Download Preventing hospitalizations for respiratory syncytial virus infection

POSITION STATEMENT
Preventing hospitalizations for
respiratory syncytial virus infection
Joan L Robinson, Nicole Le Saux; Canadian Paediatric Society
Infectious Diseases and Immunization Committee
Paediatr Child Health 2015;20(6):321-26
Posted: Sep 8 2015 Updated: May 12 2016
Abstract
Respiratory syncytial virus infection is the leading
cause of lower respiratory tract infections in young
children. Palivizumab has minimal impact on RSV
hospitilization rates as it is only practical to offer it
to the highest risk groups. The present statement
reviews the published literature and provides updat­
ed recommendations regarding palivizumab use in
children in Canada.
Key Words: At-risk infants; Chronic lung disease;
Congenital heart disease; Palivizumab; Prematurity; Prophylaxis; RSV
Epidemiology
Respiratory syncytial virus (RSV) is the most common
cause of lower respiratory tract infections (LRTIs) in
young children worldwide, with almost all experiencing
their first RSV infection by two years of age. In devel­
oped countries, 1% to 3% of all infants are hospitalized
with RSV infection. In Canada, the RSV season typi­
cally begins in November or December and persists for
four to five months. The present statement replaces
four previous position statements from the Canadian
Paediatric Society on this topic[1]-[4] because there is
evidence that the risk of RSV hospitalization does not
warrant the use of palivizumab in many children for
whom it was previously recommended.
Preventing RSV hospitalizations
Instructions for parents
Young infants (and their siblings) should not be in con­
tact with individuals with respiratory tract infections
whenever practical. A Cochrane review suggests that
hand hygiene in the home decreases the spread of
respiratory tract infections in children.[5] Breastfeeding
and avoidance of cigarette smoke are also presumed
to decrease the incidence and/or severity of viral respi­
ratory tract infections.
Palivizumab
Palivizumab, a humanized murine monoclonal im­
munoglobulin G-1 directed against an epitope on the F
glycoprotein of RSV, is produced by recombinant DNA
technology, and has 95% human and 5% murine
amino acid sequences. Rare cases of anaphylaxis are
the only recognized serious adverse event. Standard
dosing is 15 mg/kg administered intramuscularly every
30 days during RSV season for a maximum of five
doses. Some Canadian programs administer the sec­
ond dose 20 days after the first dose to prevent a low
trough level;[6][7] however, there are no data showing
an increased RSV hospitalization rate before the sec­
ond dose. Palivizumab is available in 50 mg or 100 mg
vials. Drug costs for five doses of palivizumab for an
infant with a mean weight of 5 kg are approximately
$5,600, assuming no waste.
Palivizumab use in Canada is directed by provincial or
territorial programs. When practitioners have questions
about eligibility, they should contact their local pro­
gram; contact information is available through neonatal
care units. Some programs routinely begin prophylaxis
in November or December. Others use laboratory sur­
veillance from local laboratories or from the national
Respiratory Virus Detection Surveillance System
(http://www.phac-aspc.gc.ca/bid-bmi/dsd-dsm/rvdi-divr/
index-eng.php) to determine when to start palivizumab.
The latter strategy is more complicated to organize
than having a uniform start and stop date, but has
been demonstrated to save drug costs in a recent
Canadian study.[8]
INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE, CANADIAN PAEDIATRIC SOCIETY |
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Efficacy of palivizumab
Table 1 summarizes the results of randomized con­
trolled trials (RCTs) investigating palivizumab, demon­
strating a reduction in hospitalizations of approximately
80% in infants with prematurity but without chronic
lung disease of prematurity (CLD), of 40% in infants
with CLD, and of 45% in children with congenital heart
disease (CHD). Efficacy was not demonstrated in the
CHD subgroup with cyanotic heart disease.[9]-[11]
Observational studies demonstrate effectiveness in the
‘real world’, where clinicians, in conjunction with par­
ents, decide who should receive palivizumab and
where compliance is often lower than in RCTs. A re­
cent systematic review summarized 20 published ob­
servational palivizumab studies. Estimates of effective­
ness were generally in the range predicted by the
RCTs.[12] Exceptions included one study with higher
and two with lower efficacy. A study from Korea
showed a very high 82% efficacy in children with CLD.
[13] A study from Sweden showed no efficacy, with RSV
hospitalization in 11 of 151 children (7.3%) with CLD
who were given palivizumab versus three of 44 (6.8%)
who were not (P=0.91). For infants born at <33 weeks’
gestational age (GA) without CLD, hospitalization rates
were two of 75 (2.7%) with palivizumab and 22 of 567
(3.9%) without (P=0.61).[14] A study from Japan also
showed no efficacy, with RSV hospitalization rates of
39 of 2806 (1.4%) and 45 of 3496 (1.3%) with and
without palivizumab in preterm infants, although testing
for RSV was not widely available.[15]
False-negative results for the detection of RSV in the
presence of palivizumab have been described;[16] thus,
the efficacy of palivizumab may be lower than that
demonstrated in studies.
TABLE 1
A summary of findings on the efficacy of palivizumab for preventing respiratory syncytial virus (RSV) hospitalizations in randomized controlled trials
Risk group
Illustrative comparative
Relative effect Participants, n
risks of RSV hospitalization (95% CI)
(studies, n)
(95% CI)
Assumed
risk
Corresponding
risk
Quality of the evi­
dence (GRADE)*
Comments
Control
Palivizumab
Infants born at <36 weeks’ GA with no CLD who are <6
months of age at the start of RSV season – RCT (1998)[9]
81 per
1000
18 per 1000 (8
to 39)
RR 0.22 (0.1 to 740 (1 study)
0.48)
++++ high
NNTI=16 (9–
32)
Children with CLD diagnosed clinically and treated with
steroids, bronchodilators, diuretics or supplemental oxygen
in the past 6 months who are <24 months of age at the
start of RSV season – RCT (1998)[9]
128 per
1000
78 per 1000 (51 RR 0.62 (0.4 to 762 (1 study)
to 122)
0.95)
++++ high
NNTI=20
(10–198)
Children with hemodynamically significant CHD who are
<24 months of age at the start of RSV season – RCT
(2003)[10]
97 per
1000
53 per 1000 (36 RR 0.55 (0.37
to 80)
to 0.82)
1287 (1 study)
++++ high
NNTI=23
(95% CI 14–
66)
Children with CF – RCT (2005)[11]†
11 per
1000
11 per 1000 (1
to 177)
186 (1 study)
++−−low
RR 1.02 (0.06
to 16.09)
*GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Fur­
ther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very like­
ly to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the esti­
mate. CF Cystic fibrosis; CHD Congenital heart disease; CLD Chronic lung disease of prematurity; GA Gestational age; NNTI Number needed to vaccinate to prevent
one case; RCT Randomized controlled trial; †Only ever published in abstract form, so many details are unclear
Cost-effectiveness of palivizumab
Reports concerning the cost-effectiveness of
palivizumab have varied, owing in large part to dis­
parate estimates of its short- and long-term benefits.[17]
[18] In terms of short-term benefits, there is no evidence
that palivizumab prevents mechanical ventilation or
death or that breakthrough RSV hospitalizations are
less severe than hospitalizations in controls. With re­
2 | PREVENTING HOSPITALIZATIONS FOR RESPIRATORY SYNCYTIAL VIRUS INFECTION
gard to longer-term benefits, one RCT showed that
palivizumab administered to infants 33 to 35 weeks’
GA without CLD decreased days with parent-reported
wheezing in the first year from 4.5% to 1.8% (P<0.001;
number needed to treat = 38) and decreased recurrent
wheezing from 21% to 11% (P=0.01).[19]
Prophylaxis must be provided to many infants to pre­
vent one hospitalization (Table 1), while the cost to
provide prophylaxis to a single infant (approximately
$5,600) exceeds that of a typical RSV hospitalization
(three or four days). Therefore, given the paucity of ev­
idence that palivizumab prevents severe outcomes,
palivizumab is unlikely to be cost-effective in children
with prematurity, CLD or CHD, and can only be poten­
tially cost-effective in settings where RSV hospitaliza­
tions are exceedingly common and very expensive
(such as Inuit infants in rural Baffin Island).[20]
Challenges of identifying the children at
highest risk
CHD and CLD
Higher rates and durations of hospitalization and more
intensive care unit admissions occur in RSV-infected
children with CHD or CLD compared with healthy term
infants. A common recommendation has been to offer
palivizumab to children up to 24 months of age at the
start of RSV season when they have hemodynamically
significant CHD or are still receiving therapy for CLD. A
24-month cut-off applies simply because this age limit
was used in the original studies.[9][10] One study from
Switzerland showed that only two of 10 RSV admis­
sions in children with CHD occurred in the second year
of life,[21] while a study from Norway showed a mean
admission age of 9.5 months in children with CHD.[22]
In the original palivizumab CHD trial, RSV admissions
in controls declined from 12% in infants <6 months of
age to 7% at six to 12 months, and to 4% at 12 to 24
months.[10] Admission rates in one Canadian prospec­
tive CHD trial were 16% at <6 months of age (n=42),
0% at six to 12 months of age (n=26), and 1% at 12 to
24 months of age (n=105).[23] A study involving children
on Medicaid with CLD showed an estimated RSV ad­
mission rate (extrapolated from the incidence of bron­
chiolitis) of 38.8% in year one (95% CI 30.4% to
49.0%) falling to 7.3% (95% CI 4.2% to 11.9%) in year
two, and 1.3% (95% CI 0.2% to 4.6%) in year three.[24]
Figures 1 and 2[9][10][13][21][23][25]-[33] summarize the inci­
dence of RSV hospitalization in studies that investigat­
ed proven RSV infection in children with CHD or CLD
who did not receive palivizumab. They show rates of
approximately 10% with CHD and 15% to 20% with
CLD. One limitation is that most studies were conduct­
ed in the 1990s and very few were population-based.
Hospitalized infants were not uniformly tested for RSV
and most studies were from the premolecular era of
RSV testing; thus, RSV hospitalizations may have
been missed. There have been major advances in
therapy for CHD and CLD such that children with these
conditions now have less severe disease than children
born in the 1990s. At the same time, however, increas­
es in infant survival rates mean that there are still med­
ically fragile children with severe CHD and CLD.
Prematurity without CLD
Since palivizumab was licensed in 2002, most Canadi­
an infants born before 32 weeks’ GA without CLD were
offered prophylaxis if they were <6 months of age at
the start of RSV season. Programs have offered pro­
phylaxis to selected infants born up to 35 weeks, 6
days’ GA who were believed to be at higher risk for
RSV hospitalization, typically based on a scoring sys­
tem.[34] Despite the fact that the efficacy of palivizumab
is higher in healthy preterm infants than in those with
CHD or CLD, use in healthy premature infants has re­
cently come into question[35] based on the following in­
formation:
• Although RSV hospitalization rates correlate with
GA, the magnitude of difference between preterm
infants without CLD and term infants does not war­
rant routine use of palivizumab, except possibly in
very preterm infants. Figure 3[9][30][36]-[43] shows
RSV hospitalization rates without palivizumab that
are significantly lower than for infants with CHD
(Figure 1) or CLD (Figure 2). Even in infants born
before 30 weeks’ GA, admission rates were <10%
in all but one study.[37] The main limitation of Figure
3 is that, as with Figures 1 and 2, case findings
were incomplete in some studies, but this proviso
should have applied equally to all GAs.
• There have been significant advances in neonatol­
ogy, such that infants with or without CLD are now
healthier and have less residual lung damage than
did infants of the same GA in the past.
• The parents of fragile infants are now more aware
of the principles of infection transmission than in
decades past. Parental leaves are longer and there
are fewer young infants in child care settings,
where the risk of RSV acquisition is higher.
INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE, CANADIAN PAEDIATRIC SOCIETY |
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Figure 1) Percentage of proven respiratory syncytial
virus (RSV) hospitalizations in children with congenital
heart disease who were not given palivizumab
arranged according to the year that data collection
ended. At study entry, children were up to 12 months
[26], 24 months[10][21][25][27] or 36 months[23] of age. For
the study from Sweden,[26] the number of children with
congenital heart disease was estimated
4 | PREVENTING HOSPITALIZATIONS FOR RESPIRATORY SYNCYTIAL VIRUS INFECTION
Figure 2)
Incidence of proven respiratory syncytial virus (RSV)
hospitalizations per 1000 children with chronic lung
disease of prematurity who were not given palivizum­
ab, presented according to age at the time of the
study. The bars represent 95% CIs (except for refer­
ence 29, in which raw data were not provided). For the
study from Sweden,[26] the number of children with
chronic lung disease of prematurity was estimated
Figure 3) Incidence of proven respiratory syncytial virus (RSV) hospitalizations per 1000 preterm children without chronic lung disease of prematurity who were not
given palivizumab, arranged according to gestational age. The bars represent 95% CIs. RSV testing was not performed in 38 of 118 admissions in reference 36. *The
upper limit of the 95% CI is 42.9
Aboriginal infants
High rates of hospitalization due to LRTIs have been
described in isolated Inuit populations: 484 per 1000
infants <6 months of age in the Qikiqtaaluk (Baffin) re­
gion of Nunavut in 1997/1998,[44] and 202 per 1000 in­
fants <12 months of age in 2009/2010.[45] Rates were
590 per 1000 infants in the first year of life in the Kitik­
meot region of Nunavut between 2000 and 2004[46]
and 389 per 1000 in 2009/2010.[45] Approximately onehalf of LRTIs are due to RSV. There is a high incidence
of complications when infants from remote Northern
communities are hospitalized with LRTIs.[46] Morbidity
from LRTIs appears to be far lower in non-Inuit Aborig­
inal children.
Whether palivizumab should be offered to term Inuit in­
fants in high-incidence communities is controversial.
Palivizumab would have saved costs in term infants
during the 2002 RSV season in rural Baffin Island Inuit
communities, where hospitalization requires air evacu­
ation,[20] with similar findings from the same communi­
ties in the 2009 RSV season.[47] It appears to be likely
that other measures to reduce LRTIs, such as im­
proved housing, prevention of exposure to smoke, and
optimal use of influenza and other vaccines, would be
more cost-effective than palivizumab in the long term.
[48]
Immunocompromised children
There are no population-based data for this population,
but severe disease and prolonged viral shedding are
well-recognized risks.[49] A 2010 to 2013 Canadian
Paediatric Surveillance Program study estimated an
RSV hospitalization rate of five of 488 (1.0%) for
hematopoietic stem cell transplant recipients and 13 of
274 (4.7%) for solid organ transplant recipients within
two years post-transplant, with two deaths and one
child requiring prolonged ventilation.[50] Under-report­
ing of cases is suspected and a validation study is on­
going. Lymphopenia, young age, and use of corticos­
teroids also appear to be risk factors for severe RSV in
the immunocompromised child.[35]
INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE, CANADIAN PAEDIATRIC SOCIETY |
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Children with upper airway obstruction or pulmonary disease
not related to prematurity
The risk of hospitalization due to RSV is increased but
not well quantified in children with neuromuscular dis­
orders, recurrent aspiration, pulmonary malformations,
upper airway conditions such as Pierre Robin syn­
drome, and for conditions requiring a tracheostomy or
noninvasive mechanical ventilation. Results of two
small, [11][51] and one large[52] study of palivizumab in
children with cystic fibrosis were inconclusive. RSV ad­
mission rates were low.
Children with Down syndrome
One non-population-based study showed that 39 of
395 children with Down syndrome (9.9%) experienced
RSV hospitalization in the first two years of life, at a
median age of six months, with the rate being 7.6% for
term infants without CHD, 9.4% for preterm infants,
and 11.9% for those with CHD.[53] There was no in­
creased risk of recurrent wheezing in individuals hospi­
talized with RSV infections.[54] Decisions regarding
prophylaxis are complicated by the fact that another
study showed a much older median age (1.3 years) at
the time of RSV hospitalization with Down syndrome.
[55] A Canadian study demonstrated only a small num­
ber of palivizumab breakthrough infections in children
with Down syndrome.[56]
Pharmacokinetics of palivizumab
The level of palivizumab postulated to prevent RSV
hospitalization is based on the fact that a trough of 25
mg/mL to 30 mg/mL decreased RSV titres by an aver­
age of 99% in the lungs of cotton rats,[57] with all
achieving a 99% drop at 40 mg/mL.[58] Lower doses,
less frequent doses or a smaller number of total doses
have the potential to protect children throughout RSV
season,[59] because the trough remains >40 mg/mL for
>30 days following the third dose.[60][61] A recent study
demonstrated that a presumed therapeutic level of 30
mg/mL to 40 mg/mL can be maintained for the typical
duration of the RSV season with only four doses, if
doses 2, 3 and 4 are given 38 rather than 30 days
apart.[62] Furthermore, a lower trough than 30 mg/mL
to 40 mg/mL may be sufficient. Based on these
premises, the British Columbia program administers
<5 doses. A maximum of three doses are provided to
infants born at 29 to 34 weeks’ GA without CLD, and
they have reported no RSV admissions >35 days after
the third dose in 514 infants over four RSV seasons.[63]
A maximum of four doses are provided to higher-risk
infants, and they have reported only two admissions
>35 days after the fourth dose in 666 infants over two
RSV seasons.[64]
6 | PREVENTING HOSPITALIZATIONS FOR RESPIRATORY SYNCYTIAL VIRUS INFECTION
Recommendations
Good hand hygiene in the home and avoiding contact
of high-risk children with people with RTIs, where prac­
tical, remain paramount for RSV prevention. Breast­
feeding and avoidance of exposure to cigarette smoke
should be encouraged. Given that the efficacy of
palivizumab is <50% in the highest-risk groups (CLD
or CHD), and that most hospitalizations occur in
healthy term infants, more education should be direct­
ed at such prevention strategies.
Use of palivizumab in different risk groups
• Children with hemodynamically significant CHD or
CLD (defined as a need for oxygen at 36 weeks’
GA) who require ongoing diuretics, bronchodilators,
steroids or supplemental oxygen, should receive
palivizumab if they are <12 months of age at the
start of RSV season. Because the incidence of
RSV decreases in the second year of life,
palivizumab is not indicated during the second RSV
season for infants with CHD or for the vast majority
of children with CLD (with the exception of those
still on or weaned off of supplemental oxygen in the
past three months).
• In preterm infants without CLD born before 30 +
0 weeks’ GA who are <6 months of age at the start
of RSV season, it is reasonable (but not essential)
to offer palivizumab. Infants born after 30 + 0
weeks’ GA have RSV admission rates that are con­
sistently ≤7% (Figure 3), yielding a minimum num­
ber needed to treat of 18 (90 doses of palivizumab
to prevent one RSV admission) if one assumes
80% efficacy and five doses per infant. Therefore,
palivizumab should not be prescribed for this
group.
• Infants in remote communities who would require
air transportation for hospitalization born before 36
+ 0 weeks’ GA and <6 months of age at the start of
RSV season should be offered palivizumab. It is
not clear whether this recommendation should ap­
ply only to Inuit infants, to all Aboriginal infants or to
all infants in remote communities. The incidence of
RSV hospitalization in a remote community in pre­
vious years should be taken into account when
making this decision. A practical issue is that the
onset and duration of RSV season is unpredictable
in the Far North. A logical option is to delay admin­
istering palivizumab until RSV is detected in the Far
North. The attendant risk is that significant spread
may have already occurred. Consideration may be
given to administering palivizumab during RSV
season to term Inuit infants until they reach six
months of age only if they live in communities with
documented persistent high rates of RSV hospital­
ization. However, the first priority should be to pro­
vide palivizumab to infants with prematurity, CLD or
CHD.
• Children with immunodeficiencies, Down syn­
drome, cystic fibrosis, upper airway obstruction or a
chronic pulmonary disease other than CLD should
not routinely be offered palivizumab. However, pro­
phylaxis may be considered for children <24
months of age who are on home oxygen, have had
a prolonged hospitalization for severe pulmonary
disease or are severely immunocompromised.
• Continuation of monthly palivizumab is not recom­
mended for children hospitalized with break­
through RSV infection. Repeat RSV infections in
one season are not common. Although recom­
mended on the product monograph, the number
needed to treat is no doubt very high if one contin­
ues palivizumab following RSV infection.
Optimization of program
Each jurisdiction should optimize processes to imple­
ment these recommendations in the most cost-effec­
tive manner, ensuring that health care providers who
administer palivizumab are prepared to monitor for and
treat anaphylaxis. Well-organized palivizumab clinics
decrease drug wastage.
• For eligible infants being discharged home for the
first time during RSV season, palivizumab should
be started just before discharge. Use before dis­
charge to prevent nosocomial RSV is an expensive
strategy that is not recommended.
• Programs should administer a maximum of three to
five doses, with four doses probably being sufficient
in all risk groups if palivizumab is started only when
there is RSV activity in the community, especially if
doses 2, 3, and 4 are given 38 days apart.
• There is no evidence to support giving >5 doses in
one RSV season, administration to any child >24
months of age at the start of RSV season, or using
palivizumab as RSV therapy.
Annual program review
A panel of experts should be convened in each
province or territory to review annually the palivizumab
program guidelines and outcomes. People serving on
these panels should not have conflicts of interest, in­
cluding research funding, participation in a speaker’s
bureau or financial links, with the pharmaceutical firm
that makes palivizumab.
Acknowledgements
This position statement has been reviewed by the
Acute Care, Community Paediatrics, and Fetus and
Newborn Committees of the Canadian Paediatric Soci­
ety.
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CPS INFECTIOUS DISEASES AND IMMUNIZATION
COMMITTEE
Members: Natalie A Bridger MD; Jane C Finlay MD
(past member); Susanna Martin MD (Board Representative); Jane C McDonald MD; Heather Onyett MD;
Joan L Robinson MD (Chair); Marina Salvadori MD
INFECTIOUS DISEASES AND IMMUNIZATION COMMITTEE, CANADIAN PAEDIATRIC SOCIETY |
9
(past member); Otto G Vanderkooi MD
Consultants: Noni E MacDonald MD
Liaisons: Upton D Allen MBBS, Canadian Pediatric
AIDS Research Group; Tobey Audcent MD, Committee
to Advise on Tropical Medicine and Travel (CATMAT),
Public Health Agency of Canada; Carrie Byington MD,
Committee on Infectious Diseases, American Academy of Pediatrics; Charles PS Hui, Committee to Advise
on Tropical Medicine and Travel (CATMAT), Public
Health Agency of Canada; Nicole Le Saux MD, Immunization Monitoring Program, ACTive (IMPACT);
Dorothy L Moore MD, National Advisory Committee on
Immunization (NACI); Nancy Scott-Thomas MD, College of Family Physicians of Canada; John S Spika
MD, Public Health Agency of Canada
Principal authors: Joan L Robinson MD and Nicole
Le Saux MD
Also available at www.cps.ca/en
© Canadian Paediatric Society 2017
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| PREVENTING
FOR
RESPIRATORY
SYNCYTIAL
VIRUS INFECTION
Disclaimer: The recommendations in this position statement do not indicate an
exclusive course of treatment or procedure to be followed. Variations, taking in­
to account individual circumstances, may be appropriate. Internet addresses
are current at time of publication.