Prospective Validation of a Prognostic Model for Respiratory Syncytial Virus Bronchiolitis in Late Preterm Infants: A Multicenter Birth Cohort Study

Objectives

This study aimed to update and validate a prediction rule for respiratory syncytial virus (RSV) hospitalization in preterm infants 33–35 weeks gestational age (WGA).

Study Design

The RISK study consisted of 2 multicenter prospective birth cohorts in 41 hospitals. Risk factors were assessed at birth among healthy preterm infants 33–35 WGA. All hospitalizations for respiratory tract infection were screened for proven RSV infection by immunofluorescence or polymerase chain reaction. Multivariate logistic regression analysis was used to update an existing prediction model in the derivation cohort (n = 1,227). In the validation cohort (n = 1,194), predicted versus actual RSV hospitalization rates were compared to determine validity of the model.

Results

RSV hospitalization risk in both cohorts was comparable (5.7% versus 4.9%). In the derivation cohort, a prediction rule to determine probability of RSV hospitalization was developed using 4 predictors: family atopy (OR 1.9; 95%CI, 1.1–3.2), birth period (OR 2.6; 1.6–4.2), breastfeeding (OR 1.7; 1.0–2.7) and siblings or daycare attendance (OR 4.7; 1.7–13.1). The model showed good discrimination (c-statistic 0.703; 0.64–0.76, 0.702 after bootstrapping). External validation showed good discrimination and calibration (c-statistic 0.678; 0.61–0.74).

Conclusions

Our prospectively validated prediction rule identifies infants at increased RSV hospitalization risk, who may benefit from targeted preventive interventions. This prediction rule can facilitate country-specific, cost-effective use of RSV prophylaxis in late preterm infants.     

Increased Risk of Wheeze and Decreased Lung Function after Respiratory Syncytial Virus Infection

Background

A relationship between hospitalization for respiratory syncytial virus (RSV) bronchiolitis and asthma development has been suggested in case-control studies.

Objective

The aim of this study was to assess the risk of current wheeze, asthma, and lung function at school age in infants previously hospitalized for RSV bronchiolitis compared to non-hospitalized children.

Methods

For this study, data from a prospective birth cohort of unselected, term-born infants (n = 553), of whom 4 (0.7%) were hospitalized for RSV bronchiolitis, and a prospective patient cohort of 155 term infants hospitalized for RSV bronchiolitis were used. Respiratory outcomes at age 6 in children hospitalized for RSV bronchiolitis were compared to non-hospitalized children.

Results

The risk of current wheeze was higher in hospitalized patients (n = 159) compared to non-hospitalized children (n = 549) (adjusted odds ratio (OR) 3.2 (95% CI 1.2–8.1). Similarly, the risk of current asthma, defined as a doctor’s diagnosis of asthma plus current symptoms or medication use, was higher in hospitalized patients (adjusted OR 3.1 (95% CI 1.3–7.5). Compared to non-hospitalized children, RSV bronchiolitis hospitalization was associated with lower lung function (mean difference FEV1% predicted −6.8 l (95% CI (−10.2 to −3.4).

Conclusions and Clinical Relevance

This is the first study showing that hospitalization for RSV bronchiolitis during infancy is associated with increased risk of wheezing, current asthma, and impaired lung function as compared to an unselected birth cohort at age 6.     

A High Burden of Respiratory Syncytial Virus Associated Pneumonia in Children Less than Two Years of Age in a South East Asian Refugee Population

Background

Pneumonia is a major cause of childhood mortality and morbidity approximately 1.6 million deaths and 150 million episodes occur annually in children <5 years. Respiratory syncytial virus (RSV) may be responsible for up to 25% of cases and 12% of deaths making it an important potential vaccine target, although data from South East Asia is scarce.

Methods

We followed a birth cohort of Burmese refugee children, born over a one year period, for two years. Pneumonia episodes were diagnosed using WHO criteria. A chest radiograph, nasopharyngeal aspirate and non-specific markers of infection were taken during each episode.

Results

The incidence of RSV-associated pneumonia was 0.24 (95% CI 0.22–0.26) episodes per child year. All children with pneumonia received antibiotic treatment, following WHO guidelines. The highest incidence was in the 2–12 month age group. The commonest diagnosis in a child with RSV-associated pneumonia was non-severe pneumonia (239/362∶66.0%), however the incidence of RSV-associated severe or very severe pneumonia was 0.08 (95% CI 0.01–0.10) episodes per child year. Birth in the wet season increased the risk of severe disease in children who had their first episode of RSV-associated pneumonia aged 2–11 months (OR 28.7, 95% CI 6.6–125.0, p<0.001). RSV episodes were highly seasonal being responsible for 80.0% of all the pneumonia episodes occurring each October and November over the study period.

Conclusions

There was a high incidence of RSV associated pneumonia in this refugee population. Interventions to prevent RSV infection have the potential to reduce the incidence of clinically diagnosed pneumonia and hence unnecessary antibiotic usage in this population.     

The Burden of Influenza and RSV among Inpatients and Outpatients in Rural Western Kenya, 2009–2012

Background

In Kenya, detailed data on the age-specific burden of influenza and RSV are essential to inform use of limited vaccination and treatment resources.

Methods

We analyzed surveillance data from August 2009 to July 2012 for hospitalized severe acute respiratory illness (SARI) and outpatient influenza-like illness (ILI) at two health facilities in western Kenya to estimate the burden of influenza and respiratory syncytial virus (RSV). Incidence rates were estimated by dividing the number of cases with laboratory-confirmed virus infections by the mid-year population. Rates were adjusted for healthcare-seeking behavior, and to account for patients who met the SARI/ILI case definitions but were not tested.

Results

The average annual incidence of influenza-associated SARI hospitalization per 1,000 persons was 2.7 (95% CI 1.8–3.9) among children <5 years and 0.3 (95% CI 0.2–0.4) among persons ≥5 years; for RSV-associated SARI hospitalization, it was 5.2 (95% CI 4.0–6.8) among children <5 years and 0.1 (95% CI 0.0–0.2) among persons ≥5 years. The incidence of influenza-associated medically-attended ILI per 1,000 was 24.0 (95% CI 16.6–34.7) among children <5 years and 3.8 (95% CI 2.6–5.7) among persons ≥5 years. The incidence of RSV-associated medically-attended ILI was 24.6 (95% CI 17.0–35.4) among children <5 years and 0.8 (95% CI 0.3–1.9) among persons ≥5 years.

Conclusions

Influenza and RSV both exact an important burden in children. This highlights the possible value of influenza vaccines, and future RSV vaccines, for Kenyan children.     

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 ≤ 2 months, siblings ≥ 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.     

Respiratory syncytial virus infection is associated with an altered innate immunity and a heightened pro-inflammatory response in the lungs of preterm lambs

Introduction

Factors explaining the greater susceptibility of preterm infants to severe lower respiratory infections with respiratory syncytial virus (RSV) remain poorly understood. Fetal/newborn lambs are increasingly appreciated as a model to study key elements of RSV infection in newborn infants due to similarities in lung alveolar development, immune response, and susceptibility to RSV. Previously, our laboratory demonstrated that preterm lambs had elevated viral antigen and developed more severe lesions compared to full-term lambs at seven days post-infection. Here, we compared the pathogenesis and immunological response to RSV infection in lungs of preterm and full-term lambs.

Methods

Lambs were delivered preterm by Caesarian section or full-term by natural birth, then inoculated with bovine RSV (bRSV) via the intratracheal route. Seven days post-infection, lungs were collected for evaluation of cytokine production, histopathology and cellular infiltration.

Results

Compared to full-term lambs, lungs of preterm lambs had a heightened pro-inflammatory response after infection, with significantly increased MCP-1, MIP-1α, IFN-γ, TNF-α and PD-L1 mRNA. RSV infection in the preterm lung was characterized by increased epithelial thickening and periodic acid-Schiff staining, indicative of glycogen retention. Nitric oxide levels were decreased in lungs of infected preterm lambs compared to full-term lambs, indicating alternative macrophage activation. Although infection induced significant neutrophil recruitment into the lungs of preterm lambs, neutrophils produced less myeloperoxidase than those of full-term lambs, suggesting decreased functional activation.

Conclusions

Taken together, our data suggest that increased RSV load and inadequate immune response may contribute to the enhanced disease severity observed in the lungs of preterm lambs.     

Utilization of Inhaled Corticosteroids for Infants with Bronchopulmonary Dysplasia

Objective

To determine demographic and clinical variables associated with inhaled corticosteroid administration and to evaluate between-hospital variation in inhaled steroid use for infants with bronchopulmonary dysplasia (BPD).

Design

Retrospective Cohort Study.

Setting

Neonatal units of 35 US children''s hospitals; as recorded in the Pediatric Health Information System (PHIS) database.

Patients

1429 infants with evolving BPD at 28 days who were born at <29 weeks gestation with birth weight <1500 grams, admitted within the first 7 postnatal days, and discharged between January 2007–June 2011.

Results

Inhaled steroids were prescribed to 25% (n = 352) of the cohort with use steadily increasing during the first two months of hospitalization. The most frequently prescribed steroid was beclomethasone (n = 194, 14%), followed by budesonide (n = 125, 9%), and then fluticasone (n = 90, 6%). Birth gestation <24 weeks, birth weight 500–999 grams, and prolonged ventilation all increased the adjusted odds of ever receiving inhaled corticosteroids (p<0.05). Wide variations between hospitals in the frequency of infants ever receiving inhaled steroids (range: 0–60%) and the specific drug prescribed were noted. This variation persisted, even after controlling for observed confounders.

Conclusions

Inhaled corticosteroid administration to infants with BPD is common in neonatal units within U.S. Children''s hospitals. However, its utilization varies markedly between centers from no treatment at some institutions to the majority of infants with BPD being treated at others. This supports the need for further research to identify the benefits and potential risks of inhaled steroid usage in infants with BPD.     

Breastfeeding Progression in Preterm Infants Is Influenced by Factors in Infants,Mothers and Clinical Practice: The Results of a National Cohort Study with High Breastfeeding Initiation Rates

Background and Aim

Many preterm infants are not capable of exclusive breastfeeding from birth. To guide mothers in breastfeeding, it is important to know when preterm infants can initiate breastfeeding and progress. The aim was to analyse postmenstrual age (PMA) at breastfeeding milestones in different preterm gestational age (GA) groups, to describe rates of breastfeeding duration at pre-defined times, as well as analyse factors associated with PMA at the establishment of exclusive breastfeeding.

Methods

The study was part of a prospective survey of a national Danish cohort of preterm infants based on questionnaires and structured telephone interviews, including 1,221 mothers and their 1,488 preterm infants with GA of 24–36 weeks.

Results

Of the preterm infants, 99% initiated breastfeeding and 68% were discharged exclusively breastfed. Breastfeeding milestones were generally reached at different PMAs for different GA groups, but preterm infants were able to initiate breastfeeding at early times, with some delay in infants less than GA 32 weeks. Very preterm infants had lowest mean PMA (35.5 weeks) at first complete breastfeed, and moderate preterm infants had lowest mean PMA at the establishment of exclusive breastfeeding (36.4 weeks). Admitting mothers to the NICU together with the infant and minimising the use of a pacifier during breastfeeding transition were associated with 1.6 (95% CI 0.4–2.8) and 1.2 days (95% CI 0.1–2.3) earlier establishment of exclusive breastfeeding respectively. Infants that were small for gestational age were associated with 5.6 days (95% CI 4.1–7.0) later establishment of exclusive breastfeeding.

Conclusion

Breastfeeding competence is not developed at a fixed PMA, but is influenced by multiple factors in infants, mothers and clinical practice. Admitting mothers together with their infants to the NICU and minimising the use of pacifiers may contribute to earlier establishment of exclusive breastfeeding.     

The Incidence and Clinical Burden of Respiratory Syncytial Virus Disease Identified through Hospital Outpatient Presentations in Kenyan Children

Background

There is little information that describe the burden of respiratory syncytial virus (RSV) associated disease in the tropical African outpatient setting.

Methods

We studied a systematic sample of children aged <5 years presenting to a rural district hospital in Kenya with acute respiratory infection (ARI) between May 2002 and April 2004. We collected clinical data and screened nasal wash samples for RSV antigen by immunofluorescence. We used a linked demographic surveillance system to estimate disease incidence.

Results

Among 2143 children tested, 166 (8%) were RSV positive (6% among children with upper respiratory tract infection and 12% among children with lower respiratory tract infection (LRTI). RSV was more likely in LRTI than URTI (p<0.001). 51% of RSV cases were aged 1 year or over. RSV cases represented 3.4% of hospital outpatient presentations. Relative to RSV negative cases, RSV positive cases were more likely to have crackles (RR = 1.63; 95% CI 1.34–1.97), nasal flaring (RR = 2.66; 95% CI 1.40–5.04), in-drawing (RR = 2.24; 95% CI 1.47–3.40), fast breathing for age (RR = 1.34; 95% CI 1.03–1.75) and fever (RR = 1.54; 95% CI 1.33–1.80). The estimated incidence of RSV-ARI and RSV-LRTI, per 100,000 child years, among those aged <5 years was 767 and 283, respectively.

Conclusion

The burden of childhood RSV-associated URTI and LRTI presenting to outpatients in this setting is considerable. The clinical features of cases associated with an RSV infection were more severe than cases without an RSV diagnosis.     

Neonatal White Matter Abnormalities an Important Predictor of Neurocognitive Outcome for Very Preterm Children

Background

Cerebral white matter abnormalities on term MRI are a strong predictor of motor disability in children born very preterm. However, their contribution to cognitive impairment is less certain.

Objective

Examine relationships between the presence and severity of cerebral white matter abnormalities on neonatal MRI and a range of neurocognitive outcomes assessed at ages 4 and 6 years.

Design/Methods

The study sample consisted of a regionally representative cohort of 104 very preterm (≤32 weeks gestation) infants born from 1998–2000 and a comparison group of 107 full-term infants. At term equivalent, all preterm infants underwent a structural MRI scan that was analyzed qualitatively for the presence and severity of cerebral white matter abnormalities, including cysts, signal abnormalities, loss of white matter volume, ventriculomegaly, and corpus callosal thinning/myelination. At corrected ages 4 and 6 years, all children underwent a comprehensive neurodevelopmental assessment that included measures of general intellectual ability, language development, and executive functioning.

Results

At 4 and 6 years, very preterm children without cerebral white matter abnormalities showed no apparent neurocognitive impairments relative to their full-term peers on any of the domain specific measures of intelligence, language, and executive functioning. In contrast, children born very preterm with mild and moderate-to-severe white matter abnormalities were characterized by performance impairments across all measures and time points, with more severe cerebral abnormalities being associated with increased risks of cognitive impairment. These associations persisted after adjustment for gender, neonatal medical risk factors, and family social risk.

Conclusions

Findings highlight the importance of cerebral white matter connectivity for later intact cognitive functioning amongst children born very preterm. Preterm born children without cerebral white matter abnormalities on their term MRI appear to be spared many of the cognitive impairments commonly associated with preterm birth. Further follow-up will be important to assess whether this finding persists into the school years.     

Development of Left Ventricular Longitudinal Speckle Tracking Echocardiography in Very Low Birth Weight Infants with and without Bronchopulmonary Dysplasia during the Neonatal Period

Objectives

In preterm infants, postnatal myocardial adaptation may be complicated by bronchopulmonary dysplasia (BPD). We aimed to describe the development of left ventricular function by serial 2D, Doppler, and speckle tracking echocardiography (2D-STE) in infants with and without BPD during the neonatal period and compare these to anthropometric and conventional hemodynamic parameters.

Study Design

Prospective echocardiography on day of life (DOL) 1, 7, 14, and 28 in 119 preterm infants <1500 g birth weight of whom 36 developed BPD (need for oxygen supplementation at 36 weeks gestational age). Non-BPD and BPD infants differed significantly in median (IQR) gestational age (25.5(24–26.5) weeks vs. 29(27–30) weeks, p<0.001) and birth weight (661(552–871) g vs. 1100(890–1290) g, p<0.001).

Results

The intra- and inter-observer variability of the 2D-STE parameters measured did not depend on time of measurement, although there were significant differences in the reproducibility of the parameters. Low intra- and inter-observer variability was seen for longitudinal systolic strain and strain rate mid septum with a median CV (coefficient of variation) of <4.6%. Much higher CVs (>10%) were seen for the apical segment. While anthropometric parameters show rapid development during the first 4 weeks of life, the speckle tracking parameters did not differ statistically significantly during the neonatal period. Infants with and without BPD differed significantly (p<0.001) in the development of anthropometric parameters, conventional hemodynamic parameters except for heart rate, and 2D-STE parameters: global longitudinal systolic strain rate (GLSSR) and longitudinal systolic strain for the mid left wall (LSSR). The largest differences were seen at DOL 1 and 7 in GLSSR (p<0.001) and in LSSR (p<0.01).

Conclusions

Reproducible 2D-STE measurements are possible in preterm infants <1500 g. Cardiac deformation reveals early (DOL 1 and 7) ventricular changes (GLSSR and LSSR) in very low birth weight infants who develop BPD.     

Lung Volume,Breathing Pattern and Ventilation Inhomogeneity in Preterm and Term Infants

Background

Morphological changes in preterm infants with bronchopulmonary dysplasia (BPD) have functional consequences on lung volume, ventilation inhomogeneity and respiratory mechanics. Although some studies have shown lower lung volumes and increased ventilation inhomogeneity in BPD infants, conflicting results exist possibly due to differences in sedation and measurement techniques.

Methodology/Principal Findings

We studied 127 infants with BPD, 58 preterm infants without BPD and 239 healthy term-born infants, at a matched post-conceptional age of 44 weeks during quiet natural sleep according to ATS/ERS standards. Lung function parameters measured were functional residual capacity (FRC) and ventilation inhomogeneity by multiple breath washout as well as tidal breathing parameters. Preterm infants with BPD had only marginally lower FRC (21.4 mL/kg) than preterm infants without BPD (23.4 mL/kg) and term-born infants (22.6 mL/kg), though there was no trend with disease severity. They also showed higher respiratory rates and lower ratios of time to peak expiratory flow and expiratory time (t _PTEF/t _E) than healthy preterm and term controls. These changes were related to disease severity. No differences were found for ventilation inhomogeneity.

Conclusions

Our results suggest that preterm infants with BPD have a high capacity to maintain functional lung volume during natural sleep. The alterations in breathing pattern with disease severity may reflect presence of adaptive mechanisms to cope with the disease process.     

Lower Transplacental Antibody Transport for Measles,Mumps, Rubella and Varicella Zoster in Very Preterm Infants

Background

Maternal antibodies, transported over the placenta during pregnancy, contribute to the protection of infants from infectious diseases during the first months of life. In term infants, this protection does not last until the first recommended measles-mumps-rubella vaccination at 14 months in the Netherlands, while these viruses still circulate. The aim of the study was to investigate the antibody concentration against measles, mumps, rubella and varicella (MMRV) in mothers and preterm infants or healthy term infants at birth.

Methods

Antibody concentrations specific for MMRV were measured in cord blood samples from preterm (gestational age <32 weeks and/or birth weight <1500 g) and term infants, and matched maternal serum samples, using a fluorescent bead-based multiplex immune-assay.

Results

Due to lower placental transfer ratios of antibodies against MMRV in 96 preterm infants (range 0.75–0.87) compared to 42 term infants (range 1.39–1.65), the preterm infants showed 1.7–2.5 times lower geometric mean concentrations at birth compared to term infants. Maternal antibody concentration is the most important determinant of infant antibody concentration against MMRV.

Conclusions

Preterm infants benefit to a lesser extent from maternal antibodies against measles, mumps, rubella and varicella than term infants, posing them even earlier at risk for infectious diseases caused by these still circulating viruses.     

Probiotic Supplement Use among Young Children in Taiwan: A Prospective Cohort Study

Objectives

The objective of this study is to provide details on probiotic supplement use among young children in Taiwan.

Participants and Methods

This study is based on the Taiwan Birth Cohort Study database. We used questionnaires to collect information on probiotic supplement use among young children from birth to 18 months of age, while also considering their demographic characteristics and other covariates. Low-birth-weight infants, preterm infants, those with birth defects, and those with caregivers who returned incomplete questionnaires were excluded. The final valid sample comprised 16,991 cases.

Results

Approximately half the children received probiotic supplements before the age of 18 months. Only 6.3% of the children received probiotic supplements during the two periods of birth to 6 months and 7 to 18 months. Firstborn children, native mothers, mothers with higher educational levels, higher family income, and parents who lead healthy lifestyles were positively related to probiotic supplement use among children. Young children who were breastfed, with eczema, or with gastrointestinal tract problems were significantly positively associated with probiotic supplement use.

Conclusion

The findings show that probiotic supplement usage among young children is associated with a more socially advantaged circumstance and certain child health factors, such as eczema, diarrhea, and constipation. Parents might use probiotic supplements for prevention or treatment of child diseases. The findings of this research could serve as a baseline for future studies, and provide insight into probiotic supplement use behavior for health professionals caring for infants and young children.     

Sequential Cranial Ultrasound and Cerebellar Diffusion Weighted Imaging Contribute to the Early Prognosis of Neurodevelopmental Outcome in Preterm Infants

Objective

To evaluate the contribution of sequential cranial ultrasound (cUS) and term-equivalent age magnetic resonance imaging (TEA-MRI) including diffusion weighted imaging (DWI) to the early prognosis of neurodevelopmental outcome in a cohort of very preterm infants (gestational age [GA] <31 weeks).

Study design

In total, 93 preterm infants (median [range] GA in weeks: 28.3 [25.0–30.9]) were enrolled in this prospective cohort study and underwent early and term cUS as well as TEA-MRI including DWI. Early cUS abnormalities were classified as normal, mild, moderate or severe. Term cUS was evaluated for ex-vacuo ventriculomegaly (VM) and enlargement of the extracerebral cerebrospinal fluid (eCSF) space. Abnormalities on T1- and T2-weighted TEA-MRI were scored according to Kidokoro et al. Using DWI at TEA, apparent diffusion coefficients (ADCs) were measured in four white matter regions bilaterally and both cerebellar hemispheres. Neurodevelopmental outcome was assessed at two years’ corrected age (CA) using the Bayley Scales of Infant and Toddler Development, third edition. Linear regression analysis was conducted to explore the correlation between the different neuroimaging modalities and outcome.

Results

Moderate/severe abnormalities on early cUS, ex-vacuo VM and enlargement of the eCSF space on term cUS and increased cerebellar ADC values on term DWI were independently associated with worse motor outcome (p<.05). Ex-vacuo VM on term cUS was also related to worse cognitive performance at two years’ CA (p<.01).

Conclusion

These data support the clinical value of sequential cUS and recommend repeating cUS at TEA. In particular, assessment of moderate/severe early cUS abnormalities and ex-vacuo VM on term cUS provides important prognostic information. Cerebellar ADC values may further aid in the prognostication of gross motor function.     

Local interleukin-10 production during respiratory syncytial virus bronchiolitis is associated with post-bronchiolitis wheeze

Background

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis in infants. Following RSV bronchiolitis, 50% of children develop post-bronchiolitis wheeze (PBW). Animal studies have suggested that interleukin (IL)-10 plays a critical role in the pathogenesis of RSV bronchiolitis and subsequent airway hyperresponsiveness. Previously, we showed that ex vivo monocyte IL-10 production is a predictor of PBW. Additionally, heterozygosity of the single-nucleotide polymorphism (SNP) rs1800872 in the IL10 promoter region was associated with protection against RSV bronchiolitis.

Methods

This study aimed to determine the in vivo role of IL-10 in RSV pathogenesis and recurrent wheeze in a new cohort of 235 infants hospitalized for RSV bronchiolitis. IL-10 levels in nasopharyngeal aspirates (NPAs) were measured at the time of hospitalization and the IL10 SNP rs1800872 genotype was determined. Follow-up data were available for 185 children (79%).

Results

Local IL-10 levels during RSV infection turned out to be higher in infants that later developed physician diagnosed PBW as compared to infants without PBW in the first year after RSV infection (958 vs 692 pg/ml, p = 0.02). The IL10 promoter SNP rs1800872 was not associated with IL-10 concentration in NPAs.

Conclusion

The relationship between high local IL-10 levels during the initial RSV infection and physician diagnosed PBW provides further evidence of the importance of the IL-10 response during RSV bronchiolitis.     

The Level and Duration of RSV-Specific Maternal IgG in Infants in Kilifi Kenya

Background

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined.

Methods

A birth cohort (n = 635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated.

Results

The half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (P = 0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb.

Conclusion

Maternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider.     

In Very Young Infants Severity of Acute Bronchiolitis Depends On Carried Viruses

Background

RT amplification reaction has revealed that various single viruses or viral co-infections caused acute bronchiolitis in infants, and RV appeared to have a growing involvement in early respiratory diseases. Because remaining controversial, the objective was to determine prospectively the respective role of RSV, RV, hMPV and co-infections on the severity of acute bronchiolitis in very young infants.

Methods and Principal Findings

209 infants (median age: 2.4 months) were enrolled in a prospective study of infants <1 year old, hospitalized for a first episode of bronchiolitis during the winter epidemic season and with no high risk for severe disease. The severity was assessed by recording SaO₂% at admission, a daily clinical score (scale 0–18), the duration of oxygen supplementation and the length of hospitalization. Viruses were identified in 94.7% by RT amplification reaction: RSV only (45.8%), RV only (7.2%), hMPV only (3.8%), dual RSV/RV (14.3%), and other virus only (2%) or coinfections (9%). RV compared respectively with RSV and dual RSV/RV infection caused a significant less severe disease with a lower clinical score (5[3.2–6] vs. 6[4–8], p = 0.01 and 5.5[5–7], p = 0.04), a shorter time in oxygen supplementation (0[0–1] days vs. 2[0–3] days, p = 0.02 and 2[0–3] days, p = 0.03) and a shorter hospital stay (3[3–4.7] days vs.6 [5–8] days, p = 0.001 and 5[4–6] days, p = 0.04). Conversely, RSV infants had also longer duration of hospitalization in comparison with RSV/RV (p = 0.01) and hMPV (p = 0.04). The multivariate analyses showed that the type of virus carried was independently associated with the duration of hospitalization.

Conclusion

This study underlined the role of RV in early respiratory diseases, as frequently carried by young infants with a first acute bronchiolitis. RSV caused the more severe disease and conversely RV the lesser severity. No additional effect of dual RSV/RV infection was observed on the severity.     

Fecal Calprotectin Excretion in Preterm Infants during the Neonatal Period

Background

Fecal calprotectin has been proposed as a non-invasive marker of intestinal inflammation in inflammatory bowel disease in adults and children. Fecal calprotectin levels have been reported to be much higher in both healthy full-term and preterm infants than in children and adults.

Objective

To determine the time course of fecal calprotectin (f-calprotectin) excretion in preterm infants from birth until hospital discharge and to identify factors influencing f-calprotectin levels in the first weeks of life, including bacterial establishment in the gut.

Methodology

F-calprotectin was determined using an ELISA assay in 147 samples obtained prospectively from 47 preterm infants (gestational age, and birth-weight interquartiles 27–29 weeks, and 880–1320 g, respectively) at birth, and at 2-week intervals until hospital discharge.

Principal Findings

Although median f-calprotectin excretion was 138 µg/g, a wide range of inter- and intra-individual variation in f-calprotectin values (from day 3 to day 78) was observed (86% and 67%, respectively). In multivariate regression analysis, f-calprotectin correlated negatively with ante and per natal antibiotic treatment (p = 0.001), and correlated positively with the volume of enteral feeding (mL/kg/d) (p = 0.009), the need to interrupt enteral feeding (p = 0.001), and prominent gastrointestinal colonization by Clostridium sp (p = 0.019) and Staphylococcus sp (p = 0.047).

Conclusion

During the first weeks of life, the high f-calprotectin values observed in preterm infants could be linked to the gut bacterial establishment.     

Mechanical Ventilation Drives Inflammation in Severe Viral Bronchiolitis

Introduction

Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation.

Materials and Methods

Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL)-1α, IL-1β, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α.

Results

Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1α, were elevated compared to non-ventilated infected controls: IL-1α (159 versus 4 pg/ml, p<0.01), IL-1β (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05).

Conclusions

Using pre- and post-intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis.