Effect of palivizumab on respiratory syncytial virus-associated burden of disease - a randomized controlled trial

Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is
the most frequent cause of bronchiolitis during infancy. Annually around
1500-2000 children are hospitalized with RSV-bronchiolitis. Prematurity is an
important risk factor for RSV bronchiolitis. Long-term airway morbidity occurs
in about half of hospitalized infants with RSV LRTI, which is referred to as
post-bronchiolitis wheeze (PBW). Prevention of severe RSV infection in preterm
infants with gestational age <36 weeks is possible using monthly infection with
palivizumab during the winter season. This effect of this humanized monoclonal
antibody has been established in a large randomized controlled trial. In the
Netherlands this drug is only used up to gestational age 32 weeks. Preterm
children with gestational age 32-35 weeks are not prophylactically treated with
palivizumab as decided by a national committee of pediatricians.

It is not known whether recurrent wheeze in preterm children is caused by RSV
infection (serial hypothesis) or that RSV infection is the first indication of
chronic airway morbidity that would develop anyway (parallel hypothesis). This
study aims to distinguish between these two hypotheses by investigating whether
prevention of RSV (by palivizumab) results in decreased incidence of recurrent
wheeze. We found a 61% reduction in wheezing days in the first year of life in
children treated with palivizumab versus placebo. We will now expand planned
tests at age 6. We will also perform lung function testing, allergic
sensitization testing, transcriptome analysis and a nasopharyngeal swab. At the
age of 7 years we will take a nasopharyngeal swab to provide further insight
how a single virus may have long-term implications for epigenetic regulation of
the respiratory epithelium and how integration of these different functions of
the epithelium may be instrumental to understand asthma pathogenesis. Between
the age of 6 and 8 years, a genome wide association study (GWAS) will be
performed in order to investigate the contribution of genetic variation to RSV
related short-term and long-term airway disease and the effectiveness of
RSV-prophylaxis. If available after IgE measurement, we will test whether
delayed first exposure to RSV infection by palivizumab results in different
quality or quantity of IgG antibodies against the RSV F and G glycoproteins.
Finally, we will test whether clinical diagnosis of asthma and decreased lung
function have distinct serum protein biomarkers.

double-blind randomized controlled trial

Monthly intramuscular injection with palivizumab (or placebo) during the winter
months (October until February)

This study is a therapeutic study. Children who receive palivizumab will
benefit the (established) beneficial prophylactic effect on the incidence of
severe RSV infection. There are no known severe side effects. It is acceptable
that half of the study population receive placebo, because of the equal odds to
receive palivizumab or placebo.