wGA Infants Research Articles

Impact of the Updated Guidance for Palivizumab Prophylaxis against Respiratory Syncytial Virus Infection: A Single Center Experience

To determine the differences in number of respiratory syncytial virus (RSV) hospitalizations and outcomes in infants 290/7-346/7 weeks' gestational age (wGA) the season before (season 1 [S1]; 2013-2014) and after (season 2 [S2]; 2014-2015) implementation of the 2014 American Academy of Pediatrics revised guidance for palivizumab prophylaxis. Children <12 months of age hospitalized with RSV infection were identified by the International Classification of Diseases, Ninth Revision codes and virology reports. Clinical, outcome data, palivizumab eligibility, and hospital charges were compared among infants 29-34 wGA in S1 vs S2. Of 1063 RSV hospitalizations in infants <12 months old, 7.1% (34/482) in S1 and 9.8% (57/581) in S2 occurred in 290/7-346/7 wGA infants. On the other hand, 29-34 wGA infants who were <6 months old constituted 3.5% (17/482) of RSV hospitalizations in S1 vs 7.1% (41/581) in S2 (P = .01). Among 290/7-346/7 wGA healthy infants who were <3 months old, oxygen administration (40.0% vs 78.9%; P = .05), pediatric intensive care unit admission (30.0% vs 68.4%; P = .04), mechanical ventilation (10.0% vs 52.6%; P = .04), duration of hospitalization (1.8 vs 8.8 days; P = .04), and hospital charges ($19 686 vs $30 662; P = .03) significantly increased in S2 vs S1. No differences in morbidity were observed in premature infants who were 3 to <6 and 6 to <12 months between seasons. Palivizumab eligibility decreased from 32.3% in S1 to 1.8% in S2 (P < .001). One infant died in each season. In the year following implementation of the 2014 palivizumab prophylaxis guidance, there was an increase in RSV hospitalizations and associated morbidity among 29-34 wGA infants of younger chronological age.

Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Preterm Infants Without Chronic Lung Disease or Congenital Heart Disease

IntroductionThe REGAL (RSV Evidence—a Geographical Archive of the Literature) series provide a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This second publication covers the risk and burden of RSV infection in preterm infants born at <37 weeks’ gestational age (wGA) without chronic lung disease or congenital heart disease.MethodsA systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015. Studies reporting data for hospital visits/admissions for RSV infection among preterm infants as well as studies reporting RSV-associated morbidity, mortality, and risk factors were included. Study quality and strength of evidence (SOE) were graded using recognized criteria.Results2469 studies were identified of which 85 were included. Preterm infants, particularly those born at lower wGA, tended to have higher RSV hospitalization (RSVH) rates compared with otherwise healthy term infants (high SOE). RSVH rates ranged from ~5 per 1000 children to >100 per 1000 children with the highest rates shown in the lowest gestational age infants (high SOE). Independent risk factors associated with RSVH include: proximity of birth to the RSV season, living with school-age siblings, smoking of mother during pregnancy or infant exposure to environmental smoking, reduced breast feeding, male sex, and familial atopy (asthma) (high SOE). Predictive models can identify 32/33–35 wGA infants at risk of RSVH (high SOE).ConclusionRSV infection remains a major burden on Western healthcare systems and is associated with significant morbidity. Further studies focusing on the prevalence and burden of RSV in different gestational age cohorts, the changing risk of RSVH during the first year of life, and on RSV-related mortality in preterm infants are needed to determine the true burden of disease.FundingAbbVie.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-016-0130-1) contains supplementary material, which is available to authorized users.

The influence of birth weight amongst 33–35 weeks gestational age (wGA) infants on the risk of respiratory syncytial virus (RSV) hospitalisation: a pooled analysis

Objective: To investigate the association between birth weight and respiratory syncytial virus (RSV) hospitalisation during the first year of life in 33°–356 weeks’ gestational age (wGA) infants.Study design: Pooled analysis of data (n = 1218) from Spain, Germany, France and Italy.Result: RSV hospitalised infants overall had a significantly higher birth weight than non-hospitalised infants (2.24 versus 2.14 kg; p < 0.001) for both males (2.25 versus 2.18 kg; p = 0.049) and females (2.22 versus 2.11 kg, p = 0.007). The effect was significant only in 34 wGA infants (33 wGA: hospitalised 1.95 kg versus non-hospitalised 1.95 kg, p = 0.976; 34 wGA: 2.26 versus 2.14 kg, p = 0.007; 35 wGA: 2.37 versus 2.29 kg, p = 0.070), particularly female 34 wGA infants (female: 2.24 versus 2.08 kg, p = 0.019; male: 2.27 versus 2.20, p = 0.191). Birth weight was shown to be an independent risk factor for RSV hospitalisation.Conclusions: In 33–35 wGA infants, a higher birth weight appeared independently associated with an increased risk of RSV hospitalisation.

Long-Term Burden and Respiratory Effects of Respiratory Syncytial Virus Hospitalization in Preterm Infants-The SPRING Study.

The health status of premature infants born 321-350 weeks’ gestational age (wGA) hospitalized for RSV infection in the first year of life (cases; n = 125) was compared to that of premature infants not hospitalized for RSV (controls; n = 362) through 6 years. The primary endpoints were the percentage of children with wheezing between 2-6 years and lung function at 6 years of age. Secondary endpoints included quality of life, healthcare resource use, and allergic sensitization. A significantly higher proportion of cases than controls experienced recurrent wheezing through 6 years of age (46.7% vs. 27.4%; p = 0.001). The vast majority of lung function tests appeared normal at 6 years of age in both cohorts. In children with pulmonary function in the lower limit of normality (FEV1 Z-score [-2; -1]), wheezing was increased, particularly for cases vs. controls (72.7% vs. 18.9%, p = 0.002). Multivariate analysis revealed the most important factor for wheezing was RSV hospitalization. Quality of life on the respiratory subscale of the TAPQOL was significantly lower (p = 0.001) and healthcare resource utilization was significantly higher (p<0.001) in cases than controls. This study confirms RSV disease is associated with wheezing in 32-35 wGA infants through 6 years of age.

Can we improve the targeting of respiratory syncytial virus (RSV) prophylaxis in infants born 32–35 weeks’ gestational age with more informed use of risk factors?

Objective: To evaluate the key risk factors for respiratory syncytial virus (RSV) hospitalisation in 32–35 weeks’ gestational age (wGA) infants.Methods: Published risk factors were assessed for predictive accuracy (area under the receiver operating characteristic curve [ROC AUC]) and for number needed to treat (NNT).Results: Key risk factors included: proximity of birth to the RSV season; having siblings; crowding at home; day care; smoking; breast feeding; small for GA; male gender; and familial wheezing/eczema. Proximity of birth to the RSV season appeared the most predictive. Risk factors models from Europe and Canada were found to have a high level of predictive accuracy (ROC AUC both >0.75; NNT for European model 9.5). A model optimised for three risk factors (birth ±10 weeks from start of RSV season, number of siblings ≥2 years and breast feeding for ≤2 months) had a similar level of prediction (ROC AUC: 0.776; NNT: 10.2). An example two-risk factor model (day care attendance and living with ≥2 siblings <5 years old) had a lower level of predictive accuracy (ROC AUC: 0.55; NNT: 26).Conclusions: An optimised combination of risk factors has the potential to improve the identification of 32–35 wGA infants at heightened risk of RSV hospitalisation.

The evolution of risk factors for respiratory syncytial virus-related hospitalisation in infants born at 32–35 weeks’ gestational age: time-based analysis using data from the FLIP-2 study

The aim of this study was to examine whether the risk for respiratory syncytial virus (RSV)-related hospitalisation changes through the first year of life in infants of 32-35 weeks' gestational age (wGA). Risk factors from the FLIP-2 study (190 cases/4566 age-matched controls) were included in a Cox regression analysis wherein time slices were taken at 1-month intervals from birth. Half of all RSV hospitalisations occurred in the first 68 days after birth, with 56% occurring within 90 days. The time taken for 50% of hospitalisations to occur was 148 days for those born outside the RSV season and 58 days for those born within the season. By 90 days old, 84% of infants born in the season and 20% of those born outside the season were hospitalised. In both groups, hospitalisations occurred ≥5 months after birth. Male sex, smoking whilst pregnant, month of birth, duration of breastfeeding, number of siblings at school, and number of smokers in household all contributed to the risk of RSV hospitalisation beyond the age of 90 days. The risk of RSV hospitalisation appears to persist to at least 5-6 months old in 32-35 wGA infants, which has implications for the optimal management of disease prevention.

Cost-effectiveness analysis of palivizumab among pre-term infant populations covered by Medicaid in the United States

Objective:Medicaid infants are at high risk of severe respiratory syncytial virus (RSV) disease. The study objective was to estimate the cost-effectiveness of palivizumab in a Medicaid population.Methods:A societal cost-utility analysis was conducted of prophylaxis with palivizumab vs no prophylaxis among four groups of premature infants: (1) <32 weeks gestational age (wGA) and ≤6 months chronologic age (CA); (2) 32–34 wGA, ≤3 months CA with 2009 American Academy of Pediatrics (AAP) risk factors (RF); (3) 32–35 wGA, ≤6 months CA with 2006 AAP RF; and (4) 32–35 wGA, ≤6 months CA with ≤1 RF. Full dosing of palivizumab was assumed throughout the RSV season (consistent with the FDA-approved label). All costs were in 2010 US dollars. The societal public payer spend for palivizumab was estimated using Medicaid reimbursement methodologies for the top 10 palivizumab-using states in 2010 minus mandatory manufacturer rebates. This study reports the incremental cost-effectiveness ratios (ICERs) in cost per quality-adjusted life-year (QALY) gained. Sensitivity and probabilistic analyses were also conducted.Results:Palivizumab saved costs and improved QALYs among infants <32 wGA. Palivizumab was cost-effective in infants 32–34 wGA with 2009 AAP RF ($16,037 per QALY) and in infants 32–35 wGA with 2006 AAP RF ($38,244 per QALY). The ICER for infants 32–35 wGA with ≤1 RF was $281,892 per QALY. Influential variables in the sensitivity analysis included the background rate of RSV hospitalization, the cost of palivizumab, and the efficacy of palivizumab.Key limitations:These results are not generalizable to commercially insured infants or infants outside of the US.Conclusions:This is the first cost-utility analysis of palivizumab in a Medicaid population. Palivizumab, when dosed consistent with the FDA-approved labeling, was either cost-saving or cost-effective among current guideline-eligible infants in the Medicaid population. Palivizumab did not demonstrate cost-effectiveness in 32–35 wGA infants with ≤1 RF.

Cost-effectiveness of Palivizumab for Respiratory Syncytial Virus Infection in High-risk Children, Based on Long-term Epidemiologic Data From Austria

To assess the cost-effectiveness of palivizumab, a monoclonal antibody against respiratory syncytial virus (RSV), in infants at high risk for severe RSV lower respiratory tract infection, such as premature infants, infants with bronchopulmonary dysplasia, and those with congenital heart disease, based on long-term epidemiologic data from Austria. A decision-tree model was used, and the analysis was based on a lifetime follow-up investigating cost-effectiveness of palivizumab versus no RSV infection prevention. The primary perspective of the study was that of the healthcare system, the second that of society. Cost and effects were discounted by 5%. The base case analysis included only direct medical costs, and a scenario analysis included various indirect costs. Analyses were based on epidemiologic data on a total of 1579 children hospitalized because of RSV lower respiratory tract infection during 16 seasons. The incremental cost-effectiveness ratio for the first outcome measure (life years gained) amounted to discounted costs of €34,956 (for all preterm infants), €35,056 (for < 33 weeks' gestational age [wGA] infants), €35,233 (for 33-35 wGA infants), €35,611 (for infants with bronchopulmonary dysplasia), and €8956 (for infants with congenital heart disease). Use of palivizumab compared with no prophylaxis had an incremental cost-utility ratio of €26,212, €26,292, €24,392, €24,654, and €8484, respectively, per quality-adjusted life years. Results from the society perspective were more cost-effective in all study populations. An additional scenario analysis with 7 injections for the 33 to 35 wGA group revealed cost-effectiveness as well. Our results based on nationwide long-term epidemiologic data suggest that palivizumab is cost-effective in prevention of RSV disease in high-risk infants.

The multicenter Italian birth cohort study on incidence and determinants of lower respiratory tract infection hospitalization in infants at 33 weeks GA or more: Preliminary results

Background Respiratory syncytial virus (RSV) causes respiratory infections during the first year of life. Very premature infants have more severe diseases and also ‘late preterm infants’ may be more susceptible to the infection. Aim of the study To evaluate in an Italian cohort the incidence and risk factors of severe hospitalized lower respiratory tract infection (LRTI) induced or not by RSV during the first year of life. Methods A cohort of 33 + 0d –34 + 6d wGA newborns paired with two sex- and age-matched 35 + 0d –37 + 6d wGA and ≥ 38 + 0d wGA newborns were enrolled. Hospitalization for LRTI induced or not by RSV during the first year of life was assessed through phone interview at the end of the RSV season (November–March) and at the completion of the first year of life. The parents were asked to report hospitalization for any reason. Results 1064 neonates were enrolled (November 2009–October 2010), 697 had at least one phone follow-up by September 2010. Babies of 33 + 0d –34 + 6d wGA were more frequently conceived through assisted fertilization technologies, born from cesarean delivery had more frequently acute perinatal risk factors and were more frequently twins. After a mean 6 month-follow-up, we registered 29 hospitalizations for LRTI induced or not by RSV. Hospitalizations were slightly and non-significantly more frequent in 33 + 0d –37 + 6d wGA infants. The risk of hospitalization was significantly 60% reduced in breastfed babies and four folds significantly increased during the RSV season. Conclusion The very preliminary data of this ongoing study suggest that in ‘late-preterm’ infants some individual/environmental characteristics of the infants play a relevant role in determining the risk of severe RSV infection.

Outpatient RSV lower respiratory infections among high‐risk infants and other pediatric populations

To identify the frequency of outpatient, non-hospitalized visits for respiratory syncytial virus (RSV) lower respiratory tract infection (LRI) among children and high-risk infants. Published studies that reported population-based rates of outpatient RSV illness were reviewed. In addition, we conducted a retrospective cohort study from a national claims database including preterm and full term infants born between April 2004 and April 2006 <6 months of age and continuously enrolled through their first RSV season. In the selected published studies, rates of outpatient RSV LRI were highest among infants and young children (ranging from 6.9 to 11 per 1,000 children age 1-4 years to 157.5 to 252.0 per 1,000 children age <1 year). In the cohort study, rates of outpatient RSV LRI among preterm infants <or=32 wGA or with chronic lung disease (CLD) ranged from 158.7 to 272.6 visits per 1,000 children. Rates for late preterm (33-36 wGA) infants ranged from 183.3 to 245.7 per 1,000, which was higher than full term infants (128.8 to 171.3 per 1,000). Approximately 1 in every 5 of high-risk infants will be affected during their first RSV season, which indicates a fairly high and unrecognized reservoir of disease. Outpatient RSV LRI visits increase with younger age and prematurity.

Prevalence of Respiratory Syncytial Virus (RSV) Risk Factors and Cost Implications of Immunoprophylaxis to Infants 32 to 35 Weeks Gestation for Health Plans in the United States

Background During the period of this study, the American Academy of Pediatrics (AAP) 2006 guidelines recommended respiratory syncytial virus (RSV) prophylaxis for infants 32 to 35 weeks gestation age (wGA) with two or more of five risk factors (RFs). New recommendations have recently been published in 2009. The cost implications of expanding this list of RFs to include other evidence-based RFs like passive smoke exposure (PSE), crowded living conditions (CLCs), and young chronological age (YCA) are unclear. Methods We estimated the prevalence of RSV RFs in a US sample of infants 32 to 35 wGA referred for prophylaxis from nine specialty pharmacy providers during the 2007–2008 season. We estimated the percent eligible for RSV prophylaxis under various potential RF coverage policies. Using a budget impact model, we calculated the per-member-per-month (PMPM) cost for each policy in 2007 USD for a hypothetical one million member plan. Results Infants 32 to 35 wGA represented 0.08% of the plan. Approximately 20.2% of these infants met at least two or more of five AAP RFs. Expanding this list to include one additional RF of PSE, CLC, or YCA increased the percent of infants potentially prophylaxed to 29.9%, 23.9%, and 47%, respectively. Adding all three RFs to the list (two or more of eight) increased the percent of infants potentially prophylaxed to 55.6%, and increased payer costs by 9 cents PMPM. Conclusion Expanding the AAP RF criteria to include PSE, CLC, and YCA would identify more 32 to 35 wGA infants at high risk for severe RSV disease at an acceptable budget impact.

Physiological Parameters Evaluation following Apnea in Healthy Premature Infants

To assess responses to central and obstructive apnea, we performed 10-hour polygraphic recordings in healthy 33–34 wGA infants. Each apnea period was paired with a control period. The presence of body movements (BM) and augmented breaths (AB), the EEG, heart rate (HR), respiratory rate, phase relationships between thoracic and abdominal respiratory movements, and changes in SaO₂ were evaluated. No apnea caused awakening. Apnea were not usually followed by motor events (no significant differences with control periods), with the exception of most obstructive apnea longer than 10 s. The mean percentage of changes following apnea, normalized to baseline values, was significant for the EEG (frequency slightly increased, mainly after obstructive apnea), HR (deceleration), and respiratory rate (increased). However, the mean values masked heterogeneity across apnea in the direction of the change in each parameter. The only significant correlation was between changes in HR and SaO₂. The increases in EEG frequency and respiratory rate seen in our study can be considered markers of CNS activation, but were small and inconsistent. The heart rate decelerations and SaO₂ changes are not activation markers. Thus, mechanisms underlying restarting of breathing efforts following apnea remain unclear in premature babies. Our investigation establishes the importance of using control data to distinguish between spontaneous and apnea-related events.