Five monthly doses of prophylaxis are needed to prevent RSV

January 2005

NEW YORK — No pediatrician has to be told the disease burden of respiratory syncytial virus (RSV). Almost every child has been infected at least once by 2 years of age.

“We know that approximately 2% of all children in the first year of life have been hospitalized due to RSV. Among high-risk children, the hospitalization rate in the first year of life is somewhere between 10% and 15%, making this one of the most common reasons for hospitalization in children in the first 12 months of life,” said H. Cody Meissner, MD, at the 17th Annual Infectious Diseases in Children Symposium here.

Although effective for protecting against RSV disease, immunoprophylaxis is expensive, so the AAP Committee on Infectious Diseases (the Red Book committee) has developed recommendations for optimal use of these interventions. The committee recommends that prophylaxis begin in November and continue for a total of five doses until March.

RSV-IGIV (RespiGam, MedImmune), a polyclonal hyperimmune globulin, requires IV cannulation once a month and administration over several hours. Quantities are limited this season, and after this season, RSV-IGIV will probably not be available. Palivizumab (Synagis, MedImmune) is easier to administer because it is an intramuscular injection, Meissner said.

The Red Book committee has identified three high-risk groups of children who are most likely to benefit from monthly prophylaxis:

• Children with chronic lung disease of prematurity who are 24 months of age or younger at the beginning of RSV season in November and who have required additional therapy, such as supplemental oxygen, diuretics, steroids or bronchodilators within the preceding six months;
• Children without chronic lung disease who are younger than 32 weeks of gestational age and who will be 6 months of age or younger at the start of the RSV season in November for their first RSV season; and
• Children with congenital heart disease.

“The children with congenital heart disease for whom prophylaxis is recommended are youngsters who are under 24 months of age at the start of the RSV season and particularly those children with pulmonary hypertension, children who are on medication for control of congestive heart failure and children with cyanotic disease. It’s also beneficial for certain children with severe non-cyanotic heart disease,” said Meissner, chief of the division of pediatric infectious diseases at Tufts–New England Medical Center in Boston and vice-chair of the Committee on Infectious Diseases.

Those groups are pretty straightforward. “The toughest group to deal with is the 32- to 35-week gestational age children who will be 6 months or less of age at the start of the RSV season,” Meissner said.

Children in that age group should have at least two additional risk factors before pediatricians consider prophylaxis, according to Meissner.

RSV risk factors

“A number of factors have been identified as increasing the risk of hospitalization due to RSV. The difficulty is that most — not all, but most — of those risk factors have only a modest increase in the risk of hospitalization; that is, they may increase the risk by just a few fold,” he said.

Children who are born either just before the onset of the RSV season or who are born early in the RSV season are at increased risk of RSV hospitalization. “Most children who are hospitalized with RSV disease are in fact in the first 6 months of life, typically 3, 4, 5 or 6 months of age,” he said.

The child who is born early in the season is at risk the longest, while he or she is still young. Maternal antibodies to RSV are seasonal, and children who are born to mothers with a high titer of RSV antibodies are less likely to require hospitalization than children who are born to mothers with a low titer of RSV antibody, Meissner said.

“That reflects the fact that, as the season starts, women who are pregnant, as well as anyone else, tend to experience recurrent RSV infection, boosting [their] antibodies, which are then transmitted to the child and protect that youngster or at least reduce the risk of RSV hospitalization,” Meissner said.

Children who are born before mothers can become reinfected miss the opportunity to acquire high titers of maternal antibodies. Prematurity is an important risk factor in all studies because the respiratory tract is underdeveloped.

Household crowding is a risk factor, especially if there are preschoolers or school-age siblings in the family. “As the number of children in the family increases, then the likelihood of exposure to an infected individual increases,” Meissner said.

A more tenuous link

Other predictors are weaker, he said, including child care, environmental exposures such as tobacco smoke and breast-feeding.

“Intuitively, we would think that participation in child care clearly increases the risk of RSV. But interestingly, in a number of studies it’s been difficult to demonstrate that participation in child care does increase the risk of RSV,” he said.

Some studies indicate that maternal smoking is an important risk factor. Other studies do not, making it difficult to offer firm guidelines. However, the AAP recommends that parents do not smoke around any child, especially a child at risk for lung disease.

“One should avoid exposure to tobacco smoke for the young child, and the Committee on Infectious Disease has made the point that exposure to tobacco smoke is in many situations, perhaps in most situations, a controllable risk factor. Parents should be strongly encouraged not to smoke around children for many reasons,” he said.

Breast-feeding is also important, he said, because it protects children from a number of viral infections. However, its effects on RSV are not as clear. “There is not a consistent pattern of protection against RSV infection in children who are breast-fed. Clearly, there are benefits from breast-feeding, but, in terms of the specific issue of RSV, it’s been difficult to clearly demonstrate the benefit,” said Meissner.

Still, “for high-risk children who are born before 35 weeks of age, one should encourage breast-feeding for many reasons,” he said.

Children at risk for RSV should be kept away from sick people, including relatives. “This is particularly referring to relatives who don’t live in the household. And for those children who are at high risk, if it is possible to avoid child care during the peak of the RSV season, it’s important to do so,” he said.

RSV season differs by region

Larry Anderson, MD, and his colleagues at the CDC plotted the RSV season in the United States over several seasons. In the South, the season (two consecutive weeks with 10% positive cases) tends to begin around the 47th week of the year, in late November. It then continues into mid March. “So, the median duration of the RSV season for states in the South is 16 weeks. The range is 13 weeks to 20 weeks,” Meissner said.

The parts of the United States that have the shortest RSV season are in the Midwest, where the season typically begins in early January and ends in March. These states tend to have a median duration of 13 weeks. The West and the Northeast fall somewhere in between those two.

Although the onset of RSV is predictable, the severity of the season, the month of onset, the month of peak activity and the month when it starts to fade are difficult to predict each year.

“However, within that uncertainty, one can say that quite predictably RSV will begin in November or December; it peaks in January or February, and the virus disappears in the community to a large extent by the end of March,” explained Meissner. “That’s not to say that there won’t be occasional sporadic cases that will occur before the onset or the offset of the season, but the vast majority of cases will occur within that time frame.”

Prophylactic dosing

Five monthly doses of palivizumab result in a serum concentration that is greater than 30 µg/mL in most patients for more than 20 weeks.

This dose will provide high enough titers to protect most children until April, Meissner said.

“To reduce the incidence of breakthrough disease, it’s important not to increase the first dose or to shorten the interval between doses,” he said.

There is an ongoing large clinical trial with a second-generation monoclonal antibody, MEDI-524 (Numax, MedImmune), which is being compared with palivizumab to see if there is a reduction in the breakthrough rate. This second-generation antibody has considerably more neutralizing activity than palivizumab, Meissner said.

For more information:

• Meissner HC. Approach to RSV season. Presented at the 17th Annual Infectious Diseases in Children Symposium. Nov. 20-21, 2004. New York.
• Meissner HC. The unresolved issue of risk factors for hospitalization of infants with respiratory syncytial virus infection born after 33-35 weeks gestation. Pediatr Infect Dis J. 2004;23:821-823.
• Meissner HC, Anderson LJ, Pickering LK. Annual variation in respiratory syncytial virus season and decisions regarding immunoprophylaxis with palivizumab. Pediatrics. 2004;114(4):1082-1084.