Immunoprophylaxis for Prevention of Severe RSV Bronchiolitis Ma. Teresa C. Ambat, MD Neonatology-TTUHSC11/21/2008

Immunoprophylaxis for Prevention Immunoprophylaxis for Prevention of Severe RSV Bronchiolitisof Severe RSV Bronchiolitis

Ma. Teresa C. Ambat, MDMa. Teresa C. Ambat, MD

Neonatology-TTUHSCNeonatology-TTUHSC

11/21/200811/21/2008

Development of ImmunoprophylaxisDevelopment of Immunoprophylaxis

1996: FDA approved the intravenous polyclonal antibody 1996: FDA approved the intravenous polyclonal antibody RSV immune globulin (RSV-IVIG, Respigam)RSV immune globulin (RSV-IVIG, Respigam) Prepared from donors selected for high serum titers of Prepared from donors selected for high serum titers of

RSV neutralizing antibodyRSV neutralizing antibody No longer availableNo longer available

1998: FDA approved palivizumab (Synagis) 1998: FDA approved palivizumab (Synagis) First monoclonal antibody developed into vaccine, for First monoclonal antibody developed into vaccine, for

use as immunoprophylaxis for children use as immunoprophylaxis for children <<2 yrs at risk 2 yrs at risk for severe RSV infectionfor severe RSV infection

Comparison of RSV-IVIG with PalivizumabComparison of RSV-IVIG with Palivizumab

CharacteristicsCharacteristics RSV-IVIG RSV-IVIG (Respigam)(Respigam)

Palivizumab Palivizumab (Synagis)(Synagis)

Type of immunoglobulinType of immunoglobulin PolyclonalPolyclonal MonoclonalMonoclonal

Method of administrationMethod of administration IVIV IMIM

Contraindicated in infants with Contraindicated in infants with hemodynamically significant CHDhemodynamically significant CHD

YesYes NoNo

Protects against other viral Protects against other viral infectionsinfections

YesYes NoNo

Decreased AOMDecreased AOM YesYes NoNo

Risk of fluid overload in BPDRisk of fluid overload in BPD YesYes NoNo

Blood productBlood product YesYes NoNo

Interferes with routine childhood Interferes with routine childhood immunizationimmunization

YesYes NoNo

DosageDosage 750mg/k/dose750mg/k/dose 15mg/k/g/dose15mg/k/g/dose

Dosing intervalDosing interval MonthlyMonthly MonthlyMonthly

# of doses / season# of doses / season 55 55

Clinical Practice GuidelineDiagnosis and Management of Bronchiolitis

RECOMMENDATION 8a Clinicians may administer palivizumab prophylaxis to

selected infants and children with CLD or a history of prematurity less than 35 weeks’ gestation or with congenital heart disease

Recommendation: evidence level A; RCT; preponderance of benefit over harm

Clinical Practice GuidelineDiagnosis and Management of Bronchiolitis

RECOMMENDATION 8b When given, prophylaxis with palivizumab should be

given in 5 monthly doses, usually beginning in November or December, at a dose of 15 mg/kg per dose administered intramuscularly

Recommendation: evidence level C; observational studies and expert opinion; preponderance of benefit over cost

The 2006 Red Book Recommendationsfor the use of Palivizumab

1. Palivizumab prophylaxis should be considered for infants and children < 24 months of age with chronic lung disease of prematurity who have required medical therapy (supplemental oxygen, bronchodilator or diuretic or corticosteroid therapy) for CLD within 6 months before the start of the RSV season.

Patients with more severe CLD who continue to require medical therapy may benefit from prophylaxis during a second RSV season.

Data are limited regarding the effectiveness of palivizumab during the second year of life.


2. Infants born at 32 weeks of gestation or earlier may benefit from RSV prophylaxis, even if they do not have CLD.

Major risk factors: gestational age, chronologic age at the start of the RSV season

< 28 weeks of gestation or earlier may benefit from prophylaxis during their first RSV season, whenever that occurs during the first 12 months of life

29 to 32 weeks of gestation may benefit most from prophylaxis up to 6 months of age

Once a child qualifies for initiation of prophylaxis at the start of the RSV season, administration should continue throughout the season and not stop at the point an infant reaches either 6 months or 12 months of age.


3. Prophylaxis should be considered for infants between 32 and 35 weeks of gestation younger than 6 months of age at the start of RSV season only if 2 or more of these risk factors are present:

Child care attendance School-aged siblings Exposure to environmental air pollutants Congenital abnormalities of the airways Severe neuromuscular disease

No single risk factor causes a very large increase in the rate of hospitalization, and the risk is additive as the number of risk factors for an individual infant increases.


4. Results from clinical trials indicate that palivizumab trough serum concentrations 30 days after the fifth dose will be well above the protective concentration for most infants.

If the first dose is administered in November, 5 monthly doses of palivizumab will provide substantially more than 20 weeks of protective serum antibody concentrations for most of the RSV season, even with variation in season onset and end.


5. Children who are 24 months of age or younger with hemodynamically significant cyanotic and acyanotic congenital heart disease will benefit from palivizumab prophylaxis.

Children younger than 24 months of age with congenital heart disease who are most likely to benefit from immunoprophylaxis include:

Infants who are receiving medication to control congestive heart failure

Infants with moderate to severe pulmonary hypertension Infants with cyanotic heart disease

Summary of AAP Recommendations for Use Summary of AAP Recommendations for Use of Immunoprophylaxis in RSV Infectionof Immunoprophylaxis in RSV Infection

Without BPDWithout BPD With BPDWith BPD

Former Premature InfantsFormer Premature Infants Irrespective of PrematurityIrrespective of Prematurity1.1. GA GA <<28 wks, who are 28 wks, who are <<12 months 12 months

old at the start of RSV seasonold at the start of RSV season

2.2. GA >28 to GA >28 to <<32 wks, who are < 6 32 wks, who are < 6 months old at the start of RSV months old at the start of RSV seasonseason

3.3. GA >32 to <35 wks, who are <6 GA >32 to <35 wks, who are <6 months old at the start of RSV months old at the start of RSV season and season and >> 2 of the ffg: 2 of the ffg:

Child care attendanceChild care attendance School-aged siblingsSchool-aged siblings Congenital anomalies of the airwaysCongenital anomalies of the airways Severe neuromuscular diseaseSevere neuromuscular disease Exposure to environmental air pollutants

1.1. <<12 months old at the start of the 12 months old at the start of the 11stst RSV season RSV season

2.2. <<24 months old with persistent 24 months old with persistent signs of BPD at the start of the 2signs of BPD at the start of the 2ndnd RSV seasonRSV season


1.1. Infants and children with congenital heart diseaseInfants and children with congenital heart disease

At the start of RSV seasonAt the start of RSV season<<12 months and receiving medications to control CHF12 months and receiving medications to control CHF<<12 months with uncorrected or partially corrected cyanotic heart 12 months with uncorrected or partially corrected cyanotic heart disease who remain cyanoticdisease who remain cyanotic<<24 months with hemodynamically significant cyanotic and 24 months with hemodynamically significant cyanotic and acyanotic heart diseaseacyanotic heart disease

2.2. Infants and children with pulmonary hypertensionInfants and children with pulmonary hypertension

At the start of RSV seasonAt the start of RSV season<<12 months with moderate PPHN12 months with moderate PPHN<<24 months with severe PPHN24 months with severe PPHN


Dates for initiation and termination should be based on Dates for initiation and termination should be based on the same considerations as for high-risk preterm infants. the same considerations as for high-risk preterm infants.

For children who underwent cardiopulmonary bypass For children who underwent cardiopulmonary bypass and still require prophylaxis, a postoperative dose of and still require prophylaxis, a postoperative dose of palivizumab (15mg/kg) should be considered as soon as palivizumab (15mg/kg) should be considered as soon as the patient is hemodynamically stable. the patient is hemodynamically stable.


3.3. Infants and children not considered at risk for severe Infants and children not considered at risk for severe RSV (immunoprophylax is not indicated)RSV (immunoprophylax is not indicated)

Infants with non-hemodynamically significant heart disease: ASDInfants with non-hemodynamically significant heart disease: ASD

Small VSD, Pulmonic stenosis, mild coarctation, PDASmall VSD, Pulmonic stenosis, mild coarctation, PDA

Infants with corrected cardiac lesions without cyanosis or CHFInfants with corrected cardiac lesions without cyanosis or CHF

Infants with mild cardiomyopathy who are not receiving medical Infants with mild cardiomyopathy who are not receiving medical therapytherapy

Additional AAP Remarks Once a child qualifies for immunoprophylaxis, administration should

continue for the remainder of the RSV season even if the child no longer meets the clinical criteria or age requirement prior to completion of the RSV season.

Even if a child develops RSV during immunoprophylaxis, he or she should complete the drug course.

Neither RSV-IVIG nor Palivizumab is indicated or licensed for the treatment of RSV infection.

RSV prophylaxis should begin before the onset of the RSV season (November) and terminate at the end of the RSV season (March), allowing for 6 months of protection.

Additional AAP Remarks

All high-risk infants and their contacts should be immunized against influenza beginning at age 6 months.

There is insufficient information regarding the immunoprophylaxis of infants with CF, SCID, AIDS. However, they may benefit from prophylaxis.

There are no recommendations regarding the administration of palivizumab as a means of preventing nosocomial RSV

infection.

Additional AAP Remarks High-risk infants should never be exposed to tobacco smoke.

Existing data are conflicting regarding the specific protective effect of breastfeeding against RSV infection.

High-risk infants should be kept away from crowds and from situations in which exposure to infected individuals cannot be controlled.

Participation in group child care should be restricted during the RSV season for high-risk infants whenever feasible.

Parents should be instructed on the importance of careful hand hygiene.

Controversies in RSV ImmunoprophylaxisControversies in RSV Immunoprophylaxis

Primary benefit of RSV immunoprophylaxis is decreased rate Primary benefit of RSV immunoprophylaxis is decreased rate of RSV-related hospitalizations.of RSV-related hospitalizations.

No significant decrease in rate of mortality attributable to RSV No significant decrease in rate of mortality attributable to RSV infection in infants who received prophylaxis.infection in infants who received prophylaxis.

Most of the economic analyses fail to demonstrate overall savings in health care dollars because of the high cost if all at-risk children were to receive prophylaxis.

Giving immunoprophylaxis to all infants at high risk is not cost Giving immunoprophylaxis to all infants at high risk is not cost effective.effective.

ReferencesReferences

1.1. 2006 Redbook2006 Redbook

2. Clinical Practice Guideline: Diagnosis and Management of Bronchiolitis. Endorsed by the American Academy of Family Physicians, the American College of Chest Physicians, and the American Thoracic Society.

3. Brodsky D, Quellette M. Primary Care of the Premature Infant. 2008.

Documents

Immunoprophylaxis for Prevention of Severe RSV Bronchiolitis Ma. Teresa C. Ambat, MD Neonatology-TTUHSC11/21/2008