Adoption in Canada of an international risk scoring tool to predict respiratory syncytial virus hospitalization in moderate-to-late preterm infants.

OBJECTIVE: The advisory board to the Ontario Ministry of Health considered adopting the new three-variable international risk scoring tool (IRST) to guide prophylaxis against respiratory syncytial virus hospitalization (RSVH) in moderate-to-late preterm infants born 32-35 weeks' gestational age (wGA). Canada currently uses a nationally validated, seven-variable RST, to predict RSVH in 33-35 wGA infants. We explored the potential implications of switching from the Canadian to the IRST. METHODS: Predictive accuracy (area under the receiver operating characteristic curve [AUROC]) of the two RSTs and correlations (Spearman rank) and number needed to treat (NNT) between cut-off scores for low-, moderate- and high-risk subjects were assessed. RESULTS: The RSTs contain many of the same risk factors (birth proximity to the RSV season, smoking, siblings, daycare), with the Canadian RST also including sex, small for GA and familial eczema. Predictive accuracy was similar (AUROC, IRST: 0.773 [sensitivity: 68.9%; specificity: 73.0%] vs Canadian: 0.762 [68.2%; 71.9%]). Significant correlations between cut-off scores (p < .001) and risk categories (p < .001) were apparent, although the correlation coefficients were weak for both (scores: 0.217; categories: 0.055). While the proportion of high-risk infants was similar (IRST: 0.7% vs Canadian: 0.6%), the NNT was lower for the Canadian RST (7.5 vs 14.3), and more infants were assigned moderate risk by the IRST (19.9% vs 9.8%). CONCLUSIONS: The IRST can be considered simpler (fewer risk factors) than the Canadian RST and its adoption may reduce the number of RSVHs among moderate-to-late preterm infants; however, the cost-effective implications for RSV prophylaxis warrant further investigation.

Extrauterine growth restriction in very preterm infant: etiology, diagnosis, and 2-year follow-up.

In very-preterm small-for-gestational-age (SGA) infants, long-term postnatal growth is confused with extrauterine growth restriction (EUGR). We aimed to document EUGR in SGA infants and in non-SGA infants ("true-EUGR") and its relationship with fetal, maternal, and neonatal etiological factors. Four hundred seventy-nine very-preterm infants (< 32 weeks) born between 2003 and 2014 and attending the follow-up clinic were included. INTERGROWTH-21st preterm postnatal growth standards in conjunction with WHO Child Growth Standards were used to judge the postnatal growth patterns. EUGR was defined as weight < 10th percentile according to the sex at 36-34 weeks postmenstrual age, usually at discharge. Catch-up was evaluated at 2-2.5 years. Low-weight-for-age (wasting), low-length-for-age (stunting), and low-head-circumference-for-age were diagnosed if the z-scores were below - 2 SD. Logistic regression analysis estimated the association between the risk factors and EUGR, according to the SGA status at birth. Overall, EUGR occurred in 51% at 36-34 postmenstrual weeks and 21% at 2-2.5 years. However, among 411 non-SGA infants, "true-EUGR" rates were 43% and 15%, respectively.Conclusion: By 2-2.5 years of age, a "true-EUGR" of 15% can be expected and only the head circumference normalizes in SGA infants. Low birth weight, hyaline membrane disease, bronchopulmonary dysplasia, and male sex were associated with "true-EUGR." What is Known: • Fetal, neonatal, or postnatal charts have been considered to monitor the postnatal growth of preterm infants. • This selection influences the diagnosis of "extrauterine growth restriction" (EUGR) and the clinical strategies used. What is New: • Extrauterine growth restriction (EUGR) in small-for-gestational-age (SGA) infants can not be considered a true EUGR but a postnatal evolution of fetal growth restriction. • Preeclampsia, low gestational age, severe neonatal morbidity and male sex are independently associated with EUGR in non-SGA infants (named "true-EUGR"), which can be expected in 15% of very preterm infants by 2-2.5 years of age.

Expert consensus on palivizumab use for respiratory syncytial virus in developed countries.

Respiratory syncytial virus (RSV) infection is a leading cause of hospitalisation in early childhood and palivizumab is the only licensed intervention for prevention. Palivizumab guidelines should reflect the latest evidence, in addition to cost-effectiveness and healthcare budgetary considerations. RSV experts from Europe, Canada and Israel undertook a systematic review of the evidence over the last 5 years and developed recommendations regarding prophylaxis in industrialised countries. Almost 400 publications were reviewed. This group recommended palivizumab for: preterm infants (<29 and ≤31 weeks gestational age [wGA] and ≤9 and ≤6 months of age, respectively; high-risk 32-35wGA), former preterm children ≤24 months with chronic lung disease/bronchopulmonary dysplasia, children ≤24 months with significant congenital heart disease; and other high-risk populations, such as children ≤24 months with Down syndrome, pulmonary/neuromuscular disorders, immunocompromised, and cystic fibrosis. Up to 5 monthly doses should be administered over the RSV season. It is our impression that the adoption of these guidelines would help reduce the burden of RSV.

Respiratory syncytial virus prophylaxis for children with chronic lung disease: have we got the criteria right?

INTRODUCTION: The use of palivizumab for the prevention of respiratory syncytial virus-related hospitalization is well-established and has been adopted universally in pediatric position statements. Areas covered: The definition of chronic lung disease (CLD, bronchopulmonary dysplasia) has evolved over time and has significantly impacted the reported incidence of the condition, and the description of mild, moderate and severe disease in published studies. We reviewed lung function in infancy, childhood and adulthood of healthy preterm infants and those with CLD and how alterations in airway function, especially following respiratory syncytial virus infection may set the stage for chronic obstructive pulmonary disease in adults. We also characterized the real-world experience of the use of palivizumab compared to the single, randomized trial and examined the socioeconomic burden of respiratory syncytial virus hospitalization, an element that is commonly overlooked, when considering the value of prevention in the extremely high-risk, CLD population. Expert opinion: Based on the current evidence, we propose that palivizumab should be offered to all children with CLD in the first two years of life, irrespective of CLD disease severity. This may positively influence pulmonary maturation and normalize the trajectory of compromised lung function in these children into adulthood.

Risk scoring tool to predict respiratory syncytial virus hospitalisation in premature infants.

BACKGROUND: The objective was to develop a risk scoring tool which predicts respiratory syncytial virus hospitalisation (RSVH) in moderate-late preterm infants (32-35 weeks' gestational age) in the Northern Hemisphere. METHODS: Risk factors for RSVH were pooled from six observational studies of infants born 32 weeks and 0 days to 35 weeks and 6 days without comorbidity from 2000 to 2014. Of 13 475 infants, 484 had RSVH in the first year of life. Logistic regression was used to identify the most predictive risk factors, based on area under the receiver operating characteristic curve (AUROC). The model was validated internally by 100-fold bootstrapping and externally with data from a seventh observational study. The model coefficients were converted into rounded multipliers, stratified into risk groups, and number needed to treat (NNT) calculated. RESULTS: The risk factors identified in the model included (i) proximity of birth to the RSV season; (ii) second-hand smoke exposure; and (iii) siblings and/or daycare. The AUROC was 0.773 (sensitivity: 68.9%; specificity: 73.0%). The mean AUROC from internal bootstrapping was 0.773. For external validation with data from Ireland, the AUROC was 0.707 using Irish coefficients and 0.681 using source model coefficients. Cut-off scores for RSVH were ≤19 for low- (1.0%), 20-45 for moderate- (3.3%), and 50-56 (9.5%) for high-risk infants. The high-risk group captured 62.0% of RSVHs within 23.6% of the total population (NNT 15.3). CONCLUSIONS: This risk scoring tool has good predictive accuracy and can improve targeting for RSVH prevention in moderate-late preterm infants.

Past, Present and Future Approaches to the Prevention and Treatment of Respiratory Syncytial Virus Infection in Children.

INTRODUCTION: The REGAL (RSV Evidence - A Geographical Archive of the Literature) series has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This seventh and final publication covers the past, present and future approaches to the prevention and treatment of RSV infection among infants and children. METHODS: A systematic review was undertaken of publications between January 1, 1995 and December 31, 2017 across PubMed, Embase and The Cochrane Library. Studies reporting data on the effectiveness and tolerability of prophylactic and therapeutic agents for RSV infection were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. A further nonsystematic search of the published literature and Clinicaltrials.gov on antiviral therapies and RSV vaccines currently in development was also undertaken. RESULTS: The systematic review identified 1441 studies of which 161 were included. Management of RSV remains centered around prophylaxis with the monoclonal antibody palivizumab, which has proven effective in reducing RSV hospitalization (RSVH) in preterm infants < 36 weeks' gestational age (72% reduction), children with bronchopulmonary dysplasia (65% reduction), and infants with hemodynamically significant congenital heart disease (53% reduction) (high SOE). Palivizumab has also shown to be effective in reducing recurrent wheezing following RSVH (high SOE). Treatment of RSV with ribavirin has conflicting success (moderate SOE). Antibodies with increased potency and extended half-life are currently entering phase 3 trials. There are approximately 15 RSV vaccines in clinical development targeting the infant directly or indirectly via the mother. CONCLUSION: Palivizumab remains the only product licensed for RSV prophylaxis, and only available for high-risk infants. For the general population, there are several promising vaccines and monoclonal antibodies in various stages of clinical development, with the aim to significantly reduce the global healthcare impact of this common viral infection. FUNDING: AbbVie.

Defining the Incidence and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Children with Chronic Diseases.

INTRODUCTION: REGAL (RSV Evidence-a Geographical Archive of the Literature) has provided a comprehensive review of the published evidence in the field of respiratory syncytial virus (RSV) in Western countries over the last 20 years. This review covers the risk and burden of RSV infection in children with underlying medical conditions or chronic diseases (excluding prematurity and congenital heart disease). METHODS: A systematic review of publications between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov was supplemented by papers identified by the authors through March 2017. Studies reporting data for hospital visits/admissions for RSV infection as well as studies reporting RSV-associated morbidity and mortality were included. Study quality and strength of evidence (SOE) were graded. RESULTS: A total of 2703 studies were identified and 58 were included. Down syndrome, irrespective of prematurity and congenital heart disease (moderate SOE), immunocompromised children (low SOE), cystic fibrosis (low SOE), and neurologic conditions (low SOE) were associated with a significantly increased risk of RSV hospitalization. A number of other congenital malformations and chronic conditions were also associated with severe RSV disease (low SOE). In general, pre-existing disease was also a predisposing factor for RSV-related mortality (low SOE). CONCLUSION: Severe RSV infection in infants and young children with underlying medical conditions or chronic diseases poses a significant health burden. Further studies are needed to fully quantify the epidemiology, burden and outcomes in these populations, in particular RSV-attributable mortality.

The Burden and Long-term Respiratory Morbidity Associated with Respiratory Syncytial Virus Infection in Early Childhood.

INTRODUCTION: The 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. The objective of this fifth publication was to determine the long-term respiratory morbidity associated with RSV lower respiratory tract infection (RSV LRTI) in early life. METHODS: A systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015. This was supplemented by inclusion of papers published whilst drafting the manuscript. Studies reporting data on the incidence and long-term wheezing and asthma following RSV LRTI in early life were included. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULTS: A total of 2337 studies were identified of which 74 were included. Prospective, epidemiologic studies consistently demonstrated that RSV LRTI is a significant risk factor for on-going respiratory morbidity characterized by transient early wheezing and recurrent wheezing and asthma within the first decade of life and possibly into adolescence and adulthood (high SOE). RSV LRTI was also associated with impaired lung function in these children (high SOE). Respiratory morbidity has been shown to result in reduced quality of life and increased healthcare resource use (moderate SOE). The mechanisms through which RSV contributes to wheezing/asthma development are not fully understood, but appear to relate to the viral injury, preexisting abnormal lung function and/or other factors that predispose to wheezing/asthma, including genetic susceptibility, altered immunology, eosinophilia, and associated risk factors such as exposure to environmental tobacco smoke (high SOE). CONCLUSION: There is growing evidence that RSV LRTI in early childhood is associated with long-term wheezing and asthma and impaired lung function. Future research should aim to fully elucidate the pathophysiological mechanisms through which RSV causes recurrent wheezing/asthma.

Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Infants with Congenital Heart Disease.

INTRODUCTION: The 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 fourth publication covers the risk and burden of RSV infection in infants with congenital heart disease (CHD). METHODS: A systematic review was undertaken for articles published between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among children with CHD as well as studies reporting RSV-associated morbidity, mortality, and healthcare costs were included. The focus was on children not receiving RSV prophylaxis. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULTS: A total of 1325 studies were identified of which 38 were included. CHD, in particular hemodynamically significant CHD, is an independent predictor for RSV hospitalization (RSVH) (high SOE). RSVH rates were generally high in young children (<4 years) with CHD (various classifications), varying between 14 and 357/1000 (high SOE). Children (<6 years) with RSV infection spent 4.4-14 days in hospital, with up to 53% requiring intensive care (high SOE). Infants (<2 years) with CHD had a more severe course of RSVH than those without CHD (high SOE). Case fatality rates of up to 3% were associated with RSV infection in children with CHD (high SOE). RSV infection in the perioperative period of corrective surgery and nosocomial RSV infection in intensive care units also represent important causes of morbidity (moderate SOE). CONCLUSION: CHD poses a significant risk for RSVH and subsequent morbidity and mortality. RSV infection often complicates corrective heart surgery. To reduce the burden and improve outcomes, further research and specific studies are needed to determine the longer-term effects of severe RSV infection in young children with CHD.

Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus Infection Among Infants with Chronic Lung Disease.

INTRODUCTION: The 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 third publication covers the risk and burden of RSV infection in infants with chronic lung disease (CLD), formerly called bronchopulmonary dysplasia (BPD). METHODS: A systematic review was undertaken of publications between January 1, 1995 and December 31, 2015 across PubMed, Embase, The Cochrane Library, and Clinicaltrials.gov. Studies reporting data for hospital visits/admissions for RSV infection among infants with CLD/BPD who were not prophylaxed, as well as studies reporting RSV-associated morbidity, mortality, and healthcare costs, were included. Burdens of disease data were compared with preterm infants without CLD/BPD, other high-risk groups and term infants. Study quality and strength of evidence (SOE) were graded using recognized criteria. RESULTS: A total of 1837 studies were identified and 39 were included. CLD/BPD is a significant independent risk factor for RSV hospitalization [RSVH (odds ratio 2.2-7.2); high SOE]. Infants and young children with CLD/BPD had high RSVH rates which were generally similar in Europe, the United States, and Canada, mostly varying between 12 and 21%. Infants with CLD also had a longer length of hospital stay than other high-risk groups and term infants (high SOE). On average, infants spent 4-11 days in hospital (moderate SOE). Once hospitalized for RSV, affected children were at risk for a more severe course of disease than children with no RSVH (moderate SOE). CONCLUSION: Severe RSV infection in infants and young children with CLD/BPD poses a significant health burden in Western countries. Further studies focussing on the burden of RSV infection in this well-recognized population at high risk for severe disease are needed to help improve outcomes and plan allocation of healthcare resources. FUNDING: AbbVie.

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.

INTRODUCTION: The 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. METHODS: A 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. RESULTS: 2469 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). CONCLUSION: RSV 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. FUNDING: AbbVie.

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.

Effects of parental and household smoking on the risk of respiratory syncytial virus (RSV) hospitalisation in late-preterm infants and the potential impact of RSV prophylaxis.

OBJECTIVE: To assess the impact of household smoking and palivizumab prophylaxis on the risk of respiratory syncytial virus (RSV) hospitalisation in late-preterm (32-35 weeks' gestational age) infants. METHODS: Familial smoking and other RSV risk factor data from the FLIP, FLIP-2 and IMpact studies and datasets from France, Germany and Italy, together with palivizumab prophylaxis data from the FLIP-2 and IMpact studies, were analysed using cross-correlation and Bayesian meta-analytical modelling employing Markov Chain Monte Carlo sampling. RESULTS: There were 2.35 times (95% confidence interval [CI] 1.37-4.02) as many hospitalisations amongst infants from smoking compared with those from non-smoking families. Among non-prophylaxed infants, there were 2.53 times (95% CI 1.27-4.94) as many RSV hospitalisations from smoking than from non-smoking families and that excess hospitalisation was reduced to 1.03 times (95% CI 0.38-2.99) amongst prophylaxed infants. Familial smoking correlates significantly (p < 0.01) with other RSV risk factors: positive correlation with number of school-age siblings, history of family atopy, family wheeze and gestational age; negative correlation with birth weight and breast feeding. CONCLUSIONS: Late-preterm infants from smoking families appear to be at heightened risk for severe RSV infection requiring hospitalisation of which the risk may be reduced with RSV prophylaxis.

Trends in survival among extremely-low-birth-weight infants (less than 1000 g) without significant bronchopulmonary dysplasia.

OBJECTIVE: The aim of this study was to analyze the evolution from 1997 to 2009 of survival without significant (moderate and severe) bronchopulmonary dysplasia (SWsBPD) in extremely-low-birth-weight (ELBW) infants and to determine the influence of changes in resuscitation, nutrition and mechanical ventilation on the survival rate. STUDY DESIGN: In this study, 415 premature infants with birth weights below 1000 g (ELBW) were divided into three chronological subgroups: 1997 to 2000 (n = 65), 2001 to 2005 (n = 178) and 2006 to 2009 (n = 172).Between 1997 and 2000, respiratory resuscitation in the delivery room was performed via a bag and mask (Ambu®, Ballerup, Sweden) with 40-50% oxygen. If this procedure was not effective, oral endotracheal intubation was always performed. Pulse oximetry was never used. Starting on January 1, 2001, a change in the delivery room respiratory policy was established for ELBW infants. Oxygenation and heart rate were monitored using a pulse oximeter (Nellcor®) attached to the newborn's right hand. If resuscitation was required, ventilation was performed using a face mask, and intermittent positive pressure was controlled via a ventilator (Babylog2, Drägger). In 2001, a policy of aggressive nutrition was also initiated with the early provision of parenteral amino acids. We used standardized parenteral nutrition to feed ELBW infants during the first 12-24 hours of life. Lipids were given on the first day. The glucose concentration administered was increased by 1 mg/kg/minute each day until levels reached 8 mg/kg/minute. Enteral nutrition was started with trophic feeding of milk. In 2006, volume guarantee treatment was instituted and administered together with synchronized intermittent mandatory ventilation (SIMV + VG). The complications of prematurity were treated similarly throughout the study period. Patent ductus arteriosus was only treated when hemodynamically significant. Surgical closure of the patent ductus arteriosus was performed when two courses of indomethacin or ibuprofen were not sufficient to close it.Mild BPD were defined by a supplemental oxygen requirement at 28 days of life and moderate BPD if breathing room air or a need for <30% oxygen at 36 weeks postmenstrual age or discharge from the NICU, whichever came first. Severe BPD was defined by a supplemental oxygen requirement at 28 days of life and a need for greater than or equal to 30% oxygen use and/or positive pressure support (IPPV or nCPAP) at 36 weeks postmenstrual age or discharge, whichever came first. Moderate and severe BPD have been considered together as "significant BPD". The goal of pulse oximetry was to maintain a hemoglobin saturation of between 88% and 93%. Patients were considered to not need oxygen supplementation when it could be permanently withdrawn. The distribution of the variables was not normal based on a Kolmogorov-Smirnov test (p < 0.05 in all cases). Therefore, quantitative variables were expressed as the median and interquartile range (IQR; 25th-75th percentile). Statistical analysis of the data was performed using nonparametric techniques (Kruskal-Wallis test and Mann-Whitney U test). A chi-square analysis was used to analyze qualitative variables. Potential confounding variables were those possibly related to BPD in survivors (p between 0.05 and 0.3 in univariate analysis). Logistic regression analysis was performed with variables related to BPD in survivors (p < 0.05) and potential confounding variables. The forward stepwise method adjusted for confounding factors was used to select the variables, and the enter method using selected variables was used to obtain the odds ratios. RESULTS AND CONCLUSION: There was an increase in the rate of SWsBPD (1997 to 2000: 58.5%; 2001 to 2005: 74.2%; and 2006 to 2009: 75.0%; p = 0.032). In survivors, the occurrence of significant BPD decreased after 2001 (9.5% vs. 2.3%; p = 0.013). The factors associated with improved SWsBPD were delivery by caesarean section, a reduced endotracheal intubation rate and a reduced duration of mechanical ventilation.While the mortality of ELBW infants has not changed since 2001, the frequency of SWsBPD has significantly increased (75.0%) in association with increased caesarean sections and reductions in the endotracheal intubation rate, as well as the duration of mechanical ventilation.

FLIP-2 Study: risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born in Spain at a gestational age of 32 to 35 weeks.

BACKGROUND: Ex-premature infants are more predisposed to complicated primary respiratory syncytial virus (RSV) infection. The aim of the present study was to validate the risk factors found in a previous epidemiologic case-control study regarding hospitalization as a result of RSV infection in premature infants born at 32-35 weeks of gestational age (WGA) in Spain. METHODS: A prospective 2-cohort study was conducted during the 2005-2006 (October 2005 to April 2006) and 2006-2007 (October 2006 to April 2007) RSV seasons, respectively. Cases were premature infants hospitalized for RSV infection whereas controls were premature infants of the same age who did not require any hospitalization for respiratory causes. RESULTS: During the study period 5441 children from 37 Spanish hospitals were included in the risk factor analysis. Two hundred two (3.7%) were cases and the rest controls. Of the cases, 17.8% were admitted to the intensive care unit and 7.4% required mechanical ventilation. None of the patients died. Logistic regression analysis demonstrated that the risk of RSV-related respiratory infection requiring hospital admission in preterm infants (32-35 WGA) was associated with the following factors: absolute chronologic age of < or = 10 weeks at the onset of RSV season [odds ratio (OR): 2.99; 95% confidence interval (CI): 2.23-4.01]; presence of school-age siblings or day care attendance (OR: 2.04; 95% CI: 1.53-2.74); and smoking during pregnancy (OR: 1.61; 95% CI: 1.16-2.25). CONCLUSIONS: In premature infants (32-35 WGA), only 3 independent risk factors were found to significantly increase the risk of RSV-related respiratory infection and hospitalization.

Impact of severe disease caused by respiratory syncytial virus in children living in developed countries.

Among industrialized nations, the rate of rehospitalization in the United States for respiratory syncytial virus (RSV) is approximately 30 per 1000, exceptions being noted for American Indians and Alaskan natives, two ethnic groups who tend toward higher rates of RSV hospitalization. In distinction Japan reports an admission rate of 60 per 1000 for RSV disease. Yet Japan ranks considerably lower than many of its western counterparts in premature births. Whether an RSV subtype, a new viral genotype or some other unifying characteristic exists that might explain the severity of adenovirus, parainfluenza and RSV infections in this region of Asia remains to be determined. Outcomes trials in the United States, Canada, United Kingdom, Denmark and Japan all identified crowding and exposure to tobacco smoke as significant and independent risk factors for disease severity of RSV. The epidemiology of RSV is largely consistent throughout Europe, with peak outbreaks occurring in December and January. In Europe RSV accounts for 42 to 45% of hospital admissions for lower respiratory tract infections in children younger than 2 years of age, and inpatient populations tend to be younger and to experience greater disease severity. For RSV bronchiolitis lengths of stay in European hospitals range from a low of 4 days to a high of 10 days. The Infección Respiratoria Infantil por Virus Respiratorio Sincitial Study Group in Spain conducted 2 prospective observational studies in 14 and 26 neonatal units, respectively, on nonprophylaxed neonates to determine hospitalization rates for respiratory syncytial viral illness during 2 consecutive RSV seasons. Throughout each respiratory season the study group followed premature infants of < or =32 weeks gestational age at birth, representing an annual birth cohort of approximately 100 000 infants. A total of 584 infants who were < or =32 weeks gestational age in the first season and 999 in the second season were followed at monthly intervals. The nonprophylaxed hospitalized group was compared with the nonprophylaxed, nonhospitalized group, and presumptive risk factors were determined for rehospitalization among premature infants. These independent variables, similar for both years, were identified as low gestational age, underlying chronic lung disease, living with school age siblings, exposure to tobacco smoke and a chronologic age of < 3 months at the onset of the RSV season.Stable, yet high rates of admission for RSV illness in Spain were observed in this premature group of < or =32 weeks gestational age: 13.4% for 1999; and 13.1% for the year 2000. Of those hospitalized during the 2 years of the study, 18 and 25%, respectively, were admitted to the intensive care unit. With the exception of higher rates of family allergy, multiple deliveries and a lower rate of neonatal morbidity, prognostic variables for high risk of hospital admission in the year 2000 compared with those of the 1999 sample. Findings from this comprehensive, prospective study served as the basis for the development of standards for the prevention of respiratory syncytial virus infection by the Spanish Society of Neonatology.