Safety of palivizumab in preterm infants 29 to 32 weeks' gestational age without chronic lung disease to prevent serious respiratory syncytial virus infection.

Respiratory syncytial virus is an important cause of hospitalization in preterm infants. Palivizumab, a humanized monoclonal antibody against the respiratory syncytial virus fusion protein, is currently the only licensed product in Europe available for prophylaxis of respiratory syncytial virus lower respiratory tract infection. This study was conducted to obtain additional European data on the safety of palivizumab in preterm infants 29-32 weeks' gestational age without chronic lung disease. Subjects less than 6 months old were enrolled between October 2000 and April 2001. Demographic information was obtained and physical examination was performed at enrollment. Subjects received 15 mg/kg palivizumab intramuscularly every 30 days for the duration of the respiratory syncytial virus season. Subjects hospitalized for respiratory illness were tested for respiratory syncytial virus infection with respiratory syncytial virus rapid antigen tests. At monthly visits, interim history for adverse events/respiratory illness and physical exam was performed. A total of 285 subjects were enrolled from 35 centers in 18 countries. The mean (+/-SD) gestational age was 30.8+/-1.1 weeks, the mean birth weight 1.5+/-0.4 kg, and 56% were <12 weeks of age at enrollment. Over 80% of patients received at least four palivizumab doses; all received at least one dose. The most commonly reported adverse events (>5%) were rhinitis, increased cough, fever, pharyngitis, bronchiolitis, and diarrhea. Only six subjects reported adverse events that were considered possibly related to palivizumab. No deaths were reported. Twenty subjects were hospitalized during the study; six of these were respiratory syncytial virus positive. Palivizumab is safe and well tolerated in preterm infants 29-32 weeks' gestation without chronic lung disease.

Respiratory syncytial virus prophylaxis--the story so far.

Respiratory syncytial virus (RSV) is a common and highly contagious pathogen that infects nearly all children by the age of 2 years. It is responsible for significant morbidity and mortality worldwide among certain high-risk paediatric populations. Therapy is sub-optimal for RSV, thus treatment focuses on ameliorating symptoms. Since discovery of the virus in the 1950s, efforts have been ongoing to develop a safe and effective vaccine. These efforts have met with serious obstacles. Passive immunoprophylaxis presents a viable alternative to active immunization. In 1998, the genetically engineered humanized monoclonal antibody (palivizumab) was granted FDA (Food and Drug Administration) approval for prophylaxis of high-risk children in the United States; EMEA (European Agency for the Evaluation of Medicinal Products) approval followed in 1999 for Europe. It is now approved in over 45 countries worldwide. Palivizumab was shown to significantly reduce RSV-related hospitalizations in North America and Europe with few adverse effects. Clinical trial and outcomes data documenting experience with palivizumab to date continue to extend the initial safety and efficacy observations.

Safety and tolerance of palivizumab administration in a large Northern Hemisphere trial. Northern Hemisphere Expanded Access Study Group.

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 pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (

Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. The Cardiac Study Group.

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.

Safety and immunogenicity of a purified F protein respiratory syncytial virus (PFP-2) vaccine in seropositive children with bronchopulmonary dysplasia.

Respiratory syncytial virus (RSV) causes serious respiratory illness in preterm children with bronchopulmonary dysplasia. In a prospective randomized placebo-controlled trial, 21 children received one dose of PFP-2 (purified fusion [F] protein) vaccine or influenza vaccine (placebo). Children were followed for adverse reactions and RSV illness over two respiratory seasons. Sera were obtained for determination of IgG titers to RSV F protein and neutralizing antibody titers before and 1, 6, and 12 months after vaccination. Adverse reactions were few. Four-fold F protein rises occurred in 9 of 10 PFP-2 and 0 of 11 placebo recipients. Six PFP-2 recipients had low prevaccination neutralizing antibody titers (< 1:450); all had 4-fold rises. By 12 months, F protein and neutralizing antibody titers in all 21 children were similar. RSV illness occurred in 6 of 11 placebo versus 1 of 10 PFP-2 recipients (P = .06); 1 placebo child required hospitalization. PFP-2 vaccine appears safe and immunogenic and may protect children with bronchopulmonary dysplasia against serious RSV disease on reinfection.

Respiratory syncytial virus immune globulin treatment of RSV lower respiratory tract infection in previously healthy children.

OBJECTIVE: To evaluate the efficacy of high titer respiratory syncytial virus (RSV) immune globulin (RSVIG) in the treatment of previously healthy children hospitalized with proven RSV lower tract infection (LRI). METHOD: Infants and young children /=2. 5 were enrolled. RESULTS: One hundred and one previously healthy children hospitalized with RSV LRI received either 1500 mg/kg of RSVIG (RespiGam, MedImmune Inc, Gaithersburg, MD) or albumin placebo in a randomized, double-blind, placebo-controlled trial. Forty-six RSVIG and 52 recipients of placebo met all eligibility criteria. Demographic characteristics of the two groups were similar. More RSVIG recipients (46% vs 29%) had an SaO2 /=3.0) had 1.6 fewer hospital days and 2.7 days less ICU stays. CONCLUSION: RSVIG infusions seemed safe and generally well tolerated. Although some beneficial effect trends were seen for those with more severe disease who were treated there was no evidence that treatment with RSVIG resulted in reduced hospitalization and reduced ICU stays in all children with RSV disease.

Room air challenge: prediction for successful weaning of oxygen-dependent infants.

OBJECTIVE: The objective of this study was to determine the time required for equilibration of oxygen saturation (SpO2) and the oxygen flow rate that might predict readiness for oxygen weaning to room air in preterm infants with improving bronchopulmonary dysplasia (BPD). STUDY DESIGN: This was a prospective longitudinal cohort study, conducted in the neonatal care unit and the neonatal high risk follow-up clinic. Seventeen preterm children with BPD (mean postconceptual age 39.9 [range 31.5 to 43.5] weeks) were enrolled. With the infants breathing room air, the SpO2 pulse and respiratory rates, and clinical status were monitored for 120 minutes. Factors that predicted a successful room air challenge were determined. Children successfully weaned were followed up for 6 months after discontinuation of oxygen therapy. RESULTS: A total of 20 room air challenges were done in 17 study infants. In most infants the lowest SpO2 value (mean 89.7%) was reached within the first 40 minutes. Infants with an SpO2 > or = 92% at 40 minutes continued to have values > or = 92% at 120 minutes (specificity, 100%; sensitivity, 42%). In all infants receiving oxygen flow rates < or = 20 ml/kg per minute an SpO2 > or = 92% was maintained after 40 and 120 minutes. Infants who were successfully weaned to room air showed maintenance of weight and height percentiles 6 months after discontinuation of oxygen therapy. One child was rehospitalized and oxygen support reinstituted because of viral pneumonia. CONCLUSIONS: An SpO2 value > or = 92% at 40 minutes best predicts readiness for oxygen weaning to room air in infants with improving BPD. Infants requiring oxygen flow rates < or = 20 ml/kg per minute are also likely to be weaned off oxygen support.

Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: Respiratory Syncytial Virus Immune Globulin Study Group.

OBJECTIVES: To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV. METHODS: Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding. RESULTS: One hundred seven high-risk children were randomized--54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days). When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days). The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children). CONCLUSION: RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.

The potential role of gastroesophageal reflux in the pathogenesis of food-induced wheezing.

Severe reactive airways disease (RAD) in children is frequently associated with gastroesophageal reflux or food allergy. However a relationship between these two confounding factors has yet to be investigated. We postulate that, in certain patients with micro-aspiration of gastric contents into the airways, food allergens sensitize T cells in the peribronchial lymphoid tissue and induce the production of food-specific IgE antibodies that sensitize airway cells. Subsequent exposure to these food allergens might then induce IgE dependent mediator release from mast cells as well as T cell and eosinophil activation, thus contributing to airway inflammation and RAD. In the current report, we describe the case of a patient with severe asthma who had food allergy and gastroesophageal reflux whose clinical findings support this hypothesis. We also provide additional evidence for a high rate of food sensitization in patients with bronchopulmonary dysplasia (BPD), RAD and GER. We conclude that additional studies are warranted to examine the possibility that patients who have RAD and GER require an evaluation for food allergy.

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.

Respiratory syncytial virus (RSV) infection in preterm infants and the protective effects of RSV immune globulin (RSVIG). Respiratory Syncytial Virus Immune Globulin Study Group.

OBJECTIVE: To evaluate the safety and efficacy of respiratory syncytial virus immune globulin (RSVIG) in the prevention of severe respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in infants born prematurely with or without bronchopulmonary dysplasia (BPD). METHODS: Data from a prospective, blinded, randomized, multicenter trial during three consecutive RSV seasons involving 249 children. This analysis comprises 162 preterm children, of whom 102 had BPD. The 87 children with congenital heart disease (CHD) were excluded from this analysis. Children were randomized to receive monthly infusions of RSVIG 750 mg/kg (high dose), RSVIG 150 mg/kg (low dose), or no RSVIG: Results from the preterm infants with and without BPD who received RSVIG 750 mg/kg are contrasted with control infants who did not receive RSVIG: RESULTS: As compared with controls, high-dose RSVIG administration significantly reduced the incidences of RSV LRTI (P = .01) and moderate-to-severe LRTI (P = .006). RSV-associated hospitalization also was decreased (P = .06) as well as were total RSV-associated days in the intensive care unit (P = .05). Significantly fewer preterm infants developed severe RSV LRTI in the RSVIG group compared with controls (4/58 [7%] vs 14/58 [24%], respectively; P = .01). Adverse reactions occurred in 5% of RSVIG infusions. These were generally mild and included reversible fluid overload, transient fever, and decreases in oxygen saturation. There was one death unrelated to either RSV or RSVIG administration. CONCLUSIONS: Prophylaxis with RSVIG is safe and is currently the only effective means to prevent severe RSV LRTI in high-risk preterm infants.

Safety and bioequivalency of three formulations of respiratory syncytial virus-enriched immunoglobulin.

Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We compared LYO, LYO-VI, and a more convenient liquid RSVIG (LIQ-VI) in 30 preterm infants (median age, 7 months; median weight, 5.4 kg). Infants were randomized to receive LYO (n = 10), LYO-VI (n = 10), or LIQ-VI (n = 10) in monthly infusions of 750 mg/kg of body weight per dose (December to March). Children were monitored closely for adverse reactions to RSVIG and for RSV illness.

Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections.

Respiratory syncytial virus (RSV) is an important community and nosocomial respiratory pathogen for infants and young children. RSV causes especially severe disease in the prematurely born or those with chronic cardiopulmonary diseases. Elderly persons and those with T-cell deficiencies, such as bone marrow transplant recipients, are also at high risk for serious lower respiratory tract infections. To date, prevention of RSV infections by vaccination has proven elusive and no preventive drugs exist. Studies in animals and humans have shown that the lower respiratory tract can be protected from RSV infection by sufficient circulating RSV neutralizing antibody levels. Recently, an RSV hyperimmune immune globulin (RSVIG) was developed and tested for the prevention of RSV infections or reduction of disease severity. Passive immunization of high-risk children with RSVIG during the respiratory disease season effected significant reductions in RSV infections, hospitalizations, days of hospitalization, intensive care unit admissions, days in the intensive care unit, and ribavirin use. Studies in cotton rats and owl monkeys show that RSV infections can also be treated with inhalation of immune globulin at doses substantially smaller than required for parenteral treatment. Therapeutic trials of parenteral RSVIG have been completed and are pending analysis. The use of polyclonal, hyperimmune globulins and perhaps human monoclonal antibodies provides an additional approach to the prevention and perhaps the treatment of certain viral lower respiratory tract infections such as those caused by RSV.

Efficacy and safety of aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial.

We randomly assigned children hospitalized with influenza who had been ill < or = 48 hours and who had a temperature > or = 37.8 degrees C to receive either ribavirin or placebo. All patients had evaluations performed for fever reduction, use of acetaminophen for temperature > or = 38.3 degrees C, duration and severity of influenza symptoms, and feeding behavior. Sixty-two patients (35 in the placebo group, 27 in the ribavirin group) had a diagnosis of influenza confirmed by laboratory study. The groups did not differ significantly in age, initial signs and symptoms, or in distribution of influenza A or B infections. The time to reduction of temperature < or = 38.3 degrees C for the ribavirin group was 8.9 hours compared with 22.6 hours for the placebo group (p = 0.04). The mean duration of acetaminophen use was 7.4 hours in the ribavirin group and 16.3 hours in the placebo group (p = 0.14). There were no significant differences between the groups in outcome of respiratory rate, pulse rate, cough, or level of consciousness. Convalescent influenza antibody geometric mean titer for the placebo group was 9.8 compared with 3.6 for the ribavirin group (p = 0.04). Ribavirin was more effective than placebo in accelerating normalization of temperature but there were no other significant differences.