Respiratory syncytial virus (RSV): Canadian Immunization Guide
Key information

# What
- Respiratory syncytial virus (RSV) infection is a major cause of lower respiratory illness, particularly among infants, young children and older adults.
- In Canada, RSV causes yearly outbreaks of respiratory tract disease, usually starting in late fall and running through to early spring.
- Reinfections with RSV are common but illness is usually milder with subsequent infections.
- At present there is no vaccine available in Canada to prevent RSV. The only means of prevention is temporary passive protection with the monoclonal antibody preparation palivizumab (PVZ). PVZ contains antibody only against RSV.

# Who
- PVZ should be offered to:
	+ infants born at less than 30 weeks gestational age (wGA) and less than 6 months of age at onset of or during the RSV season
	+ children less than 24 months of age with chronic lung disease (CLD) of prematurity who require ongoing oxygen therapy within the 6 months preceding or during the RSV season
	+ infants less than 12 months of age at the onset of the RSV season with haemodynamically significant congenital heart disease (hsCHD) and
	+ infants born at less than 36 weeks gestational age and who are less than 6 months of age at onset of or during the RSV season and living in remote northern Inuit communities who would require air transport for hospitalization.
- PVZ may also be considered for:
	+ infants born at 30 to less than 33 weeks gestational age and less than 3 months of age at onset of or during the RSV season and who are at high risk for exposure to RSV
	+ select children less than 24 months of age with severe chronic lung disease due to cystic fibrosis (CF) or other etiology who require ongoing oxygen therapy or assisted ventilation in the 6 months preceding or during the RSV season
	+ infants less than 12 months of age with haemodynamically significant chronic cardiopathy other than congenital
	+ children 12 to 24 months of age awaiting heart transplant or having received a heart transplant within 6 months of onset of the RSV season
	+ children less than 24 months of age who are severely immunocompromised
	+ healthy full term infants less than 6 months of age at the onset of or during RSV season living in remote Inuit communities with very high rates of hospitalization for RSV among term infants
	+ infants born at less than 36 weeks gestational age and less than 6 months of age living in other remote communities with high rates of hospitalization for RSV and where air transport would be required for hospitalization
	+ controlling an outbreak of RSV in a neonatal intensive care unit (NICU) when all other control measures have failed
- PVZ has not been evaluated in children 2 years of age and older.

# How
- The first dose of PVZ should be given at the onset of the local RSV season.
- A second dose of PVZ should follow at 21 to 28 days and the interval between subsequent doses is 28 to 35 days.
- The usual maximum number of doses is four.
- An additional dose should be given after cardiac bypass or extracorporeal membrane oxygenation.
- An additional dose may be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.
- PVZ may be co-administered with any other live or inactivated vaccines.

# Why
- RSV is the most common cause of bronchiolitis and pneumonia among infants and young children.
- PVZ is approximately 40 to 80% effective in preventing hospitalization, depending on age and underlying health condition.
Epidemiology

# Disease description

## Infectious agent
RSV is an enveloped single-stranded RNA virus of the genus Pneumovirus. RSV causes respiratory tract infections and is the most common cause of bronchiolitis and pneumonia among infants and young children.

## Reservoir
Humans are the only natural reservoir.

## Transmission
RSV is transmitted by direct and indirect contact with infectious respiratory tract secretions. Transmission occurs directly when droplets generated from coughs or sneezes of an infected person come into contact with the mucous membranes of the eyes, nose, mouth, or airway of another person. Indirect transmission occurs when people touch contaminated hands, surfaces and objects and inoculate themselves by touching their mucous membranes.

## Risk factors
RSV infects almost all infants by 2 years of age. Chronological age is an important risk factor for RSV hospitalization.
Prematurity is also a notable risk factor for RSV hospitalization. Indeed, infants born at less than 30 weeks gestation have RSV hospitalization rates of 7.7 to 13.6% in the first year of life. Also at higher risk of RSV hospitalization are young children with chronic respiratory or cardiac conditions, and immunocompromised individuals of any age. High rates of RSV lower respiratory tract infection have been observed among Inuit infants, particularly those less than 6 months of age. Other risk factors for more severe disease include exposure to cigarette smoke and family history of atopy. Factors that predispose to acquisition of RSV include the number of young children in the home, crowding in the home, attending day care or school, and lack of breastfeeding. Severe infection, including pneumonia, may develop among elderly patients with underlying respiratory or cardiac conditions.
Transmission occurs in health care settings and RSV is an important cause of healthcare associated infections in young children, immunocompromised individuals and the elderly.

## Seasonal and temporal patterns
In temperate climates in the Northern Hemisphere, annual outbreaks begin in the fall and continue to early spring. In Canada, the RSV season usually begins in October or November and lasts until April or May, with peaks in December through March.

## Spectrum of clinical illness
Most RSV infections are upper respiratory tract infections that present as nasal congestion, cough, low grade fever and loss of appetite and last approximately 1 to 2 weeks. Approximately 20 to 30% of infected infants develop bronchiolitis or pneumonia. Croup or otitis media may also occur. Recurrent infections occur throughout life, with subsequent infections usually less severe than the first. Older children and adults usually present with symptoms similar to the common cold. Severe pneumonia may occur in the elderly and in immunocompromised individuals of any age.
Mortality is rare among children receiving supportive care. The overall case-fatality rate of children hospitalized with RSV is estimated to be less than 0.5%, with most deaths occurring in children with comorbidities predisposing to more severe disease. Mortality is more common among the elderly hospitalized for RSV.

# Disease distribution
RSV occurs worldwide, with virtually all children infected by age two. Globally, RSV is an important cause of acute lower respiratory tract infection and a major cause of hospital admissions in young children, for whom it has been estimated that RSV is associated with about 28% of all episodes of acute lower respiratory tract infections. In Canada, approximately 1% of all infants are hospitalized with RSV in their first year of life. In some remote communities, RSV hospitalization rates have been as high as 20 to 50% of all live births.
Preparations authorized for use in Canada
- SYNAGIS (palivizumab) (PVZ), is a humanized IgG1 monoclonal antibody directed to the RSV fusion protein). AstraZeneca Canada Inc.
- BEYFORTUSTM (nirsevimab) is a passive immunizing agent (human monoclonal antibody). AstraZeneca Canada Inc.
NACI has not yet deliberated on the use of nirsevimab. The Canadian Agency for Drugs and Technologies in Health (CADTH) will provide an initial assessment of nirsevimab. NACI will subsequently review this passive immunizing agent relative to other prophylactic strategies for RSV and update the chapter in due course.
For complete prescribing information, consult the product leaflet or information contained within Health Canada's authorized product monographs available through the .
Efficacy and effectiveness
PVZ has been evaluated only in children less than 2 years of age at risk of severe RSV infection.
Among all infants at risk of severe RSV infection, PVZ prophylaxis is associated with risk reductions of approximately 38 to 86% for RSV-associated hospital admissions. In infants born at 32 weeks gestation or earlier PVZ has been shown to reduce the risk of all-cause mortality.
The efficacy of PVZ varies according to the infant's underlying health condition and level of prematurity, with a higher benefit for those at a greater level of prematurity.
PVZ has been shown to reduce the risk of RSV-associated hospitalization in children with chronic lung disease of prematurity. The same protective effect of PVZ on hospitalization has not been definitively demonstrated in children with cystic fibrosis.
Studies of children with hsCHD have shown conflicting results, with PVZ reducing hospitalization risk in the larger studies.
Infants living in some remote northern communities are at very high risk of hospitalization for RSV. Data on PVZ effectiveness to prevent hospitalization in this group are very limited.
Recommendations for use

# High risk children

## Schedule
In general, the usual number of doses given in a season is four. The interval between the first and second doses is 21 to 28 days, and the interval between subsequent doses is 28 to 35 days. The first dose of PVZ is given at the onset of the RSV season, as determined by local epidemiology.
 Infants born during the RSV season and who qualify for PVZ prophylaxis should receive their first dose 48 to 72 hours before discharge home if possible, or promptly after discharge. Administering the first dose before discharge avoids the need to visit a health care facility soon after discharge and may improve adherence.
 An infant who has already begun PVZ prophylaxis earlier in the season and is re-hospitalized on a date when a dose is due should receive that dose as scheduled while in hospital, providing the admitting institution is able to supply PVZ when due. Keeping to the child's existing PVZ schedule avoids the need to reschedule appointments and may improve adherence.
 PVZ should be discontinued for the season if a child is hospitalized because of RSV infection. Reported rates of second episodes of RSV hospitalization in the same season are very low.

# Additional doses
An additional, or fifth, dose is recommended after surgery requiring cardiac bypass or at conclusion of extracorporeal membrane oxygenation to maintain PVZ levels that may be decreased following these procedures. An additional, or fifth, dose may also be considered in remote northern areas where RSV outbreaks may continue longer than is usual elsewhere.

# Outbreak control
PVZ should not routinely be used to prevent health care-associated RSV infections or to control RSV hospital outbreaks. It may be considered when all other measures to control an RSV outbreak in a NICU have failed.
Vaccination of specific populations

# Preterm infants without congenital heart disease or chronic lung disease of prematurity
PVZ is recommended for all infants born at less than 30 weeks gestation and aged less than 6 months at the onset of or during the RSV season.
 PVZ may be considered for infants born at 30 to less than 33 weeks gestation and aged less than 3 months at the onset of or during the RSV season if they are at high risk of exposure to RSV from day care attendance or presence of another preschool child or children in the home.
PVZ is not recommended for healthy premature infants born at or after 33 weeks gestation or for infants or siblings of multiple births who do not otherwise have an indication for prophylaxis.

# Chronic lung disease of prematurity and other chronic lung disease
PVZ is recommended for all infants with CLD of prematurity (infants born at less than or equal to 32 weeks gestational age and with need for supplemental oxygen (O2) greater than 21% for at least the first 28 days after birth) who are less than 24 months of age at the onset of the RSV season and have required ongoing supplemental O2 therapy or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ may be considered for infants less than 24 months of age with severe chronic lung disease of other etiology (e.g., congenital cystic lung disease, chronic interstitial lung disease, congenital lung malformations, congenital airway abnormalities or neuromuscular conditions affecting ability to clear airway secretions) or who require home respiratory support (e.g., supplemental O2, mechanical ventilation, continuous positive airway pressure, tracheostomy) if requiring ongoing supplemental O2 or assisted ventilation in the 6 months prior to the onset of or during the RSV season.
PVZ is not routinely recommended for children less than 24 months of age with cystic fibrosis; however, PVZ may be considered for those less than 24 months of age with cystic fibrosis who have severe chronic lung disease as defined by the need for ongoing supplemental O2 in the 6 months prior to the onset of or during the RSV season.
PVZ is not recommended for the prevention of recurrent wheezing or asthma in the absence of other indications.

# Congenital heart disease and other chronic cardiopathy
PVZ should be offered to infants with hsCHD, as assessed by a paediatric cardiologist, who are less than one year of age at the onset of the RSV season.
PVZ may be considered for infants less than one year of age at the onset of the RSV season who have haemodynamically significant chronic cardiopathy (as assessed by a paediatric cardiologist) of other etiology.
PVZ may be considered for children 12 to 24 months of age at the onset of the RSV season if they are awaiting heart transplantation or have received a heart transplant in the previous 6 months.
For children with both haemodynamically significant heart disease and chronic lung disease, recommendations for chronic lung disease should be followed.

# Down syndrome
PVZ should be offered to children with Down syndrome who qualify for prophylaxis because of hsCHD, CLD, prematurity or immunodeficiency, but should not be routinely offered to all children less than 24 months of age with Down syndrome.

# Immunocompromised children
PVZ may be considered for children less than 24 months of age who are severely immunocompromised (e.g., primary immunodeficiency, cancer chemotherapy). Those with absolute lymphocyte counts of <100 / mm3 may be at higher risk of severe RSV disease.
 PVZ prophylaxis has not been evaluated in immunocompromised children. Refer to  in Part 3 for additional general information about vaccination of people who are immunocompromised.

# Children residing in remote communities
PVZ should be offered to infants less than 36 weeks gestational age and less than 6 months of age living in remote northern Inuit communities who would require air transport for hospitalization.
 PVZ is not routinely recommended for healthy full term infants living in remote northern Inuit communities. PVZ may be considered for these infants if aged less than 6 months and living in a community with a very high RSV hospitalization rate, taking into consideration the burden of illness in the community and need for air transport if hospitalization or specialized ambulatory care is required.
PVZ may be considered for infants less than 36 weeks gestational age and less than 6 months of age living in other remote communities with documented high rates of hospitalization for RSV who would require air transport for hospitalization.
Administration practices

# Dose and route of administration
PVZ is given at a dose of 15 mg/kg of body weight by intramuscular injection.

# Simultaneous administration with other vaccines
PVZ is a passive immunizing agent directed specifically against RSV. It does not interfere with the immune response to other vaccines. PVZ can be administered at the same time, at a separate site, as other immunization products.
Storage requirements
PVZ is supplied as 50 mg/0.5 mL and 100 mg/1 mL single use vials for injection. It should be stored between 2 C and 8 C in its original container and must not be frozen.
 PVZ should be administered immediately after drawing the dose into the syringe. If an entire vial (50 mg or 100 mg) is not required for one child, the residual may be used for another child if it is within 6 hours of opening the vial and if the recommended storage conditions have been met. Open vials containing product not used within 6 hours should be discarded. If feasible, clinics or appointments should be organized to facilitate PVZ vial sharing, to reduce costs and PVZ wastage.
Safety and adverse events

# Common and very common adverse events
The most common adverse events following administration of PVZ are injection site reactions, fever, nervousness or irritability, cough, rhinitis and diarrhea. In randomized control trials the rates of these common adverse events were similar for those receiving PVZ as for those receiving a placebo.

# Uncommon, rare and very rare adverse events
Serious adverse events following administration of PVZ, mostly hypersensitivity reactions, are rare at 1.3 to 3.4 per 10,000 doses administered. Anaphylaxis occurs in approximately 1 per 1 million doses.

# Other safety issues
Repeated injections of a humanized monoclonal antibody have raised concern for the development of immune mediated disease. However, studies have not shown an increased risk of autoimmune disease or atopy in children exposed to PVZ.

# Guidance on reporting adverse reactions following palivizumab administration
To ensure the ongoing safety monitoring of passive immunizing agents, like palivizumab, in Canada, reporting of adverse reactions by health care providers is critical.
 When a serious or unexpected adverse reaction follows the administration of a passive immunizing agent such as PVZ, report the adverse drug reaction to the  using the  available on the program web page. The Canada Vigilance Program collects and assesses reports of suspected adverse reactions to health products, including biologics. If PVZ was given along with a routine active immunizing agent, the adverse event(s) should also be reported to the provincial or territorial immunization program.

# Contraindications and precautions
Significant hypersensitivity to PVZ or to any component of PVZ is a contraindication to use of this product. Known hypersensitivity to other humanized monoclonal antibodies is also a contraindication. Minor illnesses such as the common cold, with or without fever, are not contraindications to use of PVZ. Moderate to severe illness, with or without fever, is a reason to consider deferring PVZ to avoid inadvertently attributing possible adverse effects from PVZ to the underlying illness, or vice versa. The decision to delay administration of PVZ will depend on the severity and etiology of the underlying disease.
Chapter revision process
This chapter was developed based on current evidence and the National Advisory Committee on Immunization's (NACI) expert opinion. For supporting information, additional references, please refer the related NACI statement: Recommended use of palivizumab to reduce complications of respiratory syncytial virus infection in infants. Future updates to this chapter will follow NACI's review of new RSV immunizing agents when they are approved for use in Canada by Health Canada.