The Use of Intravenous Palivizumab for Treatment of Persistent RSV... in Children With Leukemia

The Use of Intravenous Palivizumab for Treatment of Persistent RSV Infection
in Children With Leukemia
Roberto P. Santos, Jeffery Chao, Anne G. Nepo, Shafiq Butt, Kathleen A. Stellrecht,
Jennifer M. Pearce and Martha L. Lepow
Pediatrics 2012;130;e1695; originally published online November 12, 2012;
DOI: 10.1542/peds.2011-1768
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
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CASE REPORT
The Use of Intravenous Palivizumab for Treatment of
Persistent RSV Infection in Children With Leukemia
AUTHORS: Roberto P. Santos, MD, Jeffery Chao, MD, Anne
G. Nepo, MD, Shafiq Butt, BS, Kathleen A. Stellrecht, PhD,
Jennifer M. Pearce, MD, and Martha L. Lepow, MD
Albany Medical Center, Albany, New York
KEY WORDS
children, intravenous palivizumab, leukemia, RSV
ABBREVIATIONS
ALC—absolute lymphocyte count
ALL—acute lymphocytic leukemia
ANC—absolute neutrophil count
hMPV—human metapneumovirus
IV—intravenous
IVIG—intravenous immunoglobulin
LRTI—lower respiratory tract infection
RSV—respiratory syncytial virus
www.pediatrics.org/cgi/doi/10.1542/peds.2011-1768
doi:10.1542/peds.2011-1768
Accepted for publication Jul 23, 2012
Address correspondence to Roberto Parulan Santos, MD,
Department of Pediatrics, Division of Infectious Diseases, Albany
Medical Center, 47 New Scotland Ave (MC 88), Albany, NY 12208.
E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2012 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have
no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
abstract
Palivizumab is a humanized monoclonal antibody used to decrease the
threat of respiratory syncytial virus (RSV) infection among children at
high risk. There are no standard guidelines due to conflicting data on
palivizumab’s use in the treatment of RSV lower respiratory tract
infections. Intravenous (IV) palivizumab was shown to be well tolerated and associated with decreased mortality in high-risk children
who have RSV disease. However, it did not prevent lower respiratory
tract infections and did not affect the survival rate of allogeneic stem
cell transplant recipients who had RSV infection. We present 2 children with acute lymphocytic leukemia (ALL) and persistent RSV infection while receiving chemotherapy. Patient A is a 4-year-old male
with Down syndrome, ALL, and persistent RSV infection for at least 3
months. Patient B is a 3-year-old female with pre–B cell ALL whose
chemotherapy intensification phase was delayed due to a month-long
RSV infection. RSV infections were determined by using real-time
polymerase chain reaction assays from nasopharyngeal swabs before
IV palivizumab therapy; patient A was positive for RSV at 36 cycles and
patient B was positive for RSV at 29 cycles. RSV infection was cleared
in both patients within 72 hours after receiving IV palivizumab (patient A: 16 mg/kg; patient B: 15 mg/kg). IV palivizumab may be a treatment option for persistent RSV infection among immunocompromised
patients. Pediatrics 2012;130:e1695–e1699
PEDIATRICS Volume 130, Number 6, December 2012
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e1695
Respiratory syncytial virus (RSV) is
responsible for ∼120 000 pediatric
hospitalizations each year and is the
most common cause of lower respiratory tract infection (LRTI) in children aged ,1 year in the United
States.1,2 Palivizumab, a humanized
monoclonal antibody directed against
the fusion protein of RSV,3 has been
successfully used as prophylaxis in
high-risk pediatric populations, such
as those with chronic lung disease,
preterm birth, congenital heart disease,
and immunocompromised states.4 A
study in 2007 found that combining
palivizumab with the antiviral nucleoside analogue ribavirin was effective in
decreasing the mortality associated
with acute RSV infections in certain
high-risk children.5 However, another
study in bone marrow transplant
patients found that palivizumab alone
had no impact on outcome.6 We report
RSV eradication with palivizumab in 2
pediatric patients who were undergoing
treatment for acute lymphocytic leukemia (ALL) with persistent RSV infection.
CASE REPORTS
Patient A is a 4-year-old male with Down
syndrome; he was diagnosed with ALL
14 months previously and was receiving
maintenance chemotherapy. He also
had a history of reactive airway disease.
The patient presented to the hospital
with a 1-day history of fever (101.6°F),
cough, and congestion. On admission,
his absolute neutrophil count (ANC)
was 4600 cells/mL and absolute lymphocytic count (ALC) was 580 cells/mL
(Fig 1). Chest radiographs were normal, but a nasopharyngeal swab realtime polymerase chain reaction assay
tested positive for RSV infection at 23.6
cycles. The number of cycles are inversely related to the amount of RSV
RNA detected, with values $50 indicating undetectable levels.7 The
results of the blood cultures were
negative. The patient was stable and
e1696
discharged on symptomatic treatment.
He was readmitted 1 week later with
fever and treated with antibiotics for 48
hours. RSV was still present (27.0
cycles) after antibiotic treatment, but
he was subsequently discharged on
symptomatic treatment.
The patient returned 2 months later
with respiratory distress, fever, tachycardia (153 beats per minute), tachypnea (36 breaths per minute), and
pulmonary retractions. His lungs were
clear to auscultation bilaterally, and his
chest radiograph was normal. White
blood cell count was 2300 cells/mL with
an ANC of 1470 cells/mL, an ALC of
640 cells/mL, and immunoglobulin G
of 400 mg/dL (mean for age: 780 mg/
dL). RSV (36.7 cycles) and human metapneumovirus (hMPV) PCR test results
were positive. He was started on antibiotic treatment. Forty-eight hours
later, after no signs of any clinical improvement and blood culture results
were negative, he received a 500-mg
dose of intravenous immunoglobulin
(IVIG). Approximately 15 hours later,
the patient received 16 mg/kg of palivizumab (250 mg). He tolerated treatment well, and rapidly improved
clinically and was discharged on the
fourth hospital day. Three days after
discharge, his PCR assay was negative
for RSV (Fig 1). He did not have a recurrence of RSV in that year.
Patient B is a 3-year-old female with
a history of pre–B cell ALL diagnosed 7
months earlier, who presented to the
hospital for her delayed intensification
chemotherapy with fever (101.7°F) of
unknown source. She was neutropenic
with an ANC of 8 cells/mL and lymphopenic with an ALC of 180 cells/mL. Her
chest radiograph showed no evidence
of pneumonia. The PCR assay tested
positive for RSV infection (27.3 cycles)
(Fig 1). Antibiotics were started, and
the patient was discharged after the
results of initial bacterial cultures
were negative.
The patient returned 1 week later; she
was febrile (102°F) and tachycardic
(121 beats per minute), with nasal
congestion and cough. Lungs were
clear to auscultation bilaterally. She
was anemic, thrombocytopenic, her
ANC was 0 cell/mL, and ALC was 500
cells/mL. RSV tested positive (36.7
cycles) and 72-hour antibiotics were
empirically started and chemotherapy
discontinued. The patient was still febrile after 3 days, with negative results
on blood and urine cultures without
any major changes in her blood counts.
Her PCR assay was still positive
for RSV (29.4 cycles). Intravenous (IV)
palivizumab at 15 mg/kg (200 mg) was
administered. She clinically improved
within 24 hours after administration,
and her RSV PCR was negative 72 hours
after treatment (Fig 1). Her white blood
cell count also improved (1900 cells/mL).
DISCUSSION
We report the successful use of IV
palivizumab for the treatment of persistent RSV infection in children with
leukemia who are undergoing chemotherapy. Previous studies have used
palivizumab in conjunction with ribavirin
and IVIG to treat severe RSV infection.5
Both patients were severely lymphopenic at the time of palivizumab administration, and both had an
undetectable viral RNA using PCR assay
within 3 days after therapy.
Previous studies have demonstrated
the importance of adequate CD4+ and
CD8+ lymphocytes as well as RSV antibodies in terminating RSV replication.
Patients who are immunosuppressed,
such as those who are premature (,32
weeks’ gestation), HIV infected, or undergoing immunosuppressive therapy,
are at increased risk for mortality and
morbidity from RSV infection due to
diminished levels of T lymphocytes.3,8
Patients with high titers of maternally
derived anti-RSV antibodies or who are
SANTOS et al
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CASE REPORT
FIGURE 1
Serial RSV PCR determinations and IV palivizumab treatment of children who have persistent RSV infection. Less than 50 cycles (green threshold line) indicate
detectable RSV RNA. Persistent RSV infections (:) were noted in both patients until IV palivizumab therapy was administered. Both patients were cleared of
RSV infection (n) immediately after receiving IV palivizumab (patient A [red line]: ∼16 mg/kg; patient B [blue line]: ∼15 mg/kg). ANC measured as cells/mL; ALC
measured as cells/mL
administered palivizumab are better
protected against infection.9
The Infectious Diseases Society of
America does not routinely recommend
treating RSV infections with palivizumab
in neutropenic patients who have upper
respiratory diseases.10 However, this
action may be indicated in our patients
with recurrent hospitalizations due to
persistent RSV infection and severe
lymphopenia. It is important to note that
after treatment in patient B, there was
evidence of bone marrow recovery after
administration of palivizumab (Fig 1).
This finding supports the use of palivizumab in our patients, as the infection
may have contributed to myelosupression. One study found that up to
80% of upper respiratory infections due
to RSV in hematopoietic stem cell
transplant recipients and patients with
hematologic malignancies can progress
to LRTIs.11
Future uses of palivizumab at the time
of diagnosis of RSV infection in children
with malignancies who are severely
lymphopenic should be considered
and evaluated for effects on morbidity and prolonged delays in their
chemotherapy regimen. Because
palivizumab has a long half-life, it
could prevent recrudescence as it
seemed to do in our patients. Therefore,
the use of palivizumab, not only as
prophylaxis but in the setting of acute
and chronic RSV infection, should be
considered. Furthermore, there are
cost-effective considerations in decreasing repeat hospitalizations and
avoiding delays in chemotherapy with
treatment of acute RSV in high-risk
populations.3
The main methodologic issue is the
relatively small number of patients who
can benefit from IV palivizumab for treatment, including patients with leukemia
undergoing chemotherapy. Furthermore, patients with Down syndrome
have some immunodeficiencies, and
studies have found that many may have
quantitative and qualitative impairments in their lymphocyte leves.12 More
specifically, it has been found that
these patients have decreased absolute numbers of all CD4+ and CD8+
T cells, as well as decreased proliferation and cytotoxicity of T cells in
different functional assays.13 In addition
to prophylaxis, treatment of RSV with
palivizumab should be considered in
children with Down syndrome, which is
an independent risk factor for severe
RSV LRTI.14 It is important to take this
into consideration in future studies, as
immunologic issues can influence viral
clearance and recovery time.
One issue raised with our patients was
the possibility of a concurrent bacterial
infection because symptoms seemed to
stabilize after antibiotic administration.
The likelihood of simultaneous secondary bacterial infection with RSV is
low (1%) in the upper respiratory tract
of previously healthy children. The most
common bacterial coinfection of RSV
bronchiolitis is acute otitis media, with
an occurrence of 57% to 76% in patients
with RSV infection. Neither patient
exhibited any signs or symptoms of
acute otitis media.15 Furthermore, RSV
infections in the upper respiratory tract
usually last between 7 and 10 days.16
With patient A, the time frame between
the first and second admission was
fairly short (∼10 days), which suggests
the possibility of persistent infection
rather than a new exposure or a secondary bacterial infection. More importantly, the patient’s condition improved
after palivizumab therapy.
Another issue is the simultaneous infection with hMPV in patient A. Although
we cannot say for certain that the cause
of his hospitalization was due to RSV,
a few reasons may indicate more
strongly that the hospitalization was
due to RSV and not to hMPV. First,
the patient had a history of hospitalizations due to a persistent RSV
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infection. Second, although hMPV and
RSV have similar presentations, RSV
is more likely than hMPV to cause
bronchiolitis.17 Finally, 1 study reported that RSV and hMPV coinfection
leads to an increased severity of disease than when compared with each
virus alone. During patient A’s third
hospital admission, he did not exhibit
any significant difference in severity of
symptoms compared with previous
admissions for RSV alone.18
Patient B may also have had a persistent
RSV infection at her second admission.
The reason the patient was readmitted
much earlier may be associated with
the fact that she was more lymphopenic
than the first patient (Fig 1). However,
due to the shortened time intervals
between admissions, the infection was
most likely a persistent rather than
a recurrent infection and may be associated most likely with RSV because palivizumab rapidly improved
the patient’s symptoms when broadspectrum antibiotics did not.
The RSV PCR assay is a qualitative test
(Prodesse ProFlu+, Gen-Probe, Inc, San
Diego, CA)7 that can be used semiquantitatively with an inverse relationship
between the amount of viral RNA in the
respiratory specimens and the cycles
reported. It is 1 of the most sensitive
(98%) commercial tests for detection of
RSV infection and has a specificity
.99%.19 Less than 50 cycles indicates
detectable RSV RNA, and this cutoff value
is specific to our laboratory. Other cutoff
values may vary depending on the assay
being used. Compared with other diagnostic methods such as viral culture,
enzyme immunoassay, and serology, realtime polymerase chain reaction has
allowed for more accurate assessments
of RSV infection and correlates well with
active or recent infections.7,19 In addition,
the duration of RSV shedding coincided
well with the duration of symptoms
among patients with severe immunodeficiency.20 The issue of PCR detecting dead
virus is less of a problem for RNA viruses
because RNA is labile, and once a virus is
killed, its outer coat will start to break
down and expose the RNA to RNases in
the human body.
transplant. The management of RSV in
these populations has been limited to
ribavirin, IVIG, and palivizumab.21 IV
palivizumab may be an alternative
treatment option for other populations
with similar vulnerability to RSV infections.
Finally, future studies should determine the usefulness of palivizumab
in the prevention or treatment of
acute and persistent or recurrent RSV
infection in certain high-risk patients.
It would be of interest to evaluate
other monoclonal antibodies in development such as motavizumab against palivizumab as prevention or
treatment.22
CONCLUSION
Palivizumab use in 2 children with
leukemia demonstrated success in
treating persistent RSV infection.
It is important to remember that RSV
infection is not limited to the pediatric
population. It is also a common cause of
adult viral infections in those who have
undergone hematopoietic stem cell
ACKNOWLEDGMENT
This case study was approved under
“Expedited Review” by the Committee
on Research Involving Human Subjects,
Albany Medical Center (November 30,
2010).
5. Chávez-Bueno S, Mejías A, Merryman RA,
Ahmad N, Jafri HS, Ramilo O. Intravenous
palivizumab and ribavirin combination for
respiratory syncytial virus disease in highrisk pediatric patients. Pediatr Infect Dis J.
2007;26(12):1089–1093
6. de Fontbrune FS, Robin M, Porcher R, et al.
Palivizumab treatment of respiratory syncytial virus infection after allogeneic hematopoietic stem cell transplantation. Clin
Infect Dis. 2007;45(8):1019–1024
7. Gen-Probe, Inc. Prodesse Pro Flu+. Novato,
CA: Biosearch Technologies, Inc; 2010:1–29
8. Graham BS, Bunton LA, Wright PF, Karzon
DT. Role of T lymphocyte subsets in the
pathogenesis of primary infection and
rechallenge with respiratory syncytial virus in mice. J Clin Invest. 1991;88(3):1026–
1033
9. Stensballe LG, Ravn H, Kristensen K, et al.
Respiratory syncytial virus neutralizing
antibodies in cord blood, respiratory syncytial virus hospitalization, and recurrent
wheeze. J Allergy Clin Immunol. 2009;123
(2):398–403
10. Freifeld AG, Bow EJ, Sepkowitz KA, et al.
Clinical practice guideline for the use of
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patients with cancer: 2010 update by the
infectious diseases society of america. Clin
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e1699
The Use of Intravenous Palivizumab for Treatment of Persistent RSV Infection
in Children With Leukemia
Roberto P. Santos, Jeffery Chao, Anne G. Nepo, Shafiq Butt, Kathleen A. Stellrecht,
Jennifer M. Pearce and Martha L. Lepow
Pediatrics 2012;130;e1695; originally published online November 12, 2012;
DOI: 10.1542/peds.2011-1768
Updated Information &
Services
including high resolution figures, can be found at:
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2012 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
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