Preventing respiratory syncytial virus infections

Abstract

Respiratory syncytial virus infection is the leading cause of lower respiratory tract infections in young children. Palivizumab, a respiratory syncytial virus-specific monoclonal antibody, reduces the hospitalization rate of high-risk children but it is very costly. This statement replaces three previous position statements from the Canadian Paediatric Society about this topic, and was updated primarily to discuss recent changes in the American Academy of Pediatrics guidelines in the Canadian context. It reviews the published literature and provides recommendations regarding palivizumab use in high-risk children.

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RECOMMENDATIONS

The levels of evidence are described using the evaluation of evidence criteria outlined by GRADE (Grades of Recommendation Assessment, Development and Evaluation). In this system, evidence is graded as high, moderate, low or very low. Then, values and preferences of patients and of society are taken into account, leading to a weak (conditional) or strong recommendation. Only the evidence from randomized controlled studies or from observational studies with a control group was considered for the present guidelines. Such evidence had to relate to respiratory syncytial virus (RSV) and not to respiratory tract infections in general.

I. Do nonpharmacological measures prevent the spread of RSV to children at high risk for severe RSV infection?

Recommendation. Preventive measures, such as good hand hygiene in the home and limiting direct contact of high-risk children with other children and adults with respiratory tract infections, where practical, remain paramount for RSV prevention (strong recommendation/no evidence).

Remarks. Although there is no evidence supporting these simple, inexpensive interventions preventing RSV specifically, there is evidence of efficacy for preventing respiratory tract infections. Given that the prevention of RSV and its associated hospitalizations by palivizumab is only approximately 55%, and that even in the pre-palivizumab era, most hospitalizations occurred in healthy term infants, more attention should be paid to these measures.

II. Should high-risk children receive palivizumab to prevent RSV hospitalization?

1. For children with chronic lung disease of prematurity who require ongoing medical therapy, children with hemodynamically significant congenital heart disease who are younger than 24 months of age at the start of RSV season, and infants born before 32 weeks 0 days’ gestational age (GA) who are younger than six months of age at the start of the RSV season:

Recommendation. These children should receive up to five doses of palivizumab (strong recommendation/high-quality evidence).

Remarks. Decisions regarding the use of palivizumab in this and all other high-risk groups need to take competing local priorities for funding into account, which may allow for use of palivizumab in only selected infants in this cohort.

Values and preferences. This recommendation places a high value on preventing hospitalizations in these vulnerable infants despite the high cost of palivizumab.

2. For children born at 32 weeks 0 days to 35 weeks 6 days’ GA:

Recommendation #1. A panel of experts should be convened in each province or territory (weak recommendation/no evidence) to establish a policy for these infants.

Remarks. The upper limit of GA may need to be determined by available funding.

Recommendation #2. The panel may want to use the American Academy of Pediatrics (AAP) criteria, or the Canadian risk-scoring tool, to select infants eligible for palivizumab prophylaxis (weak recommendation/no evidence).

Remarks. It seems likely that applying the AAP criteria would result in more infants being prophylaxed, but for a shorter time. It is impossible to predict the relative impact on hospitalizations.

Recommendation #3. Irrespective of the criteria chosen, giving the last dose at three months’ chronological age should be considered in this GA cohort (weak recommendation/no evidence).

Remarks. This recommendation is an attempt to balance cost and benefit, and is designed to protect infants at greatest risk of hospitalization.

3. For infants in remote communities who would require air transportation for hospitalization:

Recommendation #1. Consideration should be given to administering up to five doses of palivizumab for all infants born before 36 weeks’ GA and younger than six months of age at the beginning of RSV season (strong recommendation/high-quality evidence).

Remarks. It is not clear whether this recommendation should apply only to Inuit infants, to all Aboriginal infants or to all infants in remote communities. The incidence of RSV hospitalization in a remote community in previous years should be taken into account when making this decision. A practical issue is that the onset and duration of RSV season is unpredictable in the Far North. Occasionally, more than a year goes by between RSV seasons. To save money, one would delay administering palivizumab until there is confirmed RSV activity in a remote community. The attendant risk is that significant spread may have already occurred.

Values and preferences. This recommendation places high value on preventing RSV hospitalizations because of the high cost of such admissions.

Recommendation #2. Consideration may be given to administering up to five doses of palivizumab to term Inuit infants younger than six months of age in communities with documented persistent high rates of RSV hospitalizations (weak recommendation/no evidence).

Remarks. There is no direct evidence of the efficacy of palivizumab in term Inuit infants, but observational studies in preterm Inuit infants and in term infants with other risk factors suggest that there would be efficacy. There are insufficient data regarding the morbidity from RSV to recommend use in term infants in other Northern populations.

4. For children with immunodeficiencies, Down syndrome, cystic fibrosis, upper airway obstruction or a chronic pulmonary disease other than chronic lung disease of prematurity:

Recommendation. Palivizumab is not routinely recommended. However, it may be considered for children younger than 24 months of age (because they may not yet have encountered their first RSV infection) who are likely to be exposed to RSV and are on home oxygen, have had a prolonged hospitalization for severe pulmonary disease, or are severely immunocompromised (weak recommendation/no evidence).

Remarks. This recommendation should be expanded to include more children with pulmonary disease if evidence becomes available that avoidance or delay of the initial RSV hospitalization impacts long-term pulmonary function.

III. How should palivizumab be administered?

Recommendation. Each jurisdiction should optimize processes to implement these recommendations in the most cost-effective manner. Well-organized palivizumab clinics decrease drug wastage (strong recommendation/no evidence).

RESEARCH PRIORITIES INCLUDE BUT ARE NOT LIMITED TO THE FOLLOWING:

• Further validating the criteria used to identify highest-risk infants born between 32 and 35 weeks’ GA and the study of such criteria at 29 to 31 weeks’ GA. Validation of the AAP’s criteria in previously assembled cohorts would be informative.

• Determining the efficacy of three versus five doses of palivizumab, and of lower doses of palivizumab.

• Determining the efficacy of palivizumab in term infants.

• Tracking the seasonality of RSV in Northern communities.

• Studying the impact of socioeconomic status, ethnicity and environmental factors on the severity of RSV, and the efficacy of palivizumab prophylaxis in children with immunodeficiencies, cystic fibrosis, other chronic pulmonary disorders and Down syndrome.

• Setting criteria for determining which week of the year to start and end palivizumab prophylaxis.

• Studying palivizumab resistance.