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palivizumab prophylaxis for children with bronchiolitis

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

 

Eligibility for palivizumab prophylaxis in a cohort of children with severe bronchiolitis
Kohei Hasegawa,1 Jonathan M. Mansbach,2 Pedro A. Piedra,3 Michelle B. Dunn,4 Sunday Clark,5 Ashley F. Sullivan1 and Carlos A. Camargo Jr1

Pediatrics International (2015) 57, 1031–1034          http://dx.doi.org:/10.1111/ped.12760

 

In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95% CI: 28.5–41.7%).  The  decrease was largely driven by the restriction of eligibility to preterm infants with gestational age < 29weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed.

 

Bronchiolitis remains an important public health problem in the USA. It is the leading cause of hospitalization in infants, accounting for 18% of all infant hospitalizations, with a total direct cost of $545m in 2009.1 Although many viruses are known to cause bronchiolitis, respiratory syncytial virus (RSV) is the most common etiology among children requiring hospitalization.2 Palivizumab, a humanized monoclonal antibody against the RSV Fglycoprotein, is licensed for the prevention of serious lower respiratory infection caused by RSV in high-risk children. Since palivizumab was first licensed, professional organizations have sought more precise guidance for determining who is at high risk.3

In 2014, the American Academy of Pediatrics (AAP) updated and replaced their recommendations for palivizumab prophylaxis from 2012.4  The updated guidelines support a more restrictive use of palivizumab:3 for example, they recommend against the use in infants born ≥ 29 weeks’ gestation who have no additional risk factors for severe RSV disease. Despite these substantial changes to the guideline recommendations, there are no publications that assess the potential impact on the eligibility for palivizumab prophylaxis in US children.

To address the knowledge gap in the literature, we investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis in a well-characterized national cohort of children hospitalized for bronchiolitis.

 

Over the 3year study period, we enrolled 2207 children hospitalized for bronchiolitis to one of the 16 sites. Demographic characteristics, medical history, and clinical course are summarized in Table 1. Overall, the median age was 4months (IQR, 2–9 months) and 1311 (59.4%) were male. Additionally, 285 children (12.9%) were born at gestational age <35 weeks; 460 (20.8%) had one or more major comorbid medical disorders.

Table 1 Bronchiolitis patient characteristics vs AAP palivizumab recommendations

Table 2 Eligibility for palivizumab prophylaxis vs 2012 and 2014 AAP recommendations

According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis (Table 2), while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations. Applying the more restrictive 2014 criteria would have led to 75 fewer children (34.9% relative decrease; 95%CI: 28.5–41.7%) being eligible for palivizumab prophylaxis. The most frequent reason for the loss of eligibility was the 2014 criterion for prematurity that restricts eligibility to infantswithgestationalage<29weeks;thischangeledto45fewer children being eligible (40.9% relative decrease; 95%CI: 31.6–50.7%). The next most frequent reason was the 2014 criteria that limit eligibility to infants with chronic lung disease or congenital heart disease in the first year of life;this change led to 22 fewer children being eligible for palivizumab prophylaxis (22.9%relative decrease; 95%CI: 15.0–32.6%).

Among the 2207 children in the cohort, 207 children (9.4%) had received palivizumab prophylaxis prior to the index hospitalization. Among 215 children eligible for prophylaxis based on the 2012 recommendations, 117 (54.4%) had received palivizumab prophylaxis. Among 140 children eligible for prophylaxis based on the 2014 recommendations, 72 (51.4%) had received palivizumab prophylaxis (Table 1).

 

In this analysis of a large multicenter cohort of children hospitalized for bronchiolitis, we found that approximately 10% of children were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When applying the more restrictive criteria of the 2014 updated recommendations, one-third of these children would have become ineligible for palivizumab prophylaxis. To thebestofourknowledge,thisisthe firststudytoreportthepotential impact of the change in the AAP recommendations on the eligibility for palivizumab prophylaxis in young children, a finding of public health and research importance.

In 1998, palivizumab was licensed by the US Food and Drug Administration (FDA) for prevention of severe RSV diseases in children at high risk, but the FDA did not issue more specific recommendations, nor define high risk.This absence of a specific definition has led several groups to attempt to identify children at high risk who would be eligible for palivizumab prophylaxis.3,6 The AAP published the first policy statement on the use of palivizumab in 1998.7 On the basis of the availability of additional data, the AAP has updated the guidelines in 2003, 2006, 2009, 2012,4 and 2014.3 Since the last update of the AAP recommendations, some studies have reported a high cost but limited benefit from palivizumab prophylaxis.8 In this context, the 2014 AAP guidelines recommended a more restrictive use.3 In particular, preterm infants with gestational age ≥29 weeks without additional risk factors became ineligible for palivizumab.

In parallel with this change in recommendations, within the present high risk population, the most frequent reason for the loss of eligibility was the use of the restrictive criterion for prematurity: that is, preterm infants born from 29t o35 weeks’ gestation with no additional risk factors became ineligible. This specific group of preterm infants accounts fo ra large number of births in the US:approximately 10% of US births in 2012.9 Thus, one may argue that the use of this restrictive criterion would result in an increase in the number of preventable severe RSV infections,10 even considering the potentially limited efficacy of palivizumab in this population. As described in the technical report of the 2014 AAP recommendations, however, it is challenging to define an optimal threshold of gestational age in preterm infants for which palivizumab prophylaxis may be indicated. The present observations should facilitate further investigations that seek high-quality and cost-effective preventive strategies for a large number of vulnerable children.

This study has several potential limitations. First, the analysis was not designed to examine the efficacy or effectiveness of palivizumabprophylaxis. Rather, we sought to examinethe potential impact of the updated recommendations on the eligibility for palivizumab in a well-characterized national cohort of children hospitalized for bronchiolitis. Second, the present study investigated only children hospitalized for bronchiolitis; thus, those with other types of severe respiratory infection (e.g. pneumonia) were not examined. Inclusion of these populations may yield different inferences. Nevertheless, the present findings are directly relevant to >120 000 US children hospitalized for bronchiolitis (and their families) each year.1 Finally, the study participants were those who were hospitalized in academic centers. Therefore, the present inferences may not be generalizable to the US population as a whole. Children hospitalized at academic centers, however, have disproportionately high morbidity; it is in precisely this population for which targeted preventive measures are needed.

In conclusion, we found that 10% of children hospitalized for bronchiolitis were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When we applied the more restrictive 2014criteria,one-third of these children were ineligible. The decrease was largely driven by the restriction of eligibility to preterminfantswithgestationalage <29weeks.Forpolicymakers and researchers, because bronchiolitis continues to be a substantial societal burden in an already-stressed health-care system,1 the present findings support further development and refinement of cost effective approaches for the prevention of severe RSV infection.

 

References

1 Hasegawa K,Tsugawa Y,Brown DF,Mansbach JM,Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics 2013; 132: 28 –36.

2 Hasegawa K, Mansbach JM,Camargo CAJr.Infectious pathogens and bronchiolitis outcomes. Expert Rev. Anti Infect. Ther. 2014; 12: 817 –28.

3 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Policy statement. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134: 415 –20.

4 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds). Red Book: 2012. Report of the Committee on Infectious Diseases. American Academy of Pediatrics, Elk Grove Village, IL, 2012; 609–18.

5 Hasegawa K, Jartti T, Mansbach JM etal.Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: Multicenter cohort studies in the United States and Finland. J. Infect. Dis. 2015; 211: 1550 –9.

6 NHS Commissioning Board. Clinical Commissioning Policy: Palivizumab to reduce the risk of RSV in high risk infants. 2012. Accessed 13 May 2015. Available from URL: http://www.england.nhs.uk/.

7 American Academy of P

ediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102: 1211 –6.

8 Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD,  Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst. Rev. 2013; 4 CD 006602.

9 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Technical report. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134 (2): e620–38.

Appendix I. Principal Investigators at the 16 participating sites in MARC-30
Besh Barcega, MD Loma Linda University Children’s Hospital, Loma Linda, CA, USA

John Cheng, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Carlos Delgado, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Haitham Haddad, MD Rainbow Babies and Children’s Hospital, Cleveland, OH, USA

Frank LoVecchio, MD Maricopa Medical Center, Phoenix, AZ, USA

Eugene Mowad, MD Akron Children’s Hospital, Akron, OH, USA

Brian Pate, MD Children’s Mercy Hospital and Clinics, Kansas City, MO, USA

Mark Riederer, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA

Paul Hain, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA M

Jason Sanders, MD Children’s Memorial Hermann Hospital, Houston, TX, USA

Nikhil Shah, MD New York Presbyterian Hospital, New York, NY, USA

Dorothy Damore, MD New York Presbyterian Hospital, New York, NY, USA

Michelle Stevenson, MD Kosair Children’s Hospital, Louisville, KY, USA

Erin Stucky Fisher, MD Rady Children’s Hospital, San Diego, CA, USA

Stephen Teach, MD, MPH Children’s National Medical Center, Washington, DC, USA

Lisa Zaoutis, MD Children’s Hospital of Philadelphia, Philadelphia, PA, USA