letters tO the editOr
Re: Joan L Robinson, nicole Le Saux; Canadian Paediatric
Society Infectious Diseases and Immunization Committee.
Preventing hospitalizations for respiratory syncytial virus
infection. Paediatr Child Health 2015;20(6):321-333.
To the Editor;
We are a group of paediatric health care professionals (community and hospital general paediatrics, nursing, neonatology, paediatric
respirology, paediatric infectious disease and health economics) who
wish to express concerns about the position statement published in
the August/September issue of the Journal.
While rigorously developed guidelines play a pivotal role in
establishing standards of practice, poorly developed guidelines may
cause harm. As reviewed by Haroon et al (1), a well-conducted
review process is important in avoiding potential bias, and guaranteeing validity and feasibility for practice. In this case, key
stakeholders external to the guideline group, such as respirologists and cardiologists, appear to have been omitted. Of more
concern, it is unclear what criteria were used in searching for and
evaluating the evidence behind the position statement and which
methodology was employed to reach consensus, in addition, there
was an absence of grading for each final recommendation.
Specifically, Table 1 purports to summarize results of the efficacy of palivizumab in randomized controlled trials (RCTs). This
table is incomplete both from the placebo controlled (2) or combined palivizumab-placebo trials and the comparative palivizumabmotavizumab trials perspectives. In the Cochrane review (3),
seven RCTs were identified, confirming the efficacy of palivizumab
in reducing the incidence of serious respiratory syncytial virus
(RSV) disease in children with chronic lung disease (CLD),
congenital heart disease (CHD) and those born preterm
<35 weeks gestational age (wGA).
The recommendation for palivizumab targets patients who are
oxygen dependent at 36 wGA or medically dependent in the first
year, and only oxygen dependent in the second year. This reflects a
narrow view of the limitations of using oxygen dependency alone as
a diagnostic criterion for CLD (4), the pathophysiology of lung
function in healthy preterms and those with CLD and the impact
of RSV infection, and the rates of RSV-related hospitalization
(RSVH), which are 12- to 18-fold higher in this cohort compared
with healthy infants up to two years of age (5). The mean RSVH
rate for patients with CLD across the 10 observational studies portrayed in the statement, albeit a methodologically flawed comparison, are approximately similar (16.8 first season; 14.7 first or second
season; 13.9 first and second season). Moreover, the incidence of
CLD overall has remained relatively unchanged because of its multifactorial etiology (6) and, following RSVH, both preterm and
CLD infants have two- to threefold higher rates of intensive care
unit (ICU) admission and ventilation (7,8). Although the number
needed to treat (NNT) for CLD in the Impact trial was 20 (9),
studies with larger sample sizes in ‘real world’ experience indicate a
NNT range of eight to 10 (10-12). Late preterm infants incur significant respiratory morbidities (13) and are at high risk for RSVH
(14,15). Three robust models targeting RSV prophylaxis cost effectively for these infants were overlooked (16-18) in favour of nontreatment, and strongly merits reconsideration because the
estimated NNT across all three models equals 13. Overall, the
guidelines for RSV prophylaxis restricted to infants <29 completed
wGA without CLD is a serious step back to the era before 1998, and
may result in significant burden of illness in untreated infants with
higher ICU admissions and need for mechanical ventilation (29 to
Paediatr Child Health Vol 20 No 8 November/December 2015
32 wGA [n=243]: 49%, 25%; 33 to 34 wGA [n=279]: 41%, 19%;
35 wGA [n=187] 32%, 14%, respectively) (19).
The references in support of RSV prophylaxis for one versus
two seasons for infants with CHD is limited to one RCT (20),
which showed a declining RSVH incidence from 12% to 4%
between one and two years, but >50% palivizumab efficacy for
infants <6 months of age and those one to two years of age. The
recommendation discounts both the severity of fully uncorrected,
unstable CHD, the fourfold higher RSVH rates in these infants compared with healthy babies (21) and the significant weighted mean
mortality rate of 5.2% with RSV infection (22). We have recently
demonstrated that the hazard ratio for RSVH between the first and
second RSV season for treated CHD infants is similar (HR 1.4 [95%
CI 0.5 to 4.0]; P=0.52) (23) and prophylaxis for selected, cardiology
sanctioned, high-risk infants for two seasons requires revisitation.
In regard to the “Cost-effectiveness of palivizumab”, we were
unable to determine the threshold used to determine cost effectiveness. The Canadian threshold of up to $100,000 per qualityadjusted life year (QALY) is considered to be a good use of
resources (24). Hence, we cannot assess whether the statement
that palivizumab “is unlikely to be cost effective in children with
prematurity, CLD or CHD…” is accurate. Also, the perspective
is not stated, for clarity see Guidelines for the Evaluation of Health
Technologies: Canada, 3rd edition, 2006 (25).
In a publication produced by the Canadian Paediatric Society,
which describes itself as “a national advocacy association that
promotes the health needs of children and youth”, we would
expect a societal perspective rather than a payer perspective and,
as such, consideration of the family costs of admission to hospital
with RSV infection. Our preceding comments should not be interpreted to mean that we are not sensitive to the need to examine
costs. However, the position statement starts with the assumption
that the first priority is to “save drug costs”. As advocates for children, we suggest that the first stage should be to determine the best
course of action to benefit children based on an unbiased review of
the evidence, and then examine the funding implications. The
position statement appears to have acted in the reverse order.
The position statement concludes that “people serving on
this panel (Provincial Annual Reviews) should not have conflicts of interest, including research funding and participation in
a speakers bureau or financial links with the pharmaceutical firm
that makes palivizumab”. This simplistic approach would exclude
many knowledgeable individuals on RSV infection, including
members of the committees who developed and reviewed the
document. Overall, this position statement overturns strong evidence supporting current practice for RSV prophylaxis in
Canada and, if adopted, will lead to unnecessary infections in
already vulnerable children.
I Mitchell MA MB FRCPC
Alberta Children’s Hospital, Calgary Alberta
B Paes MD FRCPC
Department of Pediatrics, McMaster University,
Hamilton, Ontario
K Lanctot PhD
Medical Outcomes and Research in Economics (MORE®)
Research Group, Sunnybrook Health Sciences Centre,
University of Toronto, Toronto, Ontario
Rupesh Chawla MD MSc FRCPC
Pediatric Infectious Diseases Residency Training Program
Alberta Children's Hospital, Calgary, Alberta
©2015 Canadian Paediatric Society. All rights reserved
463
Aaron Chiu MD FRCPC FAAP MBA
Manitoba RSV Prophylaxis Program;
Department of Pediatrics, University of Manitoba;
Women's Hospital, Winnipeg, Manitoba
Marianna Mitchell MD FRCPC
Queen's University, Lakeridgehealth Corporation,
Oshawa, Ontario
Cecil Ojah FRCPC
Department of Paediatrics, Saint John Regional Hospital,
Saint John, New Brunswick
April Price MD FRCPC FCCP
Western University,
Division of Paediatric Respiratory Medicine,
Children's Hospital, London Health Sciences Centre,
London, Ontario
Sandra Seigel,
Department of Pediatrics, McMaster University;
Division of General Pediatrics, St Joseph's Healthcare;
McMaster Children's Hospital, Hamilton, Ontario
Amanda Symington RN(EC) BSc BScN MHSc
McMaster Children's Hospital;
School of Nursing, McMaster University,
Hamilton, Ontario
REFEREnCES
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Paediatrics and Child Health Clinical Standards Committee.
Developing clinical guidelines: How much rigour is required?
Arch Dis Child Educ Pract Ed 2014;0:1-8.
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The authors respond;
Thank you for sharing your perspective on palivizumab. As a
national advocacy organization, the Canadian Paediatric Society
(CPS) welcomes feedback from members and other expert stakeholders. The aim of CPS guidelines is to provide concise practical advice for paediatricians and family physicians on how to
interpret the literature in a Canadian context. For the RSV
prophylaxis guideline, a traditional review of the literature was
employed. Consensus was reached by face-to-face discussion at
the CPS Infectious Diseases and Immunization Committee
(IDIC) meeting followed by review of the guideline by IDIC
members, CPS Fetus and Newborn Committee members, and
CPS board members until all were satisfied with the content.
This is the fifth version of the CPS RSV prophylaxis guideline.
As far as we are aware, an objection to this process has not previously been raised. However, we agree that input from respirologists and cardiologists may be valuable for future guidelines.
The previous CPS RSV prophylaxis guideline applied Grading
of Recommendations Assessment, Development and Evaluation
(GRADE) (1). For the current guideline, the decision was made
to omit GRADE (apart from ranking the quality of evidence in
Table 1), primarily because adding in the required “Remarks” and
“Values and Preferences” put the guideline over the word limit for
CPS statements. However, to summarize the levels of evidence
using GRADE, there is high-quality evidence that palivizumab
prevents hospitalizations in children <36 wGA and <6 months of
age, and in children with CLD or hemodynamically significant
CHD <24 months of age at the start of the RSV season. There is
low-quality, very low-quality or no evidence for all other aspects of
the guideline. Palivizumab was not recommended for some groups
in which efficacy has been demonstrated because the low risk for
Paediatr Child Health Vol 20 No 8 November/December 2015