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. 2016 Jun-Jul;21(5):260–261. doi: 10.1093/pch/21.5.260

Letters to the Editor

Karen Chang 1, Dennis Gurwitz 2, Peter Azzopardi 3, Shaheen Doctor 4, Ronik Kanani 5, Constantine Petrou 6, Paul Meinert 7, Meera Umamaheswaran Kissoon 8
PMCID: PMC4933058  PMID: 27441022

Re: Robinson JL, Le Saux N. Preventing Hospitalizations for Respiratory Syncytial Virus (RSV) Infection. Canadian Paediatric Society Infectious Diseases and Immunization Committee. Paediatr Child Health 2015;20(6):321–33.

To the Editor;

We are a group of paediatricians who wish to express major concerns about this particular Position Statement, published in the August/September 2015 issue of the Journal, and its implications for children and families within our community. Several of the quotes are incorrect, which reflects an incomplete search of the relevant scientific literature. In the United States outcomes registry (2000–2001), 75% of all RSV-related hospitalizations (RSVH) occurred between the first and second injection intervals (1), and the highest RSVH percentage (31%) was also noted in the same time interval in 2000–2004 (2). Palivizumab does prevent intensive care unit admissions, and the Cochrane meta-analysis (n=2789) confirms the same (RR 0.50 [95% CI 0.30 to 0.81]) (3). In a randomized trial, palivizumab recipients also had a statistically lower incidence of medically attended, non-hospitalized RSV infection, suggesting an attenuated effect on disease severity (4). The recommendation for three to five doses is based on low-quality evidence through observational studies without palivizumab levels (5,6). Reports confirm that after three doses, 52% and 85% of infants have palivizumab levels <5th percentile, respectively (7,8). Moreover, the quoted article recommending four doses “emphasizes the importance of testing the regimen in randomized trials before adoption” (9). The key message from the systematic review of observational studies was similarly overlooked (10). The review supports palivizumab for preterms < 33 weeks’ gestational age (GA), children with chronic lung (CLD) and hemodynamically significant congenital heart disease (HSCHD) (10). Finally, healthy preterms are at greater risk for RSVH than term infants and the magnitude of difference is two-to threefold higher up to two years of age (11).

From the respirology perspective, healthy preterm infants, when compared with term babies, have compromised, obstructive lung function without catch-up at two years of age (12,13). This is more prominent in CLD infants (14) and is further enhanced in preterm infants up to school age both with and without CLD following RSV illness (15,16). The recommendation fails to recognize that, in preterms, lung development is a continuum of airway remodelling and vascularization that peaks in adulthood and RSV infection may compromise lung function beyond adolescence (17,18). A distinction between oxygen dependency and drug therapy for prophylaxis in the first versus second season minimizes the consequences of RSV across the full spectrum of CLD. Moreover, restricting prophylaxis to healthy preterms <29 completed weeks GA, underestimates the serious pulmonary sequelae and outcomes resulting from RSV illness in preterms ≤35 weeks (19). Prophylaxis was deemed appropriate for HSCHD for only one season. The recommendation does not account for infants with univentricular physiology, or those requiring further reconstructive surgery and are hypoxemic with cardiac failure. This underplays the burden of RSV illness in complex HSCHD infants <2 years of age, who incur high morbidity and mortality rates (20). Several statements are speculative and unreferenced. Costs are briefly discussed without addressing the benchmark of the cost utility of palivizumab. Overall, as a group of community paediatricians, we feel the position statement is driven by cost containment rather than advocating for patients and families. We are equally surprised that because the guideline was not constructed using the established domains for quality reporting, that it was uniformly approved by the Fetus and Newborn and Acute Care Community Paediatrics Committees (21). A well-developed guideline should optimize patient care and facilitate unified practice provincially. The current statement, unfortunately, encourages divisiveness and deserves re-consideration and timely revision.

REFERENCES

  • 1.Parnes C, Guillermin J, Habersang R, et al. Palivizumab prophylaxis of respiratory syncytial virus disease in 2000–2001: Results from the Palivizumab Outcomes Registry. Pediatr Pulmonol. 2003;35:484–9. doi: 10.1002/ppul.10288. [DOI] [PubMed] [Google Scholar]
  • 2.Frogel M, Nerwen C, Cohen A, et al. Prevention of hospitalization due to respiratory syncytial virus: results from the Palivizumab Outcomes Registry. J Perinatol. 2008;28:511–7. doi: 10.1038/jp.2008.28. [DOI] [PubMed] [Google Scholar]
  • 3.Andabaka T1, Nickerson JW, Rojas-Reyes MX, et al. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev. 2013;34:CD006602. doi: 10.1002/14651858.CD006602.pub4. [DOI] [PubMed] [Google Scholar]
  • 4.Blanken MO1, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. N Engl J Med. 2013;368:1791–9. doi: 10.1056/NEJMoa1211917. [DOI] [PubMed] [Google Scholar]
  • 5.Solimano A, Eastman P, Butler A, Taylor R, MacRae S. Three seasonal palivizumab doses over four seasons is perfectly adequate RSV prophylaxis for moderate risk infants. Pediatric Academic Societies Meeting; San Diego. April 25–28, 2015. (Abstract 4159.437) [Google Scholar]
  • 6.Solimano A, Eastman P, Butler A, et al. The approval of four seasonal palivizumab doses provides cost-effective protection in infants at high risk of RSV admission during the five-month British Columbia season – a multi-season analysis. Pediatric Academic Societies Meeting; San Diego. April 25 to 26, 2015. (Abstract 4159.436) [Google Scholar]
  • 7.La Via WV, Notario GF, Yu XQ, et al. Three monthly doses of palivizumab are not adequate for 5-month protection: A population pharmacokinetic analysis. Pulm Pharmacol Ther. 2013;26:666–71. doi: 10.1016/j.pupt.2013.03.007. [DOI] [PubMed] [Google Scholar]
  • 8.Makari D, Checchia PA, Devincenzo J. Rationale for full-season dosing for passive antibody prophylaxis of respiratory syncytial virus. Hum Vaccin Immunother. 2014;10:607–14. doi: 10.4161/hv.27426. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Gutfraind A, Galvani AP, Meyers LA. Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection. JAMA Pediatr. 2015;169:341–8. doi: 10.1001/jamapediatrics.2014.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Homaira N, Rawlinson W, Snelling TL, Jaffe A. Effectiveness of palivizumab in preventing RSV hospitalization in high risk children: A real-world perspective. Int J Pediatr. 2014;2014:571609. doi: 10.1155/2014/571609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Boyce TG, Mellen BG, Mitchel EF, Jr, Wright PF, Griffin MR. Rates of hospitalization for respiratory syncytial virus infection among children in Medicaid. J Pediatr. 2000;137:865–70. doi: 10.1067/mpd.2000.110531. [DOI] [PubMed] [Google Scholar]
  • 12.Friedrich L, Pitrez PM, Stein RT, et al. Growth rate of lung function in healthy preterm infants. Am J Respir Crit Care Med. 2007;176:1269–73. doi: 10.1164/rccm.200703-476OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.McEvoy C, Venigalla S, Schilling D, et al. Respiratory function in healthy late preterm infants delivered at 33–36 weeks of gestation. J Pediatr. 2013;162:464–9. doi: 10.1016/j.jpeds.2012.09.042. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Vom Hove M, Prenzel F, Uhlig HH, Robel-Tillig E. Pulmonary outcome in former preterm, very low birth weight children with bronchopulmonary dysplasia: A case-control follow-up at school age. J Pediatr. 2014;164:40–5e4. doi: 10.1016/j.jpeds.2013.07.045. [DOI] [PubMed] [Google Scholar]
  • 15.Broughton S, Bhat R, Roberts A, et al. Diminished lung function, RSV infection, and respiratory morbidity in prematurely born infants. Arch Dis Child. 2006;91:26–30. doi: 10.1136/adc.2005.087270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Greenough A, Alexander J, Boit P, et al. School age outcome of hospitalisation with respiratory syncytial virus infection of prematurely born infants. Thorax. 2009;64:490–5. doi: 10.1136/thx.2008.095547. [DOI] [PubMed] [Google Scholar]
  • 17.Szabo SM, Levy AR, Gooch KL, et al. Elevated risk of asthma after hospitalization for respiratory syncytial virus infection in infancy. Paediatr Respir Rev. 2013;(13 Suppl 2):S9–15. doi: 10.1016/S1526-0542(12)70161-6. [DOI] [PubMed] [Google Scholar]
  • 18.Sigurs N1, Aljassim F, Kjellman B, et al. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax. 2010;65:1045–52. doi: 10.1136/thx.2009.121582. [DOI] [PubMed] [Google Scholar]
  • 19.Willson DF, Landrigan CP, Horn SD, Smout RJ. Complications in infants hospitalized for bronchiolitis or respiratory syncytial virus pneumonia. J Pediatr. 2003;143(5 Suppl):S142–9. doi: 10.1067/s0022-3476(03)00514-6. [DOI] [PubMed] [Google Scholar]
  • 20.Szabo SM, Gooch KL, Bibby MM, et al. The risk of mortality among young children hospitalized for severe respiratory syncytial virus infection. Paediatr Respir Rev. 2013;(13 Suppl 2):S1–8. doi: 10.1016/S1526-0542(12)00095-4. [DOI] [PubMed] [Google Scholar]
  • 21. Appraisal of Guidelines Research and Evaluation < www.agreetrust.org> (Accessed October 30, 2015)
Paediatr Child Health. 2016 Jun-Jul;21(5):261–262.

Letters to the Editor

Joan L Robinson 1, Nicole Le Saux 1

The authors respond:

We thank Dr Chang and colleagues for the comments regarding the CPS statement “Preventing hospitalizations for respiratory syncytial virus infections”. The comments have provided us with the opportunity to clarify some issues and to correct wording. This does not, however, affect the essence of our original recommendations.

Although the palivizumab product monograph recommends dosing every 28 to 30 days, some programs administer the first two doses 21 days apart. The rationale is that palivizumab levels are more likely to be sub-therapeutic 28 days after the first dose than 28 days after subsequent doses. However, studies have shown that most levels are still well above 25 mg/dL to 30 mg/dL (the level at which RSV titres decreased by a mean of 99% in cotton rats) 28 days following the first dose (1). As pointed out by Chang et al, one of the original post-marketing studies showed that 75% of breakthrough RSV hospitalizations in a single RSV season occurred between the first and second dose (2). Other potential reasons for a predominance of breakthrough infections during the first 28 days of prophylaxis would be: 1) in the year that was studied, RSV season may have started early; and 2) the average age of infants offered palivizumab increases as the RSV season proceeds while the risk of RSV hospitalization decreases with age (3). In other words, breakthrough RSV hospitalization rates during the period of prophylaxis would not be predicted to be random. In the second study quoted by Dr Chang, covering four RSV seasons, 31% of breakthrough RSV hospitalizations occurred between the first and second doses, and 25% between the second and third doses (4) for a difference of only 6%, demonstrating that there is not usually a major difference in the incidence of breakthrough infections between the first two doses versus the next two doses. It would be informative to compare the timing of RSV hospitalizations in children given palivizumab to a control group. Pending such data, there is no major disadvantage to administering the first two doses 21 days apart if programs wish to continue that practice.

We thank the authors of the letter for pointing out the error in our statement “In terms of short-term benefits, there is no evidence that palivizumab prevents intensive care unit (ICU) admission or death…”. Meta-analysis shows that palivizumab does prevent ICU admission (number needed to immunize = 56 [95% CI 33 to 166]) (5). The statement should have indicated that there is no evidence that palivizumab prevents mechanical ventilation or death. This wording change will be made in the statement.

The statement says “There is no evidence that … the severity of breakthrough RSV is less than in controls”. The authors of the letter point out that there is evidence that palivizumab prevents outpatient visits due to RSV. The statement was referring to the severity of breakthrough RSV hospitalizations rather than to the incidence of outpatient RSV infections. This will be clarified in the statement.

Randomized controlled trials are not always necessary if evidence from observational studies overwhelmingly supports a conclusion. With regard to three- or four-dose palivizumab programs, a recent publication from British Columbia Children’s Hospital reported RSV hospitalizations from 2010–2014 that could potentially have been averted by more doses of palivizumab in only one of 514 infants on a three-dose regimen and two of 666 on a four-dose regimen (6). As explained in the statement, according to modelling and pharmacokinetic data in simulated concentration-time profiles, palivizumab levels are likely to remain protective for more than 28 days following three or four doses (7). A study of 18 immunocompromised children with off-label use of palivizumab demonstrated a mean level of 92 mg/dL 30 days following the fourth dose (1). Giving fewer doses will yield lower palivizumab levels near the end of the RSV season; however, there is accumulating evidence that this will lead to very minimal additional RSV hospitalizations (6,8).

The primary reason to change the indications for palivizumab is because of accumulating data that the burden of disease in specific settings no longer warrants use. Chang et al point out that a systematic review of observational studies concluded that palivizumab should be used routinely in infants <33 weeks’ gestational age (9). They express concern that even healthy preterm infants have two to three times the RSV hospitalization rate of term infants up to two years of age. However, there is evidence that for infants born at 32 to 34 weeks’ gestational age, this risk approaches that of a term one-month-old once they reach four months (versus two years) of age (10). It is debatable whether an RSV hospitalization rate of two to three times baseline justifies monthly injections throughout RSV season when the baseline rates are low. A recent small study demonstrated almost identical RSV hospitalization rates in both term and preterm infants before and after implementation of more restrictive palivizumab guidelines (11).

We are not clear what Chang et al mean by “the benchmark of the cost utility of palivizumab”. Because the cost of the drug is so high and it has not been shown to prevent death, palivizumab can only meet the usual criteria for cost effectiveness if it prevents long-term sequelae, which is yet to be demonstrated.

Chang et al imply that prevention of RSV hospitalization in healthy preterm infants in the first year of life and in infants with CLD in the first two years of life will improve long-term pulmonary outcomes. The counter argument is that the children who are the most likely to be hospitalized with RSV are those with the most severe baseline pulmonary disease; therefore, it is not surprising that RSV hospitalizations are more common in those who go on to have long-term pulmonary sequelae. There are no data to show that attenuation or delay of this initial RSV infection can prevent chronic lung disease or its consequences.

With regard to congenital heart disease (CHD), the reference that the authors use to support their statement that mortality rates are high from RSV quotes studies that date back to 1982, when paediatric cardiac surgery and intensive care were far less advanced than they are in 2016. A 2010 study from California concluded that the burden of RSV hospitalization from CHD in more recent times is small and that palivizumab had minimal impact (11). There may be a subset of infants with incompletely corrected CHD who will benefit significantly from palivizumab in the second year of life, but it is not yet clear how to identify these infants. Of note, in the original CHD palivizumab study, post hoc analysis suggested that palivizumab may have minimal if any efficacy in cyanotic children (RSV hospitalization rate 7.9% in placebo group versus 5.6% in palivizumab group; P=0.285) (12).

We agree that it would be ideal if CPS guidelines followed The Appraisal of Guidelines for Research & Evaluation (AGREE) standards (13). Worldwide, most guidelines including those from the larger and presumably more well-resourced American Academy of Pediatrics fall short of this standard (14). Continuous updating of guidelines also poses a challenge. Furthermore, it is difficult to ensure that guidelines are evidence-based in a field such as RSV prophylaxis where there is ever-evolving observational evidence rather than randomized-controlled clinical trials. However, our committee will do our best to update the guidelines as new evidence becomes available.

REFERENCES

  • 1.Mori M, Onodera M, Morimoto A, et al. Palivizumab use in Japanese infants and children with immunocompromised conditions. Pediatr Infect Dis J. 2014;33:1183–5. doi: 10.1097/INF.0000000000000392. [DOI] [PubMed] [Google Scholar]
  • 2.Parnes C, Guillermin J, Habersang R, et al. Palivizumab prophylaxis of respiratory syncytial virus disease in 2000–2001: Results from The Palivizumab Outcomes Registry. Pediatr Pulmonol. 2003;35:484–9. doi: 10.1002/ppul.10288. [DOI] [PubMed] [Google Scholar]
  • 3.Homaira N, Oei JL, Mallitt KA, et al. High burden of RSV hospitalization in very young children: A data linkage study. Epidemiol Infect. 2015 Dec;2:1–10. doi: 10.1017/S0950268815003015. [Epub ahead of print] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Frogel M, Nerwen C, Cohen A, et al. Prevention of hospitalization due to respiratory syncytial virus: Results from the Palivizumab Outcomes Registry. J Perinatol. 2008;28:511–7. doi: 10.1038/jp.2008.28. [DOI] [PubMed] [Google Scholar]
  • 5.Andabaka T1, Nickerson JW, Rojas-Reyes MX, et al. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst Rev. 2013;34:CD006602. doi: 10.1002/14651858.CD006602.pub4. [DOI] [PubMed] [Google Scholar]
  • 6.Lavoie PM, Solimano A, Taylor R, et al. Outcomes of respiratory syncytial virus immunoprophylaxis in infants using an abbreviated dosing regimen of palivizumab. JAMA Pediatr. 2016;170:174–6. doi: 10.1001/jamapediatrics.2015.3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Robbie GJ, Zhao L, Mondick J, Losonsky G, Roskos LK. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother. 2012;56:4927–36. doi: 10.1128/AAC.06446-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Gutfraind A, Galvani AP, Meyers LA. Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection. JAMA Pediatr. 2015;169:341–8. doi: 10.1001/jamapediatrics.2014.3804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Homaira N, Rawlinson W, Snelling TL, Jaffe A. Effectiveness of palivizumab in preventing RSV hospitalization in high risk children: A real-world perspective. Int J Pediatr. 2014;2014:571609. doi: 10.1155/2014/571609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Winterstein AG, Knox CA, Kubilis P, Hampp C. Appropriateness of age thresholds for respiratory syncytial virus immunoprophylaxis in moderate-preterm infants: A cohort study. JAMA Pediatr. 2013;167:1118–24. doi: 10.1001/jamapediatrics.2013.2636. [DOI] [PubMed] [Google Scholar]
  • 11.Grindeland CJ1, Mauriello CT, Leedahl DD, Richter LM, Meyer AC. Association between updated guideline-based palivizumab administration and hospitalizations for respiratory syncytial virus infections. Pediatr Infect Dis J. 2016 Apr 13; doi: 10.1097/INF.0000000000001150. (Epub ahead of print) [DOI] [PubMed] [Google Scholar]
  • 12.Chang R-KR, Chen AY. Impact of palivizumab on RSV hospitalizations for children with hemodynamically significant congenital heart disease. Pediatr Cardiol. 2010;31:90–5. doi: 10.1007/s00246-009-9577-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Feltes TF, Cabalka AK, Meissner HC, Cardiac Synagis Study Group Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr. 2003;143:532–40. doi: 10.1067/s0022-3476(03)00454-2. [DOI] [PubMed] [Google Scholar]
  • 14. Appraisal of Guidelines for Research and Evaluation II < www.agreetrust.org/wp-content/uploads/2013/10/AGREE-II-Users-Manual-and-23-item-Instrument_2009_UPDATE_2013.pdf> (Accessed April 28, 2016)
  • 15.Isaac A, Saginur M, Hartling L, Robinson JL. Quality of reporting and evidence in American Academy of Pediatrics guidelines. Pediatrics. 2013;131:732–8. doi: 10.1542/peds.2012-2027. [DOI] [PubMed] [Google Scholar]

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