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• Palivizumab for children with Down syndrome: is the time right for a universal recommendation?
  Bosco Paes, Souvik Mitra
  Published on: 19 July 2019
• Palivizumab for children with Down syndrome: is the time right for a universal recommendation?
  Levinus A Bok, Lonneke van Onzenorrt-Bokken and Johannes LP Kuijpens
  Published on: 19 July 2019

• Published on: 19 July 2019

  Palivizumab for children with Down syndrome: is the time right for a universal recommendation?

  • Bosco Paes, Neonatologist McMaster University
  • Other Contributors:
    • Souvik Mitra, Neonatologist

  We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS).[1] However, most of their arguments are not pertinent to DS. First, they describe the general incidence of respiratory syncytial virus (RSV) in children aged <5years. Second, they discuss the efficacy of palivizumab based on the IMpact trial [2] that did not include children with DS. We provided concrete evidence from [3] metanalyses conducted in 1.1 million children with DS, that the risk of RSV-related hospitalisation (RSVH) is 6.1–8.7- fold higher than children without DS.1 Drs Bok et al. also fail to appreciate that the overall relative risk of RSVH without palivizumab, is 5.5-fold (95% CI 3.97 to 7.7) higher based on robust, high quality evidence.[3] In our previous study we also reported that for every 1000 children with DS with RSV there will be 200 more (95% CI,131-297) hospitalisations compared with 1000 children without DS with RSV (RR, 5.53; 95% CI,3.97-7.73; high GRADE).[4] Moreover, Drs Bok et al. have extrapolated the number needed to treat (NNT) with prophylaxis to prevent one RSVH in children with DS using sub-optimal data. In a prospective case-control, cohort study conducted in the Netherlands and Canada, the estimated NNT in children with DS, adjusted for confounding variables, is 12 and not 20.[5] This number also aligns with the report from the CARESS registry [6] and compares favourably with the NNT of 16 for preter...

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  We thank Drs Bok et al. for their comments on our recent editorial about the use of palivizumab in children with Down syndrome (DS).[1] However, most of their arguments are not pertinent to DS. First, they describe the general incidence of respiratory syncytial virus (RSV) in children aged <5years. Second, they discuss the efficacy of palivizumab based on the IMpact trial [2] that did not include children with DS. We provided concrete evidence from [3] metanalyses conducted in 1.1 million children with DS, that the risk of RSV-related hospitalisation (RSVH) is 6.1–8.7- fold higher than children without DS.1 Drs Bok et al. also fail to appreciate that the overall relative risk of RSVH without palivizumab, is 5.5-fold (95% CI 3.97 to 7.7) higher based on robust, high quality evidence.[3] In our previous study we also reported that for every 1000 children with DS with RSV there will be 200 more (95% CI,131-297) hospitalisations compared with 1000 children without DS with RSV (RR, 5.53; 95% CI,3.97-7.73; high GRADE).[4] Moreover, Drs Bok et al. have extrapolated the number needed to treat (NNT) with prophylaxis to prevent one RSVH in children with DS using sub-optimal data. In a prospective case-control, cohort study conducted in the Netherlands and Canada, the estimated NNT in children with DS, adjusted for confounding variables, is 12 and not 20.[5] This number also aligns with the report from the CARESS registry [6] and compares favourably with the NNT of 16 for preterms <35 weeks gestation without bronchopulmonary dysplasia, 20 for children with bronchopulmonary dysplasia and 23 for those with congenital heart disease, based on randomised trials.

  Last, regarding costs, Drs Bok et al. also fall short in their attempt to reconcile that palivizumab is not cost-effective in children with DS using data derived from preterm infants, which unfortunately has little relevance. In our editorial[1] and original report,[4] we emphasised that a well-conducted cost-utility analysis of RSV prophylaxis in children with DS that measures RSV-related disease burden on both the quality and quantity of life.is still lacking. What we do know from solid evidence is that the burden of illness associated with RSVH in children with DS and those without congenital heart disease compared to children without DS is significant,[1],[4] and is steadily increasing with concurrent healthcare expenditure.[7] Our editorial provides concrete information about the risks of RSVH in all children with DS while indicating that the real-world use of prophylaxis in this population is of greater benefit versus harm, and that non-intervention has significant clinical, healthcare costs and socioeconomic implications, the latter of which is often overlooked.[1],[8] After systematically weighing the pros and cons, we re-affirm that the time is right to consider RSV prophylaxis for all children with DS aged < 2 years, since the opposing data provided by Dr Bok et al. is at best hypothetical. However, we do agree that the adoption of a global policy for RSV prophylaxis in all children with DS must be balanced in each country against available funding, overall costs for RSVH and incurred short and long-term morbidity.

  References
  1 Paes B, Mitra S. Palivizumab for children with Down syndrome: is the time right for a universal recommendation? Arch Dis Child doi:10.1136/archdischild-2018-316408.
  2 The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk children. Pediatrics 1998; 102:531-7.
  3 Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence—study limitations (risk of bias). J Clin Epidemiol 2011; 64:407-15.
  4 Mitra S, El Azrak M, McCord H et al. Hospitalization for respiratory syncytial virus in children with Down syndrome less than 2 years of age: A systematic review and meta-analysis. J Pediatr. 2018; 203:92-100.e3.
  5 Yi H, Lanctôt KL, Bont L, Bloemers BL, et al. Respiratory syncytial virus prophylaxis in Down syndrome: a prospective cohort study. Pediatrics 2014; 133:1031-7.
  6 Paes B, Mitchell I, Yi H, et al. Hospitalization for respiratory syncytial virus illness in Down syndrome following prophylaxis with palivizumab. Pediatr Infect Dis J 2014; 33:e29-33.
  7 Doucette A, Jiang X, Fryzek J, et al. Trends in respiratory syncytial virus and bronchiolitis hospitalization rates in high-risk infants in a United States nationally representative database, 1997-2012. PLoS One 2016; 11: e0152208.
  8 Martínez-Valverde S, Salinas-Escudero G, García-Delgado C et al. Out-of-pocket expenditures and care time for children with Down Syndrome: A single-hospital study in Mexico City. PLoS One 2019;14:e0208076.

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  Conflict of Interest:
  BP has received an investigator-initiated research grant from AbbVie Corporation and compensation as an advisor and speaker for AbbVie. SM has no conflicts to declare.

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• Published on: 19 July 2019

  Palivizumab for children with Down syndrome: is the time right for a universal recommendation?

  • Levinus A Bok, Pediatrician PhD Máxima Medical Centre, Veldhoven, the Netherlands
  • Other Contributors:
    • Lonneke van Onzenorrt-Bokken, Pediatrician PhD
    • Johannes LP Kuijpens, MD PhD MPH

  In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
  For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year...

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  In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
  For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
  What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
  Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.

  In their editorial Paes and Mitra suggest that all patients with down syndrome (DS) <2 years should be considered to give palivizumab (Synagis®) to prevent respiratory syncytial virus (RSV) infection. We agree with the authors that DS children are at increased risk to develop RSV infections. However, we do not agree with their recommendation for palivizumab prevention in all DS children <2 years. In our opinion there is insufficient evidence on the efficiency and cost effectiveness and the recommendation is therefore premature.
  For the evaluation of preventive interventions the incidence and the absolute risk of acquiring the disease, and the effectiveness of the proposed intervention are important factors. The reported incidence of clinical relevant RSV infections in the general population in western countries is about 18/1,000 in newborns <2 months, 17/1,000 in children <6 months and 3/1,000 in children <5 years ( 2,3). Considering a relative extra risk of 5.5 in DS children (1) the calculated RSV incidence is 99/1,000 <2 months ( one out of 10) , 94/1,000 <6 months and 17/1,000 <5 years, respectively. The effectiveness of prevention of clinical treatment in premature children with palivizumab is about 50% (4). The extrapolated number needed to treat (NNT) for newborns with DS is 20 to prevent one hospitalization due to RSV infection. But what is the harm of this treatment as 19 out of 20 DS newborns will be given 114 injections per year. For DS patients <5 years these numbers are even worse: 594 injections are given to prevent 1 clinical admission, as the NNT in this DS age group is about 100. In our opinion the potential harm of palivizumab treatment does not outweigh the harm of one prevented hospital admission.
  What about the financial burden? For the DS newborns <2 years in The Netherlands the costs to prevent one hospitalization will be about Euro 76.200 (20 * 6 * Euro 635); for DS children < 5 years these costs to prevent one admission rise to Euro 630.000 (100 * 6 * Euro 1,050). Recent studies from various countries, including The Netherlands, have evaluated the cost effectiveness of palivizumab prophylaxis for RSV infections in risk groups (5,6). These studies concluded that palivizumab prophylaxis is not cost effective with a probable exception for patients with a strongly increased risk (not DS).
  Conclusion. We do not agree with the authors to treat all DS children with palivizumab. Palivizumab should only be given in well proven risk populations. We do agree with the authors that a randomized controlled trial (RCT) to prove the efficacy, safety and (cost)effectiveness of palivizumab prevention is needed in DS children.

  References.
  1. Paes B, Mitra S. Palivizumab for Children with Down syndrome: is the time right for a universal recommendation? Arch Dis Child doi:10.1136/archdischild-2018-316408
  2. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009; 360: 588-98.
  3. Hall CB, Weinberg GA, Blumkin AK, et al. Respiratoy syncytial virus-associated hospitalizations among children less than 24 months of age. Pediatrics 2013; 132: e341-8.
  4. The Impact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102: 531-7.
  5. Olchanski N, Hansen RN, et al. Palivizumab prophylaxis for respiratory syncytial virus: examining the evidence around value. Open Forum Infectious Diseases OFID 2018. Doi: 10.1093/ofid/ofy031.
  6. Blanken MO, Frederix GW, et al. Cost-effectiveness of rule-based immunoprophylaxis against respiratory syncytial virus infections in preterm infants. Eur J Pediatr 2018; 177: 133-44 Doi.org/10.1007/s00431-017-3046-1.

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  Conflict of Interest:
  None declared.

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