Jessie R. Groothuis

Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease

Abstract Objective: To examine the effectiveness of respiratory syncytial virus immune globulin administered intravenously (RSV-IGIV) in reducing hospitalization for treatment of RSV in children with congenital heart disease (CHD). Methods: Children younger than 4 years of age were randomly assigned to a treatment group receiving RSV-IGIV, 750 mg/kg, monthly or to a control group not receiving infusions. Surveillance for respiratory tract infections was carried out and management decisions were made by physicians blinded to treatment group. Results: Hospitalization for treatment of an RSV infection occurred in 32 of 214 (15%) of control children and 21 of 202 (10%) of the children receiving RSV-IGIV, a 31% reduction ( P = .16). However, in infants younger than 6 months of age at study entry, 20 of 82 (24%) in the control group and 10 of 96 (10%) in the RSV-IGIV group had RSV hospitalizations (58% reduction, P = .01). The incidence of hospitalization for any respiratory tract symptomatology was lower in the RSV-IGIV group (34 of 202, 17%) than in the control group (57 of 214, 27%; P = .02). There was a significantly higher frequency of unanticipated cyanotic episodes and of poor outcomes after surgery among children with cyanotic CHD in the RSV-IGIV group (22 of 78, 28%) than in the control group (4 of 47, 8.5%; P = .009). Conclusion: RSV-IGIV should not be used for prophylaxis of RSV disease in children with cyanotic CHD. RSV-IGIV did not reduce RSV hospitalization in all children with CHD, but it was effective in preventing RSV hospitalization in infants younger than 6 months of age. Further studies in these children are indicated. (J Pediatr 1998;133:492-9)

Respiratory syncytial virus–enriched globulin for the prevention of acute otitis media in high-risk children

Acute otitis media (AOM) has been associated with respiratory syncytial virus (RSV) infection; AOM develops in up to one third of children with RSV illness. A masked multicenter trial used an immune globulin enriched with RSV-neutralizing antibodies (RSVIG) to prevent RSV infection of the lower respiratory tract in 249 children with either bronchopulmonary dysplasia, congenital heart disease, or prematurity. To determine whether monthly RSVIG therapy might decrease the incidence of AOM, we retrospectively analyzed the records of 109 children in two of the centers. RSVIG was administered during RSV season of a high dose of 750 mg/kg monthly or a low dose of 150 mg/kg monthly; control children received no RSVIG. Children were examined for AOM by masked observers using pneumatic otoscopy. No difference in sex, race, underlying diagnosis, number of persons in the home, exposure to smoking, or atopy was found between groups studied. In recipients of high doses of RSVIG, significantly less AOM developed per season than in control children (mean episodes, 0.15 vs 0.78; p = 0.003), and fewer episodes of RSV-related AOM occurred (0 vs 5; p = 0.047). Low doses of RSVIG did not have a clinically significant impact. High doses of RSVIG appeared to have a significant impact on preventing AOM (both RSV- and non-RSV-related AOM) in these-high risk populations. This finding may have important implications in the development of improved preventive modalities for AOM.

Controlled trial to evaluate protection of high-risk infants against respiratory syncytial virus disease by using standard intravenous immune globulin.

We performed a randomized, controlled trial of intravenous immune globulin (respiratory syncytial virus [RSV] neutralizing [Nt] antibody titer of 1:950 in 5% solution) to evaluate protection against RSV-induced disease over two respiratory virus seasons. Forty-nine children (mean age at enrollment, 4.5 months) with severe congenital heart disease or bronchopulmonary dysplasia were randomized as follows. Twenty-four patients were followed as controls and received no immune globulin. Twenty-five patients received monthly infusions of immune globulin at a dose of 500 mg/kg of body weight. There was a similar distribution between groups of patients with heart disease and bronchopulmonary dysplasia. There were 12 culture-proven RSV infections, 6 in the prophylaxis group and 6 in the control group. There was a trend toward less severe RSV illness in immune globulin recipients, as measured by length of hospitalization. Four of the six immune globulin recipients were hospitalized for a total of 35 days (mean, 8.8 +/- 5.0 days) because of RSV illness, in contrast to 51 hospital days (mean, 12.8 +/- 7.6 days) among RSV-infected controls. We conclude that monthly infusions of standard immune globulin containing RSV Nt antibodies may be safely administered to high-risk children, but that standard intravenous immune globulin does not contain sufficient RSV Nt antibody titer to fully protect against severe RSV illness.

Respiratory Syncytial Virus Disease in Preterm Infants in the US Born at 32-35 Weeks Gestation Not Receiving Immunoprophylaxis

Background: The Respiratory Syncytial Virus (RSV) Respiratory Events Among Preterm Infants Outcomes and Risk Tracking (REPORT) study evaluated RSV disease burden in US preterm infants 32–35 weeks gestational age (wGA) not receiving RSV prophylaxis. Methods: Preterm infants <6 months of age as of November 1st were followed prospectively at 188 clinics from September to May 2009–2010 or 2010–2011. Nasal and pharyngeal swabs were collected for medically attended acute respiratory illnesses (MAARI) and tested for RSV by qRT-polymerase chain reaction. Risk factors were assessed using multivariate Cox proportional hazard model adjusted for seasonality. Results: Of 1642 evaluable infants, 287 experienced RSV MAARI. Rates of RSV-related MAARI, outpatient lower respiratory tract illness, emergency department visits and hospitalization (RSVH) during November to March were 25.4, 13.7, 5.9 and 4.9 per 100 infant-seasons, respectively. Preschool-aged, nonmultiple-birth siblings and daycare attendance were consistently associated with increased risk of RSV. RSVH rates were highest in infants 32–34 and 35 wGA who were <6 months of age during November to March with daycare attendance or nonmultiple-birth, preschool-aged siblings (8.9 and 9.3 per 100 infant-seasons, respectively, versus 3.5 for all other infants, P<0.001). Chronologic age <3 months was associated with a higher RSVH rate for infants 35 wGA but not for infants 32–34 wGA. Conclusions: In US preterm infants who were 32–35 wGA, <6 months on November 1st and not receiving RSV prophylaxis, the burden of RSV MAARI was 25 per 100 infant-seasons. The highest RSVH rates occurred among those with daycare attendance or nonmultiple-birth, preschool-aged siblings while they were <6 months of age during the RSV season.

Immune response to split-product influenza vaccine in preterm and full-term young children

Humoral and cellular immune responses to two doses of influenza antigens were measured in children 6-48 months of age. These vaccinees comprised a previously unimmunized cohort of 18 healthy full-term children and 15 sick preterm children with bronchopulmonary dysplasia and an additional 30 ex-preterm children who were reimmunized. Half of the reimmunized cohort were recovered from bronchopulmonary dysplasia and half had active bronchopulmonary dysplasia. Antibody response was measured by haemagglutination inhibition (HI) and ELISA, and cellular immunity was measured by enumerating memory T cells. Six weeks after immunization, ELISA antibody levels were significantly higher in previously unimmunized full-term vaccinees than in previously unimmunized sick preterm infants (p less than 0.002). No difference was found between sick and recovered reimmunized children. By HI testing greater than 90% of children in both cohorts developed titres greater than or equal to 1:32, and these were generally maintained for at least 20 weeks. T-cell proliferative responses to influenza antigen were greater in the full-term children than in the preterm children (p less than 0.02), irrespective of state of health or prior immunization status. Split-product vaccine was immunogenic in all the cohorts studied; however, factors such as prematurity, health status and previous influenza immunization played important roles in the magnitude of some responses.

Safety and tolerance of palivizumab administration in a large northern hemisphere trial

An Expanded Access Study was conducted to collect additional safety data on palivizumab. Preterm infants with or without bronchopulmonary dysplasia received palivizumab every 30 days during the respiratory syncytial virus season. Adverse events were low (6.9%) in the 565 subjects. Serious adverse events included hospitalization and 1 case of respiratory syncytial virus bronchiolitis not requiring hospitalization. This study reaffirms the safety and tolerability of palivizumab.

Safety and immunogenicity of a purified haemagglutinin antigen in very young high-risk children

Forty-three high-risk preterm children received either one of three doses of purified hemagglutinin antigen (HA) (7.5 micrograms/0.25 ml, 22.5 micrograms/0.25 ml or 67.5 micrograms/0.25 ml) or standard split product vaccine (ST) (22.5 micrograms/ml dose) over the 1990-1991 influenza season. Components for all vaccines included A/Shanghai 16/89, A/Taiwan 1/86 and B/Yamagata 16.88. Sera for antibody was drawn before, 6 weeks and 4 months after the first vaccine dose. The study was randomized and blinded. All children received two 0.25 ml doses of vaccine 4 weeks apart. No significant local or systemic reactions occurred. Six weeks after the first dose, children receiving ST vaccine had significantly higher seroconversion rates to A/Shanghai (p = 0.03) and to A/Taiwan (p = 0.01) than did those receiving equivalent HA vaccine. However, seroconversion rates were significantly higher for those children receiving the highest HA dose. All four vaccine groups responded poorly to B/Yamagata. Geometric mean titres were low for all groups and declined over 4 months. These results suggest that the equivalent dose of HA vaccine offers no advantage over ST vaccine in the immunization of high-risk preterm children.

Use of Palivizumab for prevention of hospitalization as a result of respiratory syncytial virus in infants with cystic fibrosis.

The Palivizumab Outcomes Registry collected data on 19,548 high-risk infants who received ≥1 dose of palivizumab and followed prospectively from 2000 through 2004. Ninety-one children with cystic fibrosis (CF) were identified who received palivizumab off label. None of the infants with CF who received prophylaxis was hospitalized as a result of respiratory syncytial virus lower respiratory tract infection. Evaluations of palivizumab use in infants with CF could be warranted.

Improved Outcomes With Home-Based Administration of Palivizumab : Results From the 2000-2004 Palivizumab Outcomes Registry

Background: Palivizumab Outcomes Registry data collected during 4 years were examined to assess compliance and respiratory syncytial virus (RSV) hospitalization rates in high-risk children receiving palivizumab prophylaxis at home compared with an outpatient setting. Methods: Prospective observational registry enrolling high-risk infants who received ≥1 dose of palivizumab throughout the 2000–2001 to 2003–2004 RSV seasons at participating U.S. pediatric sites. Results: Registry data were analyzed for compliance and RSV hospitalization outcomes in 19,548 infants receiving doses at home versus an outpatient setting. Compliance with the injection regimen was determined by comparing the number of palivizumab injections received versus the projected number of anticipated doses and by comparing infants receiving all injections within a 35-day interval. Compliance was significantly greater for infants who received palivizumab at home (n = 1226) as compared with those who received palivizumab in a clinic or office (n = 17,641), whether measured by the number of doses received (88% versus 81%, P < 0.0001) or by the timing of doses (73% versus 66%, P < 0.0001). Infants who received palivizumab at home also had fewer RSV-associated hospitalizations compared with those who received palivizumab in a clinic or office [0.4% (5/1226) versus 1.2% (207/17,641), P = 0.0139]. Conclusions: Home administration of palivizumab was associated with a significantly higher rate of compliance and lower hospitalization rate for RSV illness in high-risk infants.

The role of RSV neutralizing antibodies in the treatment and prevention of respiratory syncytial virus infection in high-risk children

Studies assessing the use of RSV immune globulin in the treatment of RSV illness are not yet completed. However, a large multicenter trial demonstrated that prophylaxis with RSV immune globulin was safe and efficacious in prevention of serious RSV disease in high-risk infants. Refinements in the practical application of RSVIG are needed, as intravenous lines are difficult to place and maintain in these fragile infants. With the development of concentrated polyclonal and/or effective monoclonal antibody preparations, it may be possible to immunize intramuscularly (Tempest et al., 1993; Barbas et al., 1992). The efficacy of RSV-specific monoclonal antibodies must still be defined, and the appropriate viral epitopes targeted. While these issues still need to be addressed, it is exciting to have finally produced a safe and effective way to prevent severe RSV disease in high-risk young children.