Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants

What

a) Respiratory syncytial virus disease

Respiratory syncytial virus (RSV) causes yearly outbreaks of respiratory tract disease, in Canada from late fall to early spring. It is the most common cause of lower respiratory tract illness in young children worldwide. While many infections are simple colds, children less than 2 years of age are at risk of severe disease such as bronchiolitis or pneumonia and may be hospitalized. Underlying health conditions, especially premature birth, chronic lung disease and congenital heart disease (CHD) redispose to severe RSV illness. Reinfections occur throughout life as infection produces only partial and temporary immunity, although reinfections are usually milder than the initial one.

b) Palivizumab

At present there is no vaccine available to prevent RSV. The only means of prophylaxis against RSV disease is temporary passive protection with the monoclonal antibody preparation Palivizumab (SynagisTM). Palivizumab (PVZ) has only been studied in children less than 2 years of age with underlying health conditions. Efficacy in early studies was 38-78% in different patient groups, and further studies, mainly observational, showed wide variation in effect with some studies showing no benefit. PVZ has been used for over 2 decades in many countries and has a good safety record, with very rare cases of anaphylaxis being the major serious adverse event (SAE). It is an expensive product, with wide ranging estimates of cost-effectiveness (or value for money). Estimated incremental effectiveness ratios (ICERs) ranged from less than $1,000 per quality-adjusted life year (QALY) to over 2 million dollars per QALY in various scenarios. In various high risk groups, 64% to 100% of estimates were < $50,000 per QALY. In rare scenarios it may be dominant (i.e, less costly and more effective). RSV vaccines are currently under study.

Who

NACI makes the following recommendations for public health program level decision-making:

• PVZ should be offered to premature infants of < 30 weeks gestational age (wGA) and < 6 months of age at onset of or during the RSV season; children aged < 24 months with chronic lung disease of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season; infants aged < 12 months with haemodynamically significant CHD and infants born at < 36 wGA and age < 6 months old living in remote northern Inuit communities who would require air transport for hospitalization. For children with both CHD and chronic lung disease, recommendations for chronic lung disease should be followed.
• PVZ may be considered for premature infants of 30-32 wGA and age <3 months who are at high risk for exposure to RSV; selected children <24 months of age with severe chronic lung disease due to cystic fibrosis or other etiology who require ongoing oxygen therapy or assisted ventilation in the 6 months preceding or during the RSV season; infants <12 months of age with haemodynamically significant chronic cardiopathy other than congenital; children aged 12-24 months awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season; and children aged <24 months with severe immunodeficiency. It may also be considered for term infants aged <6 months living in remote Inuit communities with very high rates of hospitalization for RSV among term infants and for infants of < 36 weeks gestational age and age <6 months living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization. PVZ may be considered when all other measures to control a RSV outbreak in a NICU have failed.
• PVZ should not be offered to otherwise healthy infants born at or after 33 wGA; or to siblings in multiple births who do not otherwise qualify for prophylaxis. It should not be offered routinely for children <24 months of age with cystic fibrosis; for children <24 months of age with Down syndrome without other criteria for PVZ; or for healthy term infants living in remote northern Inuit communities,unless hospitalization rates for RSV are very high. It should not be used for the prevention of recurrent wheezing or asthma in the absence of other indications.
• PVZ should not be given to prevent hospital-associated RSV infection in eligible children who remain in hospital. It may be considered when all other measures have failed to control an RSV outbreak in a neonatal intensive care unit.

Since in Canada PVZ is not readily available for purchase, no specific recommendations are made for individual-level decision making.

How

• The dose of PVZ is 15 mg/kg by intramuscular injection, starting with the onset of the local RSV season. Eligible children who are in hospital should receive their first dose on discharge (or within 48-72 hr before discharge to facilitate vial sharing). The interval between the first and second doses should be 21-28 days and between subsequent doses 28-35 days, for a maximum of 4 doses.
• An extra dose should be given after cardiac bypass or extracorporeal membrane oxygenation. An extra dose may be considered in remote Northern areas where RSV outbreaks may continue longer than is usual elsewhere.
• PVZ should be discontinued for the season if a child is hospitalized for RSV infection.
• If feasible, clinics or appointments should be organized to facilitate vial sharing, to reduce costs.
• PVZ is contraindicated in individuals with known significant hypersensitivity reaction to PVZ or any component of the product (humanized monoclonal antibody, glycine, histidine). Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ, to avoid superimposing adverse effects from PVZ on the underlying illness, or mistakenly identifying a manifestation of the underlying illness as a complication of PVZ. The decision to delay PVZ depends on the severity and etiology of the underlying disease. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ.
• PVZ contains antibody only against RSV and may be co-administered with any other live or inactivated vaccines.

Why

PVZ is recommended for infants and young children with health conditions that make them more vulnerable to severe RSV disease requiring hospitalization and possibly admission to an intensive care unit and mechanical ventilation.

Although the risk of severe RSV disease is reduced, PVZ does not prevent all hospitalizations for RSV. It is thought to prevent 40 to 80% of hospitalizations, depending on age and underlying health condition. Therefore other means of protection against RSV (limiting exposure of high risk children to persons with cough and colds, appropriate hand hygiene, preventing exposure to cigarette smoke) are important.

Although any young child may be hospitalized with RSV, most will not have severe illness. PVZ is not recommended for children at lower risk of severe disease, in some instances because of cost, in others because of lack of information about whether it will work.