR therapies, with a dip in hemoglobin following
each de-escalation of therapy. This delayed and unstained response to
eculizumab led to a prolonged need for treatment lasting for 22 months,
and a stepwise removal of each component of her therapy.
While long term use of eculizumab has been described in other
populations, this is the first description of its protracted use in
SCD. We sought to examine not only the efficacy, but also safety of long
term use of eculizumab in this patient by comparing the incidence of VOC
pain, ACS, and serious infectious complications during her treatment
period to the time period after she was treated with
eculizumab. Patients with SCD have increased risk for infectious
complications at baseline particularly due to encapsulated organisms.8 In the 22 months prior to her DHTR, our patient had
one episode of bacteremia with mycobacterium porcinum requiring
central line removal. She had no other significant infectious
complications related to her underlying SCD. During the 22 months
of eculizumab therapy, our patient had three documented episodes of
bacteremia. The first with methicillin susceptible staphylococcus
aureus 64 days after her first dose of eculizumab. The second episode
of bacteremia due to methicillin-sensitive staphylococcus
aureu s occurred 114 days into eculizumab therapy, and a third episode
of bacteremia due to enterobacter cloacae on day 370
of eculizumab therapy. The second episode of staph aureus
bacteremia was associated with likely acute osteomyelitis, diagnosed by
imaging without biopsy/culture. All infectious complications in this
patient occurred when multiple immune suppressive therapies including
steroids and rituximab were prescribed and with adherence to
antimicrobial prophylaxis including fluconazole, sulfamethoxazole
trimethoprim, and penicillin. She had no infectious complications after
being weaned off from other DHTR therapies when she was maintained on
eculizumab as a single agent.
During 22 months of eculizumab therapy, our patient had 11
hospitalizations, 7 were for VOC pain. During the 12 months after she
completed all therapy with eculizumab, she had 22 hospital
admissions. 16 were due to VOC. Outpatient opioid prescriptions were
assessed during the same two time periods and found a median of 76 MME
per day during eculizumab therapy compared to a median 98 MME per day
during the 12 months after eculizumab therapy. There were no incidences
of acute chest syndrome during her therapy, or the 12 months after
completion of therapy. This suggests that eculizumab did not worsen the
incidence of VOC events.
Long term eculizumab therapy for DHTR in this pediatric patient with
SCD was effective and well tolerated. There were no infectious
complications during the time period where she was treated with
eculizumab monotherapy. Similarly, she had fewer VOC episodes during the
time she was treated with eculizumab compared to the time period after
discontinuation of therapy. Further studies are required to understand
the true role of eculizumab in SCD DHTR.
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Figure 1: Hemoglobin trend after DHTR illustrating response to various
interventions. There was no sustained increase in hemoglobin with the
addition of IVIG, Prednisone, or Rituximab. However, there was an upward
trend in hemoglobin following initiation of eculizumab at day +46. This
figure also demonstrates the transient dips in hemoglobin following
weans in her steroid therapy, suggesting that her response to therapy
would not be sustained, prohibiting a rapid de-escalation in
interventions.