We will offer palivizumab to infants who meet the JCVI preterm and BPD recommendations below¹, including those ex-preterm babies who are at home still receiving oxygen for BPD and for whom it will be their first RSV season. The list of eligible infants will be collated in September by nominated consultants in the Simpson Neonatal Unit and St John’s SCBU. Any eligible babies whose parents wish them to receive palivizumab and who will be discharged home between 1^st October and 29^th February should receive the first dose 24-48 hours prior to discharge. Please see the flowchart appendix for further details on the process of identification of eligible infants.

Other eligible children already at home will receive their first dose either at the RHSC Synagis Clinic in PIU (Simpson graduates) or the Children’s ward at St John’s (St John’s graduates). The remaining doses, up to a maximum of 5, given monthly through the RSV season, will be arranged directly by the RHSC Synagis Clinic and the St John’s Children’s Ward respectively. Please see the Palivizumab monograph for specific information on dosing, administration and monitoring.

1. High Risk due to Bronchopulmonary dysplasia (also known as chronic lung disease)

a. Pre-term infants who have moderate or severe BPD. Moderate or severe BPD is defined as ‘preterm infants with compatible x-ray changes who continue to receive supplemental oxygen or respiratory support at 36 weeks post-menstrual age ’. Children who fall into the light and dark green shaded area of Table 1 should be offered prophylaxis.

b. Infants with respiratory diseases who are not necessarily pre-term but who remain in oxygen at the start of the RSV season are also considered to be at higher risk. These infants may include those with conditions including:

1. 1. 1. pulmonary hypoplasia due to congenital diaphragmatic hernia
      2. other congenital lung abnormalities (sometimes also involving congenital heart disease or lung malformation)
      3. interstitial lung disease

and including those receiving long term ventilation at the onset of the season.

2. High Risk due to Congenital Heart Disease (CHD)

a. Preterm infants with haemodynamically significant, acyanotic CHD at the chronological ages at the start of the RSV season and gestational ages at birth covered within the light green shaded area in Table 1.

b. Cyanotic or acyanotic CHD plus significant co-morbidities particularly if multiple organ systems are involved

3. High Risk due to Severe Combined Immunodeficiency Syndrome (SCID)

a. Children less than 24 months of age with SCID - the most severe form of inherited deficiency of immunity, who are unable to mount either T-cell responses or produce antibody against infectious agents – until immune reconstituted.

Chronological age refers to the age of outpatients on 1^st October or

inpatients discharged between 1^st October and 29^th February

Respiratory Syncytial Virus (RSV) is the most common virus responsible for the paediatric winter illness, bronchiolitis. Symptoms can range from a mild cold to severe breathing difficulties. There is not a specific treatment for RSV and care is otherwise supportive. Most infants and children with RSV/ bronchiolitis can be cared for at home, but if hospital admission is required for hypoxia, apnoea or poor feeding, then care may encompass nasal suction, NG feeding, supplemental oxygen, CPAP/BiPAP and rarely ventilation. 30,000 babies and children under 5 years are estimated to be hospitalised every year in the UK due to RSV². 6% of these require admission to paediatric intensive care units. RSV accounts for around 30 infant deaths each year in the UK and in high risk children the mortality is around 3%³.

RSV is very contagious and is passed easily from person to person through close contact respiratory droplet spread or with contaminated surfaces or objects. RSV can live on hard surfaces for many hours. Simple steps can be undertaken to reduce transmission:

• Regular hand washing with soap and water before touching babies
• Catching sneezes and coughs in a tissue and throwing it away
• Staying away from others with a cough or a cold
• Wiping down surfaces regularly
• Avoiding smoke inhalation

The UK Government’s Joint Committee on Vaccination and Immunisation (JCVI) recommends that some higher risk infants and children may benefit from passive immunisation against RSV⁴. This is achieved by monthly intramuscular injection through the winter (October to March) with the humanised monoclonal antibody, palivizumab. The JCVI advice is based largely upon data from the Impact-RSV trial⁵ and two cost-effective health technology assessments (HTAs) undertaken by Wang et al in 2008⁶ and 2010⁷.

The Impact RSV trial was published in 1998 in Pediatrics. This was a randomized, double-blind, placebo-controlled trial, conducted at 139 centres in the United States, the United Kingdom and Canada. 1502 children with prematurity (≤35 weeks) or bronchopulmonary dysplasia (BPD) were enrolled and randomised – 500 to the placebo group and 1002 to the palivizumab group. This was a well conducted trial with a high completion rate (99%).

The primary outcome was hospitalisation with confirmed RSV infection. Monthly prophylaxis with palivizumab in the whole group was associated with a 55% (95% CI 38%, 72%) reduction in hospitalisation as a result of RSV. When the BPD group was analysed alone, the effect size was smaller. Infants with BPD had a 39% relative reduction (12.8% vs. 7.9%) or an absolute reduction of 4.9%. This equates to a number need to treat of 20 (95% confidence interval 10 – 424), to prevent 1 hospital admission with RSV. The average duration of hospitalisation in the placebo group was 2.4 days per infant. Secondary outcomes in the trial showed that those in the palivizumab group spent significantly fewer days in hospital, fewer days with increased oxygen, and fewer days with a worse illness score. There was no significant difference between the groups with respect to days spent in intensive care or length of ventilation.

The two HTAs carried out by Wang et al to help inform the JCVI used methodology to assess cost effectiveness also applied by the National Institute for Health and Clinical Excellence (NICE). Both underwent independent peer-review commissioned by the National Institute for Health Research (the sponsor of both HTAs). The HTAs found palivizumab to be effective in lowering the risk of serious lower respiratory tract infection caused by RSV infection requiring hospitalisation in high-risk children. In considering the HTAs, the JCVI sub-committee noted that there “are large uncertainties in estimating the cost effectiveness of Palivizumab prophylaxis to prevent serious RSV infection. As a consequence the cost effective estimates derived are imprecise”⁴.

Some data have been reported since the JCVI recommendation. A systematic review and meta-analysis published in 2011 by Checchia et al in Pediatric Critical Care Medicine⁸, sought to review all-cause mortality in the higher risk groups. This included data from 3 RCTs and 7 observational studies. The authors acknowledged that the strength of evidence is an important limitation of the study when interpreting their results. Nonetheless, they report a statistically significant beneficial effect of palivizumab prophylaxis on all-cause mortality. The authors surmised that the group receiving prophylaxis had a higher frequency of underlying illness such as chronic lung disease, which might be expected to increase their risk of death. Despite this, they observed an effect favouring prophylaxis. Palivizumab was also associated in this meta-analysis with a reduction in RSV hospitalisation.

Figure 1. Meta-analysis of all cause mortality⁸

Figure 2. Meta-analysis of RSV hospitalisation⁸

At the time of writing, the NHS cost of a 100mg vial is £563.64⁹. Many units advocate the use of ‘vial sharing’ in palivizumab clinics in order to reduce monetary cost as much as possible. There are additional ‘costs’ over and above the medicine itself – clinic set-up and maintenance, family travel and parking, hospital attendance ‘risk’, potential time away from work.

A vaccine to prevent RSV infection might be a cost-effective way of reducing the burden of severe RSV disease. Hospital treatment for babies with RSV costs the NHS millions of pounds every year. There is currently no licensed RSV vaccine, but a number of vaccines are now in the later stages of development and are expected to be licensed. The Oxford Vaccine Group is currently undertaking a number of projects that try to better understand the burden of RSV disease, and looking at several approaches to vaccine prevention².

1. Green Book Chapter 27a Respiratory Syncytial Virus
2. Vaccine Knowledge Project. Ovg.ox.ac.uk/research/vaccine-knowledge-project
3. Müller-Pebody B, Edmunds WJ, Zambon MC et al. Contribution of RSV to bronchiolitis and pneumonia-associated hospitalizations in English children, April 1995- March 1998. Epidemiol Infect. 2002; 129 (1): 99-106
4. JCVI Statement on immunisation for Respiratory Syncytial Virus: https://www.nitag-resource.org/sites/default/files/ddf283f66b77b34a6821e8d6f000947b74f6b68b_1.pdf
5. 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 (3 pt 1): 531–7
6. Wang, D., Cummins, C., Bayliss, S., Sandercock, J. and Burls, A. Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation. Health Technology Assessment. 2008; 12 No. 36
7. Wang D, Bayliss S, Meads C. Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses. Health Technol Assess.2011;15(5)
8. Checchia P, Nalysnyk L, Fernandes A, Mahadevia P, Xu Y, Fahrbach K, Welliver R. Mortality and morbidity among infants at high risk for severe respiratory syncytial virus infection receiving prophylaxis with palivizumab: A systematic literature review and meta-analysis. Pediatric Critical Care Medicine: September 2011; 12 (5): 580-588
9. AbbVie RSV immunisation planner - https://www.abbviepro.com/content/dam/abbvie-pro/uk/synagis/documents/CERT%20Print%20-%20Synagis%20BPD%20Guidelines%20and%20planner%20Digital%20UK-SYNA-200025.pdf