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.

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.

AIM: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A predictive model for respiratory syncytial virus (RSV) hospitalisation of premature infants born at 33-35 weeks of gestational age, based on data from the Spanish FLIP Study.

BACKGROUND: The aim of this study, conducted in Europe, was to develop a validated risk factor based model to predict RSV-related hospitalisation in premature infants born 33-35 weeks' gestational age (GA). METHODS: The predictive model was developed using risk factors captured in the Spanish FLIP dataset, a case-control study of 183 premature infants born between 33-35 weeks' GA who were hospitalised with RSV, and 371 age-matched controls. The model was validated internally by 100-fold bootstrapping. Discriminant function analysis was used to analyse combinations of risk factors to predict RSV hospitalisation. Successive models were chosen that had the highest probability for discriminating between hospitalised and non-hospitalised infants. Receiver operating characteristic (ROC) curves were plotted. RESULTS: An initial 15 variable model was produced with a discriminant function of 72% and an area under the ROC curve of 0.795. A step-wise reduction exercise, alongside recalculations of some variables, produced a final model consisting of 7 variables: birth +/- 10 weeks of start of season, birth weight, breast feeding for < or = 2 months, siblings > or = 2 years, family members with atopy, family members with wheeze, and gender. The discrimination of this model was 71% and the area under the ROC curve was 0.791. At the 0.75 sensitivity intercept, the false positive fraction was 0.33. The 100-fold bootstrapping resulted in a mean discriminant function of 72% (standard deviation: 2.18) and a median area under the ROC curve of 0.785 (range: 0.768-0.790), indicating a good internal validation. The calculated NNT for intervention to treat all at risk patients with a 75% level of protection was 11.7 (95% confidence interval: 9.5-13.6). CONCLUSION: A robust model based on seven risk factors was developed, which is able to predict which premature infants born between 33-35 weeks' GA are at highest risk of hospitalisation from RSV. The model could be used to optimise prophylaxis with palivizumab across Europe.

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.

Serum soluble ICAM-1, VCAM-1, L-selectin, and P-selectin levels as markers of infection and their relation to clinical severity in neonatal sepsis.

Adhesion molecules may play a role in the evolution and severity of neonatal sepsis. The purposes of this study were to determine whether serum soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, L-selectin, and P-selectin levels are useful tools in the diagnosis of proven sepsis in newborn infants, and whether their levels are related to the clinical severity of the disease. A cohort of 25 consecutive newborns meeting criteria for clinical sepsis, 10 hemoculture-negative (HC - ) and 15 hemoculture-positive (HC + ), were prospectively followed and compared with 12 healthy newborns (six /= 39 weeks). Serum soluble (s)ICAM-1, sVCAM-1, sL-selectin, and sP-selectin concentrations were measured at the time of the septic workup, then followed by up to three determinations in each newborn every third day. The Score for Neonatal Acute Physiology (SNAP)-II severity was assessed at the moment of highest clinical severity of the disease. At the beginning of sepsis, sICAM-1 levels increased in both groups, being higher in HC + sepsis than in HC - ; sVCAM-1 only increased slightly in HC + sepsis. Soluble ICAM-1 levels were independently related to group of sepsis, and not to days of life. The best initial sICAM-1 cutoff level for diagnosing HC + neonatal sepsis was 274 microg/L. The highest sICAM-1 levels were positively correlated with SNAP-II scores. Soluble L-selectin and sP-selectin did not change. Soluble ICAM-1 levels increased in HC - and HC + sepsis, but concentrations > 274 microg/L suggest HC + sepsis. These levels were related to the clinical severity of the disease. Soluble VCAM-1 levels increased only slightly in HC + sepsis. Soluble L-selectin and sP-selectin did not change.

Antenatal glucocorticoid treatment decreases mortality and chronic lung disease in survivors among 23- to 28-week gestational age preterm infants.

The purpose of this study was to analyze the influence of antenatal glucocorticoid therapy (AGT) on mortality and chronic lung disease (CLD) in surviving preterm infants 23 to 28 weeks gestational age (WGA). This was a multicenter, prospective, observational study. A total of 2448 infants 23 to 28 WGA were born in 2002 to 2003; 27.7% did not receive AGT, 18.8% were exposed to partial AGT, and 53.5% were exposed to complete AGT. A total of 883 died and 22.9% of 1537 survivors were affected by CLD. Unadjusted univariate analysis showed AGT was associated with a reduction in mortality (p<0.001), either with partial or complete AGT courses, and also with a reduction in CLD in survivors (p<0.001), but only with complete AGT courses. In logistic regression analysis adjusted for confounding factors and a propensity score for AGT, AGT was significant and independently associated with a reduction of mortality, but only for complete AGT course (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.47 to 0.87; p=0.004), and with a decrease in CLD if a complete AGT course was administered (OR, 0.63; 95% CI, 0.45 to 0.89; p=0.009). A complete course of AGT in 23 to 28 WGA pregnancies is associated with decreased rates of neonatal mortality and CLD disease in surviving infants.

Plasma endothelin-1 and clinical manifestations of neonatal sepsis.

AIM: To determine whether plasma endothelin-1 (ET-1) relates to clinical manifestations of sepsis in the newborn, especially with systemic hypotension, acidosis, severe hypoxemia (which may represent pulmonary hypertension) and oliguria. METHODS: Prospective study of 35 consecutive newborns with clinical sepsis: 22 with hemoculture-positive (HC+) sepsis and 13 hemoculture-negative (HC-). Plasma ET-1 concentrations were measured within 2 days of the diagnosis of sepsis. SNAP-II severity score was performed at the time of highest clinical severity. RESULTS: Newborns with HC+ sepsis had higher plasma ET-1 concentrations and SNAP-II scores (especially PO 2 /FiO 2 ratio) than HC- septic children. Plasma ET-1 concentrations increased linearly with each item of the SNAP-II score, but only reached significant differences in lowest mean blood pressure (P=0.030), lowest pH (P=0.048), multiple seizures (P=0.010) and lowest urine output (P=0.013). Leukocyte count, immature/total neutrophil ratio and C-reactive protein value were not different. Each item of the SNAP-II score was independently related only to ET-1 level. Oliguria, acidosis and systemic hypotension were more correlated (R 2 >0.5). CONCLUSIONS: Plasma ET-1 levels in neonatal sepsis are related to the severity of clinical manifestations, especially oliguria, acidosis and systemic hypotension.

Identifying risk factors for severe respiratory syncytial virus among infants born after 33 through 35 completed weeks of gestation: different methodologies yield consistent findings.

BACKGROUND: Prematurity is a proven risk factor for severe respiratory syncytial virus (RSV) infection. Prematurity leads to an increased need for, and duration of, hospital admission, intensive care, mechanical ventilation and supplemental oxygen, as well as increased mortality. METHODS: The Pediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study was a prospective, multicenter, cohort study conducted in 16 regions across Canada during 2 successive RSV seasons: November 2000-June 2001, and November 2001-June 2002. The study regions were defined to capture all births and all hospital admissions. The FLIP [identify those risk Factors that most Likely may lead to development of RSV-related respiratory Infection and subsequent hospital admission among Premature infants born 33-35 weeks gestational age (GA)] study was a prospective, case-control study comparison of premature infants hospitalized for RSV infection and infants who had not been hospitalized to identify the risk factors that most likely would lead to development of RSV infection and subsequent hospital admission in this population. RESULTS: The overall hospitalization rate for RSV in the PICNIC study was 3.6% for infants of 33-35 weeks GA. In the FLIP study, the severity of RSV infection in the 33- to 35-week GA infants was similar to that in the younger infants of <33-week GA studied previously by the Infeccion Respiratoria Infantil por Virus Respiratorio Sincitial Study Group. Similar risk factors were noted in both studies. CONCLUSIONS: RSV is a major cause of hospitalization in preterm infants. There is great variability among hospital admission rates globally, despite the commonality of severe RSV in many countries. Furthermore there are numerous independent risk factors for severe RSV, including socioeconomic and environmental factors, that merit further investigation. There is likely an additive effect when multiple risk factors are present. More research is needed on the various risk factors and their significance.

Case-control study of the risk factors linked to respiratory syncytial virus infection requiring hospitalization in premature infants born at a gestational age of 33-35 weeks in Spain.

BACKGROUND AND OBJECTIVE: The aim of this study was to identify those risk factors most likely to lead to the development of RSV-related respiratory Infection and subsequent hospital admission among premature infants born at 33-35 WGA (FLIP study) METHODS: This was a prospective case-control study. Cases (186) hospitalized for respiratory syncytial virus (RSV) illness were recruited from 50 participating Spanish hospitals during the 2002-2003 RSV season (October 2002-April 2003). Controls (371) were selected in June 2003 but born at same time as cases. RESULTS: Of these cases, 20.5% were admitted to the intensive care unit intensive care unit, and 7.6% required mechanical ventilation. None of the patients died. Conditional logistic regression analysis adjusted for medical center demonstrated that the risk of RSV-related respiratory infection requiring hospital admission in preterm infants 33-35 weeks of gestation (WGA) in Spain was most often associated with absolute chronologic age at start of RSV season < or =10 weeks [ie, born between July 15 and December 15; odds ratio (OR), 3.95; 95% confidence interval (CI), 2.65-5.90], breast-feeding for < or =2 months total (OR 3.26; 95% CI 1.96-5.42), presence of > or =1 school age siblings (OR 2.85; 95% CI 1.88-4.33), > or =4 residents and visitors at home (discounting school age siblings and the case/control him/herself) (OR 1.91; 95% CI 1.19-3.07) and a family history of wheezing (OR 1.90; 95% CI 1.19-3.01). CONCLUSIONS: In premature infants born 33-35 WGA, certain underlying risk factors significantly increase the risk of RSV-related respiratory infection and hospitalization. Premature infants 33-35 WGA with additional risk factors should be considered for RSV prophylaxis with palivizumab.

Effect of palivizumab prophylaxis in decreasing respiratory syncytial virus hospitalizations in premature infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of hospitalization in preterm infants and infants with chronic lung disease (CLD). Palivizumab, a humanized monoclonal antibody, was approved in Europe in 1999 as prophylaxis against severe RSV-related respiratory illness. No multiple season data have been published on palivizumab effectiveness in European populations. Data collected during 4 years in Spain compared RSV hospitalization rates and risk factors in a cohort of palivizumab-prophylaxed and nonprophylaxed preterm infants. METHODS: The first cohort was derived from 2 previous studies and included 1583 infants followed during 2 RSV seasons (1998 to 1999, 1999 to 2000) before palivizumab initiation in Spain. The second cohort included 1919 infants who received palivizumab prophylaxis for 2 subsequent respiratory seasons (2000 to 2001, 2001 to 2002). Both cohorts were preterm (< or =32 weeks gestational age) and < or =6 months old at onset of RSV season. RESULTS: The RSV hospitalization rate in the palivizumab-prophylaxed cohort was 3.95, and it was 13.25% in nonprophylaxed infants This 70% overall difference in RSV hospitalization was observed despite the palivizumab-prophylaxed group's lower gestational ages, more severe neonatal intensive care unit respiratory courses and higher incidence of CLD. Significant risk factors for RSV hospitalization in both cohorts included: lower gestational age; chronologic age <3 months at RSV season onset; school age siblings; and lower parental education. Nonprophylaxed children had a higher risk for RSV-related hospitalization than did prophylaxed patients (odds ratio, 3.86; 95% confidence interval, 2.83 to 5.25). CONCLUSION: Data from this study support the effectiveness of palivizumab in significantly modifying RSV-related hospitalizations in high risk preterm infants, with and without CLD, during two respiratory seasons.