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Aim: To evaluate the association between hospitalisation for respiratory syncytial virus lower respiratory tract infection (RSV LRTI) in infancy and asthma, respiratory health-related quality of life and lung function at 28-31 years of age., Methods: In 2010, we carried out a 30-year follow-up on 43 adults admitted to Kuopio University Hospital, Finland, for RSV LRTI, 27 for bronchiolitis and 16 for pneumonia, between 1981 and 1982. Together with 86 population-based controls, they completed the Saint George's Respiratory Questionnaire and underwent prebronchodilator (pre-BD) and post-BD spirometry tests to measure percentage of predicted forced vital capacity (FVC%), percentage of predicted forced expiratory volume in 1 sec (FEV1%) and percentage of predicted FEV1/FVC (FEV1/FVC%)., Results: Both the pre-BD and post-BD FEV1% and FEV1/FVC% were significantly lower in former RSV LRTI patients than in the controls. The bronchiolitis patients had more asthma in adulthood than the controls and pneumonia in infancy was associated with lower St George's Respiratory Questionnaire (SGRQ) scores., Conclusion: Respiratory tract infection LRTI hospitalisation in infancy was associated with an increased risk of permanent obstructive lung function reduction in adulthood. The asthma risk was higher after hospitalisation for bronchiolitis, than in the controls, and respiratory health-related quality of life was lower after hospitalisation for pneumonia., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Unlabelled: Most wheezing episodes in infants are caused and exacerbated by virus-induced lower respiratory tract infections. However, there are few reports of epidemiologic and clinical virus-specific research with a focus on virus-induced wheezing. The purpose of the current study was to characterize the clinical presentation of virus-induced wheezing in pediatric patients <3 years of age who were hospitalized with lower respiratory tract infections. Of the 412 patients in the study, 216 were followed for 3 years. Nasopharyngeal aspirates collected from the patients at the time of admission were examined for the presence of respiratory syncytial virus (RSV), rhinovirus (RV), parainfluenza-3 virus (PIV-3), human metapneumovirus (hMPV), and influenza virus (Flu) using reverse-transcription polymerase chain reaction and rapid diagnostic tests. Clinical signs were assessed using a severity scoring system. In patients with wheezing at the time of admission, RSV, RV, RSV+RV, Flu, PIV-3, and hMPV were detected in 33, 14, 8, 8, 5, and 3 % of samples, respectively. There were no differences in age and severity scores between patients harboring more prevalent viruses (RSV and RV) and those with less common infections. Patients with wheezing and RV-positive aspirates at the time of admission were more likely to develop subsequent wheezing during the following 3 years., Conclusion: RSV and RV infections are factors in the development and exacerbation of wheezing after virus-induced lower respiratory tract infections. Moreover, RV-induced wheezing may be associated with subsequent recurrent wheezing and the development of asthma.

Background and Aim: The purpose of this study was to examine the association between celiac disease (CD) and prior respiratory syncytial virus (RSV) infection or any viral bronchiolitis., Methods: This was a retrospective case-control study. During 2006-2008 small intestinal biopsy data were collected from Sweden's 28 pathology departments. We identified 3,835 children diagnosed with CD (villous atrophy, Marsh stage 3) before the age of 2 years in 1987 or later. Using conditional logistic regression we calculated odds ratios (ORs) for having a prior diagnosis of respiratory syncytial virus or other viral bronchiolitis compared to 19,102 age- and sex-matched controls., Results: Of the 3,835 children with CD, 36 (0.9 %) had a prior diagnosis of RSV compared to 117/19,102 (0.6 %) matched controls. This corresponded to an OR of 1.46 (95 % CI 1.03-2.07). ORs were similar in girls and boys. The highest ORs were seen in children developing early CD (before 1 year of age (OR 1.82; 95 % CI 0.91-3.62). Prior record of any type of viral bronchiolitis was found in 3.4 % (132/3,835) of individuals with CD and in 2.0 % (390/19,102) of the matched controls corresponding to an OR of 1.60 (95 % CI 1.33-1.92)., Conclusions: Children with CD diagnosed <2 years of age were more likely to have attended hospital for a prior RSV infection or any viral bronchiolitis than other children.

Human rhinoviruses (HRV) have been linked to the development of childhood asthma and recurrent acute asthma exacerbations throughout life, and contribute considerably to the healthcare and economic burden of this disease. However, the ability of HRV infections to trigger exacerbations, and the link between allergic status and HRV responsiveness, remains incompletely understood. Whilst the receptors on human airway cells that detect and are utilized by most HRV group A and B, but not C serotypes are known, how endosomal pattern recognition receptors (PRRs) detect HRV replication products that are generated within the cytoplasm remains somewhat of an enigma. In this article, we explore a role for autophagy, a cellular homeostatic process that allows the cell to encapsulate its own cytosolic constituents, as the crucial mechanism controlling this process and regulating the innate immune response of airway epithelial cells to viral infection. We will also briefly describe some of the recent insights into the immune responses of the airway to HRV, focusing on neutrophilic inflammation that is a potentially unwanted feature of the acute response to viral infection, and the roles of IL-1 and Pellinos in the regulation of responses to HRV., (© 2013 John Wiley & Sons Ltd.)

The aim of this study was to evaluate the risk of airway and/or pulmonary food or saliva aspiration in infants with moderate respiratory distress who are hospitalized with respiratory syncytial virus (RSV) bronchiolitis. This prospective, descriptive study was conducted during two epidemic RSV seasons at the Ricardo Gutiérrez Children's Hospital in Buenos Aires, Argentina. Included were otherwise healthy infants in their first wheezing episode with a modified Tal clinical score between 5 and 9. Swallowing was evaluated using a dynamic technetium-99 m colloid radionuclide salivagram using a gamma camera, followed by video fluoroscopy using nonionic and ionic contrast material. Fifteen patients (7 boys) were included. Age at evaluation (mean ± SD) was 4.3 ± 1.5 months; clinical score was 7.5 ± 1.4. Patients required (mean ± SD) supplemental oxygen and hospitalization 7.5 ± 3.7 and 8.8 ± 4.3 days, respectively. All technetium-99 m salivagram (10/10, as the gamma camera equipment was out of service during part of the study) and video fluoroscopy (15/15) studies were normal. No episodes of aspiration or laryngeal penetration were detected in any patient. Our study found that infants hospitalized with moderate respiratory distress due to RSV bronchiolitis did not show aspiration.

Viral illness with wheezing during infancy is associated with the inception of childhood asthma. Small airway dysfunction is a component of childhood asthma, but little is known about how viral illness at an early age may affect the structure and function of small airways. We used a well-characterized rat model of postbronchiolitis chronic airway dysfunction to address how postinfectious small airway lesions affect airway physiological function and if the structure/function correlates persist into maturity. Brown Norway rats were sham- or virus inoculated at 3 to 4 weeks of age and allowed to recover from the acute illness. At 3 to 14 months of age, physiology (respiratory system resistance, Newtonian resistance, tissue damping, and static lung volumes) was assessed in anesthetized, intubated rats. Serial lung sections revealed lesions in the terminal bronchioles that reduced luminal area and interrupted further branching, affecting 26% (range, 13-39%) of the small airways at 3 months of age and 22% (range, 6-40%) at 12 to 14 months of age. At 3 months of age (n = 29 virus; n = 7 sham), small airway lesions correlated with tissue damping (rs = 0.69) but not with Newtonian resistance (rs = 0.23), and Newtonian resistance was not elevated compared with control rats, indicating that distal airways were primarily responsible for the airflow obstruction. Older rats (n = 7 virus; n = 6 sham) had persistent small airway dysfunction and significantly increased Newtonian resistance in the postbronchiolitis group. We conclude that viral airway injury at an early age may induce small airway lesions that are associated quantitatively with small airway physiological dysfunction early on and that these defects persist into maturity.

Bronchiolitis in infancy is a risk factor for development of asthma in the first decades of life, although the majority may be asymptomatic at school age. Respiratory symptoms are common in early life, and prediction of later asthma may be challenging. We aimed to study if simple clinical variables assessed at 2 years of age could predict asthma at 11 years of age and thereby provide a basis for follow-up and treatment after bronchiolitis in infancy. The study included 105 children hospitalized for bronchiolitis during their first year of life. Of these, 101 (96.2%) participated in the first follow-up at 2 years of age and 93 (88.6%) in the second follow-up at age 11. The overall prevalence of asthma at 11 years of age was 22.6%. Among the risk factors assessed at 2 years of age, recurrent wheeze appeared most important (odds ratio for later asthma: 7.2; 95% confidence interval: 1.3, 41.6; P = 0.015). Tested separately, recurrent wheeze had high sensitivity (90.5%), but low specificity (58.3%), low negative likelihood ratio (LR) (0.2) and low negative post-test probability (4.5%); indicating that absence of recurrent wheeze was better suited to exclude than to predict asthma at 11 years of age. Combining recurrent wheeze with either parental atopy, parental asthma or atopic dermatitis improved the specificity (>80), positive LR (>3) and positive post-test probability (∼50%), rendering the combinations more appropriate for the prediction of later asthma. In conclusion, after bronchiolitis in infancy, simple clinical non-invasive variables assessed at 2 years of age could predict asthma at 11 years of age with reasonable accuracy. However, the data were better suited to exclude than to predict later asthma., (Copyright © 2012 Wiley Periodicals, Inc.)

The concept of sudden infant death syndrome (SIDS) is defined as the sudden, unexpected death of an infant less than a year old which remains unexplained after in-depth investigations comprising a complete autopsy, biological analyses, and a clinical examination of the circumstances surrounding the death. This definition underlines the importance of finding the cause of this disease in order to improve preventative measures to reduce the number of deaths due to sudden infant death syndrome. Among the causes of SIDS, pediatric infectious diseases may be neglected and must be systematically sought after. We report upon a SIDS death case of a four and a half month-old that occurred during his sleep. Following the absence of an evident cause of death a scientific autopsy was performed. The histological examination of pulmonary tissue revealed broncolitic lesions associated with numerous micro-abscesses. The post mortem microbiological analyses revealed evidence of an infection by the respiratory syncytial virus complicated by a bacterial infection due to Haemophilus influenzae. The case underlines the necessity of a multidisciplinary approach to researching SIDS, involving both clinicians and biologists, in order to determine the causes of these deaths.

Unlabelled: PROPOSE OF REVIEW: Cumulative evidence suggest that early life bronchiolitis is a major risk factor for subsequent wheezing episodes and asthma. The purpose of this review is to present the recent findings and current perspectives regarding the interplay between bronchiolitis and long-term respiratory outcomes., Recent Findings: Recent studies have supported the long-recognized link between early life severe respiratory syncytial virus bronchiolitis and the physician diagnosis of asthma by school age, and this association appears to continue into early adulthood. Evidence is accumulating regarding the role of early life infection with human rhinovirus as an important antecedent for future asthma. Whether viral bronchiolitis is causal or an early manifestation of future asthma remains uncertain. Vitamin D status has emerged as a potential modifying factor for viral-induced wheeze and could potentially influence the development of asthma., Summary: Viral bronchiolitis early in life is a major and potential long-term risk factor for subsequent wheezing and asthma. Whether the association between bronchiolitis and subsequent asthma is due to causality or a reflection of predisposition may be dependent on host factors and virus-specific effects.

Respiratory syncytial virus is the most common pathogen causing lower respiratory tract infection in infants. Respiratory syncytial virus infection is also associated with a number of extrapulmonary manifestations, including the cardiac system. Pericardial effusion, however, is a very rare occurrence with respiratory syncytial virus infection. We report a very young infant with respiratory syncytial virus bronchiolitis whose clinical course was associated with pericardial effusion, treated conservatively.

Background: Little is known about the potential of syndromic surveillance to provide early warning of pertussis outbreaks. We conducted a time series analysis to assess whether an emergency department (ED) cough syndrome would respond to changes in the incidence of pertussis in children aged under 10 years in New South Wales (NSW), Australia, and to evaluate the timing of any association. A further aim was to assess the lag between the onset of pertussis symptoms and case notification in the infectious diseases surveillance system in NSW., Methods: Using routinely collected data, we prepared a daily count time series of visits to NSW EDs assigned a provisional diagnosis of cough. Separate daily series were prepared for three independent variables: notifications of cases of pertussis and influenza and ED visits with bronchiolitis (a proxy measure of respiratory syncytial virus (RSV) infection). The study period was 1/1/2007-31/12/2010. A negative binomial multivariate model was used to assess associations between the outcome and independent variables. We also evaluated the median delay in days between the estimated onset of a case of pertussis and the date the local public health authority was notified of that case., Results: When notified pertussis increased by 10 cases in one day, ED visits with cough increased by 5.2% (95% confidence interval (CI): 0.5%-10.0%) seven days later. Daily increases in the other independent variables had a smaller impact on cough visits. When notified influenza increased by 10 cases in one day, ED visits with cough increased by 0.8% (95% CI: 0%-1.7%) seven days later. When ED visits with bronchiolitis increased by 10 visits in one day, ED visits with cough increased by 4.8% (95% CI: 1.2%-8.6%) one day earlier. The median interval between estimated onset of pertussis and case notification was seven days., Conclusions: Pertussis appears to be an important driver of ED visits with cough in children aged under 10 years. However, the median delay in notification of cases of pertussis was similar to the lag in the pertussis-associated short-term increases in ED visits with cough. Elevations in RSV and influenza activity may also explain increases in the ED cough syndrome. Real time monitoring of ED visits with cough in children is therefore unlikely to consistently detect a potential outbreak of pertussis before passive surveillance.

Reactive airway disease (RAD) is a general term for respiratory illnesses manifested by wheezing. Respiratory syncytial virus (RSV) results in wheezing, either by causing bronchiolitis or by inducing acute exacerbations of asthma. There has been a long-standing interest in whether severe RSV bronchiolitis in infancy is a risk factor for the development of asthma later in childhood. While epidemiologic studies have suggested that such a link exists, a very recent study suggests that infants with greater airways responsiveness to methacholine instead have an increased prevalence of severe RSV bronchiolitis. Increased airways responsiveness to methacholine has been implicated as a key factor for loss of lung function in asthmatic subjects, suggesting that instead of being causal, severe RSV infection may instead be a marker of a predisposing factor for asthma. In this chapter, we will explore the evidence that RSV infection leads to RAD in infants and adults, and how these different forms of RAD may be linked.

Infection with respiratory syncytial virus (RSV) can result in a wide spectrum of pulmonary manifestations, from mild upper respiratory symptoms to severe bronchiolitis and pneumonia. Although there are several known risk factors for severe RSV disease, namely, premature birth, chronic lung disease, congenital heart disease, and T cell immunodeficiency, the majority of young children who develop severe RSV disease are otherwise healthy children. Genetic susceptibility to RSV infection is emerging as a complex trait, in which many different host genetic variants contribute to risk for distinct disease manifestations. Initially, host genetic studies focused on severe RSV disease using the candidate gene approach to interrogate common single nucleotide polymorphisms (SNPs). Many studies have reported genetic associations between severe RSV bronchiolitis and SNPs in genes within plausible biological pathways, such as in innate host defense genes (SPA, SPD, TLR4, and VDR), cytokine or chemokine response genes (CCR5, IFN, IL6, IL10, TGFB1), and altered Th1/Th2 immune responses (IL4, IL13). Due to the complexity of RSV susceptibility, genome studies done on a larger scale, such as genome-wide association studies have certainly identified more of the host factors that contribute to the development of severe RSV bronchiolitis or excessive pathology. Furthermore, whole-genome approaches can reveal robust associations between genetic markers and RSV disease susceptibility. Recent introduction of 'exome' genotyping or sequencing, which specifically analyzes the majority of coding variants, should be fruitful in sufficiently large, well-powered studies. The advent of new genomic technologies together with improved computational tools offer the promise of interrogating the host genome in search of genetic factors, rare, uncommon, or common that should give new insights into the underlying biology of susceptibility to or protection from severe RSV infection. Careful assessment of novel pathways and further identification of specific genes could identify new approaches for vaccine development and perhaps lead to effective risk modeling.

Hypothermia may reduce the CO(2) production by decreasing the metabolism of the cooled tissue. We describe the first clinical use of hypothermia to lower hypercarbia in a case of bronchiolitis related respiratory failure unresponsive to maximal respiratory support. In this case, hypothermia allowed sparing the use of extracorporeal life support. Conclusion Hypothermia might be useful for severe acute respiratory failure unresponsive to aggressive respiratory support.

Unlabelled: A systematic literature review has been undertaken. Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in infancy is associated with chronic respiratory morbidity. Premorbid abnormal lung function may predispose to RVS LRTI in prematurely born infants., Conclusion:   Single-nucleotide polymorphisms in genes coding for IL-8, IL-19, IL-20, IL-13 mannose-binding lectin, IFNG and a RANTES polymorphism have been associated with subsequent wheeze following RSV LRTI in term-born infants., (© 2012 The Author(s)/Acta Paediatrica © 2012 Foundation Acta Paediatrica.)

Objectives: (1) To examine whether infants with severe bronchiolitis, fulfilling criteria for further respiratory support, could be managed outside a Pediatric Intensive Care Unit (PICU) with non-invasive ventilation (NIV) alone. (2) To study the characteristics, clinical course and outcome of NIV responders and non responders to assess safety and efficacy and inform guideline construction., Hypothesis: Infants with severe bronchiolitis can be safely managed with NIV outside a PICU., Study Design: Retrospective case review., Patient Selection: Cohort of infants with objective evidence of severe bronchiolitis requiring respiratory support nursed in a Pediatric High Dependency Unit (PHDU) and/or Intensive Care Unit (ICU) between 2001 and 2007., Methodology: Analysis of patient characteristics and respiratory parameters at admission and initiation of ventilation, changes after 2 and 4 hr of NIV or invasive ventilation, complications, short and long-term outcomes were analyzed., Results: One thousand and thirty-five infants with bronchiolitis were admitted with 67 ventilation episodes identified from 65 patients. Fifty-five episodes, including 34 with apnea, were treated exclusively with NIV. Six infants failed to respond and were invasively ventilated. Six patients were invasively ventilated at presentation. Non-responders had a significantly higher rate of bacterial infection. Significant improvements in respiratory parameters in responders occurred by 2 hr and sustained at 4 hr. Duration of hospital stay, ventilation requirement and oxygen requirement were significantly shorter in responders. Short and longer-term follow up data did not identify any adverse effects related to NIV., Conclusions: NIV was effective in 80% of infants receiving respiratory support for severe bronchiolitis., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: Respiratory syncytial virus and other respiratory tract viruses lead to common colds in most infants, whereas a minority develop acute severe bronchiolitis often requiring hospitalization. We hypothesized that such an excessive response to respiratory tract viral infection is caused by host factors reflected in pre-existing increased bronchial responsiveness., Objective: We sought to compare bronchial responsiveness and lung function in 1-month-old neonates who later develop acute severe bronchiolitis with those who do not., Methods: We measured infant lung function (n=402) and bronchial responsiveness to methacholine (n=363) using the raised-volume rapid thoracoabdominal compression technique before any respiratory symptoms in 1-month-old neonates from the Copenhagen Prospective Study of Asthma in Childhood birth cohort born to mothers with asthma. The children were prospectively monitored for respiratory symptoms and given a diagnosis of acute severe bronchiolitis according to a fixed algorithm., Results: Thirty-four (8.5%) infants had acute severe bronchiolitis before 2 years of age, 21 (62%) were hospitalized, and 23 (67%) of the cases were associated with respiratory syncytial virus. Children who later had acute severe bronchiolitis irrespective of viral species had a 2.5-fold increased responsiveness to methacholine (provocative dose of methacholine producing a 15% decrease in transcutaneous oxygen pressure [PD(15)]) at age 1 month compared with control subjects (median PD(15) in cases vs control subjects, 0.13 vs 0.33 μmol; P=.01), whereas differences in baseline airflow were not significant for forced expiratory volume at 0.5 seconds (mean z score for cases vs control subjects, -0.18 vs -0.01; P=.36) and forced expiratory flow at 50% of forced vital capacity (mean z score for cases vs control subjects, -0.37 vs -0.09; P=.13)., Conclusion: Bronchial hyperresponsiveness in at-risk neonates precedes acute severe bronchiolitis in response to infections with respiratory tract virus., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined., Objectives: We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy., Methods: We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells., Results: Forty-eight percent of children had physician-diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7-15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3-7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1-55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04-0.84; P = .029) had a decreased risk of physician-diagnosed asthma., Conclusions: Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Objectives: To assess the potential effect of two guideline discharge oxygen saturation (SpO(2)) recommendations (≥90% and ≥94%) in recovering bronchiolitis., Methods and Patients: Infants aged up to 18 months requiring therapeutic oxygen for SpO(2) (≤93%) had SpO(2) assessed in air every 2 h. Time from admission to re-establish feeding (>75% normal) and for SpO(2) to become stable for at least 4 h at ≥90% and ≥94% were noted., Results: 68 infants, median age 14 weeks, were included. Feeding problems resolved at a median of 11 h (inter-quartile range, IQR 0-47). SpO(2) became stable for at least 4 h at 17 h (IQR 0-49) for ≥90% and 63 h (IQR 34-105) for ≥94%. Time for infants to achieve a stable SpO(2)≥90% and resolve feeding difficulties was a median of 22 h (IQR 7-39 h) sooner than the equivalent for stable SpO(2)≥94%., Conclusions: Accepting lower SpO(2) at discharge could significantly reduce length of stay, but require the clinical and safety effects to be studied.

Chest physiotherapy (CP) using passive expiratory manoeuvres is widely used in Western Europe for the treatment of bronchiolitis, despite lacking evidence for its efficacy. We undertook an open randomised trial to evaluate the effectiveness of CP in infants hospitalised for bronchiolitis by comparing the time to clinical stability, the daily improvement of a severity score and the occurrence of complications between patients with and without CP. Children <1 year admitted for bronchiolitis in a tertiary hospital during two consecutive respiratory syncytial virus seasons were randomised to group 1 with CP (prolonged slow expiratory technique, slow accelerated expiratory flow, rarely induced cough) or group 2 without CP. All children received standard care (rhinopharyngeal suctioning, minimal handling, oxygen for saturation ≥92%, fractionated meals). Ninety-nine eligible children (mean age, 3.9 months), 50 in group 1 and 49 in group 2, with similar baseline variables and clinical severity at admission. Time to clinical stability, assessed as primary outcome, was similar for both groups (2.9 ± 2.1 vs. 3.2 ± 2.8 days, P = 0.45). The rate of improvement of a clinical and respiratory score, defined as secondary outcome, only showed a slightly faster improvement of the respiratory score in the intervention group when including stethoacoustic properties (P = 0.044). Complications were rare but occurred more frequently, although not significantly (P = 0.21), in the control arm. In conclusion, this study shows the absence of effectiveness of CP using passive expiratory techniques in infants hospitalised for bronchiolitis. It seems justified to recommend against the routine use of CP in these patients.

Mechanisms underlying the increased risk of recurrent wheeze after respiratory syncytial virus lower respiratory tract infection (RSV LRTI) are unclear. Specifically, information about genetic determinants of recurrent wheeze after RSV LRTI is limited. We performed a candidate gene association study to identify genetic determinants of recurrent wheeze after RSV LRTI. We investigated 346 single nucleotide polymorphisms (SNPs) in 220 candidate genes in 166 Dutch infants hospitalized for RSV LRTI. Logistic regression analysis was used to study associations between genotypes and haplotypes and recurrent wheeze after RSV LRTI. We found associations with recurrent wheeze for SNPs in IL19, IL20, MUC5AC, TNFRSF1B, C3, CTLA4, CXCL9, IL4R, and IL7 genes. Haplotype analysis of the combined IL19/IL20 genotyped polymorphisms demonstrated an inverse association between the TGG haplotype and recurrent wheeze after RSV LRTI. IL19 and IL20 genes were notably associated with recurrent wheeze in infants without asthmatic parents. The association of IL20 SNP rs2981573 with recurrent wheeze was confirmed in a healthy birth cohort. We concluded that genetic variation in adaptive immunity genes and particularly in IL19/IL20 genes associates with the development of recurrent wheeze after RSV LRTI, suggesting a role for these IL10 family members in the etiology of airway disease during infancy.

Objective: To summarize the risk of occult serious bacterial infection in the youngest febrile infants presenting with either clinical bronchiolitis or respiratory syncytial virus infection., Data Sources: We performed a systematic search of the Medline database for studies reporting rates of serious bacterial infection in infants younger than 90 days with clinical bronchiolitis and/or respiratory syncytial virus infection., Study Selection: Studies reporting on cultures performed at the time of presentation to care and providing a denominator, ie, total number of each type of culture obtained, were analyzed., Main Exposure: Admission for bronchiolitis., Main Outcome Measures: Age-specific rates of urinary tract infection, bacteremia, and meningitis were extracted., Results: The weighted rate of urinary tract infections in the youngest infants in the 11 studies analyzed was 3.3% (95% confidence interval, 1.9%-5.7%). No case of bacteremia was reported in 8 of 11 studies. No case of meningitis was reported in any of the studies. Summary statistics for meningitis and bacteremia are not provided because of an excess of zero events in these samples., Conclusions: A screening approach to culturing for serious bacterial infections in febrile infants presenting with bronchiolitis or respiratory syncytial virus infection is very low yield. The rate of urine cultures positive for bacteria remains significant, though asymptomatic bacteriuria may confound these results.

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.

Myocarditis in the pediatric population is commonly caused by viral pathogens, notably entero virus and adeno virus. Respiratory syncytial virus, although widespread among this population, is rarely associated with myocarditis. The incidence of myocarditis is unknown due to the variability of clinical presentation and diagnostic limitations. Data regarding prognosis is lacking in children. Patients should be monitored in a pediatric intensive care unit secondary to the risk of hemodynamic compromise. We present the case of fulminant myocarditis in a seven-month old female in the setting of respiratory syncytial virus bronchiolitis.

With the advent of highly sensitive and specific screening of respiratory specimens for viruses, new viruses are discovered, adding to the growing list of those associated with wheezing illness and asthma exacerbations. It is not known whether early childhood infections with these viruses cause asthma, and, if so, what exactly are the pathophysiologic mechanisms behind its development. The current consensus is that respiratory viral infection works together with allergy to produce the immune and physiologic conditions necessary for asthma diasthesis. One link between viruses and asthma may be the eosinophil, a cell that plays a prominent role in asthma and allergy, but can also be found in the body in response to viral infection. In turn, the eosinophil and its associated products may be novel therapeutic targets, or at the very least, used to elucidate the complex pathophysiologic pathways of asthma and other respiratory illnesses. Together or separately, they can be used for diagnosis, treatment and monitoring. Not only symptoms, but also the underlying disease mechanisms must be taken into consideration for the optimal care of a patient., (Copyright © 2010 S. Karger AG, Basel.)

Background: An increased prevalence of asthma/recurrent wheeze (RW), clinical allergy and allergic sensitisation up to age 13&emsp14;years has previously been reported in subjects hospitalised with respiratory syncytial virus (RSV) bronchiolitis in their first year of life compared with matched controls. A study was undertaken to examine whether these features persist into early adulthood, to report longitudinal wheeze and allergy patterns, and to see how large and small airway function relates to RSV infection and asthma., Methods: Follow-up at age 18 years was performed in 46 of 47 subjects with RSV and 92 of 93 controls. Assessments included questionnaire, clinical examination, skin prick tests, serum IgE antibodies to inhaled allergens, blood eosinophils, fraction of exhaled nitric oxide (FeNO), spirometry, multiple breath washout (lung clearance index, LCI) and dry air hyperventilation challenge., Results: Increased prevalence of asthma/RW (39% vs 9%), clinical allergy (43% vs 17%) and sensitisation to perennial allergens (41% vs 14%) were present at age 18 in the RSV cohort compared with controls. Persistent/relapsing wheeze associated with early allergic sensitisation predominated in the RSV cohort compared with controls (30% vs 1%). Spirometric function was reduced in subjects with RSV with or without current asthma, but not in asthmatic controls. LCI was linked only to current asthma, airway hyperresponsiveness and FeNO., Conclusions: Severe early RSV bronchiolitis is associated with an increased prevalence of allergic asthma persisting into early adulthood. Small airway dysfunction (LCI) is related to current asthma and airway inflammation but not to RSV bronchiolitis. Reduced spirometry after RSV may reflect airway remodelling.

Rationale: Respiratory syncytial virus (RSV) bronchiolitis in infants may be followed by the development of asthma-like symptoms. Age at first infection dictates consequences upon reinfection. Reinfection of mice initially exposed as neonates to RSV enhanced development of airway hyperresponsiveness (AHR), eosinophilic inflammation, and mucus hyperproduction. RSV lower respiratory tract disease is associated with activation of the leukotriene pathway., Objectives: To determine the effects of montelukast (MK), a cysteinyl leukotriene (cysLT) receptor antagonist, in primary and secondary RSV-infected newborn and adult mice., Methods: BALB/c mice were infected with RSV at 1 week (neonate) or 6 to 8 weeks (adult) of age and reinfected 5 weeks later. MK was administered 1 day before the initial infection and through Day 6 after infection. Seven days after primary or secondary infection, airway function was assessed by lung resistance to increasing doses of inhaled methacholine; lung inflammation, goblet cell metaplasia, and cytokine levels in bronchoalveolar lavage fluid were monitored., Measurements and Main Results: RSV infection induced cysLT release in bronchoalveolar lavage fluid. MK decreased RSV-induced AHR, airway inflammation, and increased IFN-gamma production in primary infected adult and neonatal mice. MK, administered during initial infection of neonates but not during secondary infection, prevented subsequent enhancement of AHR, airway eosinophilia, and mucus hyperproduction upon reinfection., Conclusions: MK attenuated the initial responses to primary RSV infection in both age groups and altered the consequences of RSV reinfection in mice initially infected as neonates. These data support an important role for cysLT in RSV-induced AHR and inflammation.

Background: Respiratory syncytial virus (RSV) bronchiolitis has been associated with later development of asthma, wheezing, abnormal pulmonary function, and sensitization. Our aim was to determine the differential effect within monozygotic (MZ) twin pairs discordant for severe RSV bronchiolitis in infancy on the subsequent development of asthma, pulmonary function, and allergy., Methods: Thirty-seven MZ twin pairs discordant for RSV hospitalization in infancy (mean age 10.6 months) were compared at the mean age of 7.6 years for lung function, bronchial responsiveness, fractional exhaled nitric oxide (Feno), asthma diagnosis, use of asthma medication, and skin prick test to common inhalant allergens., Results: There were no differences within MZ twin pairs discordant for RSV hospitalization in infancy with respect to pulmonary function, Feno, asthma prevalence, asthma medication use, or sensitization (P > .1 for all comparisons)., Conclusions: We found no differential effect from severity of RSV infection on the development of asthma and allergy in MZ twin pairs discordant for RSV hospitalization in infancy. This argues against a specific effect of severe RSV infection in the development of asthma and allergy. Because of the small sample size, this study must be considered as a hypothesis-generating study.

Aim: We have designed a study with the objective of describing the clinical impact of other viruses different from the respiratory syncytial virus (RSV) in hospitalized infants with bronchiolitis., Methods: A 3 year prospective study was conducted on infants admitted to the Paediatrics Department of the Severo Ochoa Hospital (Spain). We studied the frequency of 16 respiratory viruses. Clinical characteristics of RSV-only infections were compared with other single agent viral infections., Results: Positive results were confirmed in 275 (86.5%) of the 318 children studied. A single virus was detected in 196 patients and 79 were dual or multiple viral infections. RSV was detected in 61.3% of total bronchiolitis. Rhinovirus (RV) was 17.4% of the identified virus, followed by human bocavirus (HBoV), adenovirus and metapneumovirus (hMPV). Only RV, HBoV and hMPV were significant as single infections. RSV patients were younger than HBoV (p > 0.0001) and hMPV (p = 0.025). Seasonality was clearly different between them. Children with RSV infection needed treatment in the intensive care unit more frequently than others., Conclusions: In hospitalized infants, RSV was the most frequent agent in bronchiolitis in winter, but other viruses were present in 47% of the patients. RV, HBoV and hMPV had a significant proportion of single infections. Clinical characteristics were similar amongst them, but seasonality was clearly different.

Objectives: To determine the viruses and risk factors associated with hospital and intensive care unit (ICU) admissions in infants with acute bronchiolitis., Introduction: Bronchiolitis is a major cause of morbidity in infants. Widespread use of molecular-based methods has yielded new insights about its etiology, but the impact of viral etiologies on early outcomes is still unclear., Methods: Seventy-seven infants with bronchiolitis who were under two years of age and visited an emergency unit were included. Using molecular-based methods, samples were tested for 12 different respiratory viruses. Logistic regression models were used to identify clinical and virological variables associated with the main endpoints: hospital admission and ICU admission., Results: We identified at least one virus in 93.5% of patients, and coinfections were found in nearly 40% of patients. RSV was the most common pathogen (63.6%), followed by rhinovirus (39%). Identification of RSV was only associated with an increased risk of hospital admission in the univariate model. Younger age and enterovirus infection were associated with an increased risk of hospital admission, while atopy of a first-degree relative showed a protective effect. Prematurity was associated with an increased risk of admission to the ICU. Coinfections were not associated with worse outcomes., Conclusions: Molecular-based methods resulted in high rates of viral identification but did not change the significant role of RSV in acute bronchiolitis. Younger age and enterovirus infection were risk factors for hospital admission, while prematurity appeared to be a significant risk factor for admission to the ICU in acute viral bronchiolitis.

Background: Secondary thrombocytosis is associated with a variety of clinical conditions, one of which is lower respiratory tract infection. However, reports on thrombocytosis induced by viral infections are scarce., Objectives: To assess the rate of thrombocytosis (platelet count > 500 x 10(9)/L) in hospitalized infants with bronchiolitis and to investigate its potential role as an early marker of respiratory syncytial virus infection., Methods: Clinical data on 469 infants aged < or = 4 months who were hospitalized for bronchiolitis were collected prospectively and compared between RSV-positive and RSV-negative infants., Results: The rate of thrombocytosis was significantly higher in RSV-positive than RSV-negative infants (41.3% vs. 29.2%, P=0.031). The odds ratio of an infant with bronchiolitis and thrombocytosis to have a positive RSV infection compared to an infant with bronchiolitis and a normal platelet count was 1.7 (P= 0.023, 95% confidence interval 1.07-2.72). There was no significant difference in mean platelet count between the two groups., Conclusions: RSV-positive bronchiolitis in hospitalized young infants is associated with thrombocytosis.

Study Objectives: To examine the hypothesis that children who suffered from severe respiratory syncitial virus (RSV) bronchiolitis during infancy may be at higher risk for obstructive sleep apnea (OSA) later in childhood., Methods: Survey of Kosair Children's Hospital medical records allowed for identification of potential candidates for the study. Twenty-one randomly selected children (mean age +/- SD: 5.2 +/- 1.5 years) with a history of verified RSV-induced bronchiolitis during their first year of life underwent overnight sleep study (NPSG). Children recruited from the general population with no history of RSV bronchiolitis served as a control group. After matching for age, gender, ethnicity, gestational age at birth, body mass index (BMI) z scores, household cigarette smoking, history of asthma and allergies, 63 control subjects (mean age +/- SD: 5.1 +/- 0.7 years) were also studied., Results: Children who had RSV bronchiolitis as infants had significantly higher obstructive apnea/hypopnea index compared to controls (2.3 +/- 1.9 vs. 0.6 +/- 0.8 /hr total sleep time (TST); P < 0.05). In addition, significantly higher respiratory arousal indices were apparent among children with previous RSV bronchiolitis compared to controls (1.3 +/- 1.0 vs. 0.1 +/- 0.2 /hr TST; P < 0.05). There were no significant differences between the groups in the lowest SpO(2), ETCO(2), and sleep indices., Conclusions: RSV bronchiolitis may contribute to the pathophysiology of OSA in vulnerable children.

To evaluate whether KL-6 concentration is a useful biomarker of the severity of respiratory syncytial virus (RSV) bronchiolitis, we determined KL-6 concentrations in patients with RSV bronchiolitis with or without chronic heart disease (CHD). We enrolled 52 patients who had been diagnosed with RSV bronchiolitis and required admission to the hospital at the Department of Pediatrics of Fukushima Medical University School of Medicine from 2004 to 2005. These patients were divided into two groups: Group 1 consisted of patients without any underlying disease, and Group 2 consisted of patients with CHD. These patients were assigned to three categories. Stage A consisted of patients without oxygen dosage, stage B of patients who required oxygen dosage, and stage C of patients required artificial respiration. We evaluated baseline characteristics, clinical features, and serum KL-6 concentration in Group 1, Group 2, and a control group (healthy infants without infection). Mean serum KL-6 concentrations in patients with RSV bronchiolitis were higher than those in the control group (471.8 +/- 236.9 and 127.1 +/- 69.1 U/ml, respectively). Mean serum KL-6 concentration was higher in Group 2 than in Group 1 (692.8 +/- 313.1 and 390.4 +/- 132.7 U/ml, respectively). Mean serum KL-6 concentrations were higher in stage C than in stages A and B, and mean serum KL-6 concentrations were higher in stage B than in stage A. These findings suggest that serum KL-6 is associated with the severity of RSV bronchiolitis and that it may be a useful biomarker for the severity of RSV bronchiolitis., ((c) 2009 Wiley-Liss, Inc.)

Bronchiolitis is the leading cause of hospitalization for children younger than 1 year of age and these hospitalized children have an increased risk for developing childhood asthma. It remains unclear, however, which children who have severe bronchiolitis (eg, an episode requiring hospitalization) will develop recurrent wheezing or asthma. Although many environmental and genetic factors may play a role in the pathway from bronchiolitis to asthma, this article focuses on the viruses that have been linked to bronchiolitis and how these viruses may predict or contribute to future wheezing and asthma. The article also discusses vitamin D as an emerging risk factor for respiratory infections and wheezing.

Plasmacytoid dendritic cells (pDC) play a crucial role in antiviral immunity and promoting Th1 polarization, possibly protecting against development of allergic disease. Examination of the relationship between peripheral blood plasmacytoid DC levels and manifestations of asthma and atopy early in life. We have isolated peripheral blood mononuclear cells (PBMC) from 73 children (mean age +/- SD: 6.6 +/- 0.5 yr old) participating in the RSV Bronchiolitis in Early Life (RBEL) study. Flow cytometry was performed on PBMC detecting DC surface-markers: Blood Dendritic Cell Antigens (BDCA) 1, 3, and 2 which identify myeloid type 1, type 2, and plasmacytoid cells, respectively. Total serum IgE, peripheral eosinophil count, and allergy skin tests were documented. About 45% (n = 33) of study participants had physician-diagnosed asthma by 6 yr of age. These children had significantly lower quantities (mean +/- SD) of plasmacytoid DC than their non-asthmatic counterparts (1020 +/- 921 vs. 1952 +/- 1170 cells per 10(6) PBMC, p = 0.003). We found significantly lower numbers of myeloid dendritic cells in children with asthma (3836 +/- 2472 cells per 10(6) PBMC) compared with those without asthma (4768 +/- 2224 cells per 10(6) PBMC, p = 0.02); however, this divergence was not significant after adjusting for covariates of age, gender, race, skin test reactivity, smoke exposure, and daycare attendance. We did not identify any direct association between DC levels and markers of atopy: skin test reactivity, peripheral eosinophilia, and IgE level. Children who are diagnosed with asthma after severe RSV bronchiolitis appear to have a relative deficiency of plasmacytoid DC in peripheral blood.

Rationale: Bronchiolitis during infancy is associated with an increased risk of childhood asthma. Whether winter viral infections cause asthma or are a manifestation of a predisposition to asthma development is unknown., Objectives: To study the relationship of winter virus infection during infancy and the development of childhood asthma., Methods: We studied over 95,000 infants born between 1995 and 2000 and followed through 2005 who were enrolled in the Tennessee Medicaid program from birth through early childhood to determine whether infant birth in relationship to the winter virus peak alters the risk of developing early childhood asthma., Measurements and Main Results: Among 95,310 children studied during five winter virus seasons from birth through early childhood, the risk of developing asthma tracked with the timing of infant birth in relationship to the winter virus peak. Infant birth approximately 4 months before the winter virus peak carried the highest risk, with a 29% increase in odds of developing asthma compared with birth 12 months before the peak (adjusted odds ratio, 1.29; 95% confidence interval, 1.19-1.40). Infant age at the winter virus peak was comparable to or greater than other known risk factors for asthma., Conclusions: Timing of birth in relationship to winter virus season confers a differential and definable risk of developing early childhood asthma, establishing winter virus seasonality as a causal factor in asthma development. Delay of exposure or prevention of winter viral infection during early infancy could prevent asthma.

Background: Immune response after viral infection usually involves T(H)1-mediated response; however, severe respiratory syncytial virus (RSV) infection appears to be associated with the development of asthma, a T(H)2-predominant phenotype., Objective: To understand the early and subsequent immunologic response to a serious RSV infection in children over time., Methods: A total of 206 previously healthy infants hospitalized with severe RSV bronchiolitis were enrolled in a prospective cohort called the RSV Bronchiolitis in Early Life study. Peripheral blood T cells were obtained immediately after RSV infection and at 2, 4, and 6 years of age, stimulated with phorbol 12-myristate 13-acetate and ionomycin, and analyzed for IL-2, IL-4, IL-13, and IFN-gamma by flow cytometry and real-time PCR., Results: Of the children, 48% (n = 97) developed asthma (physician-diagnosed), and 48% (n = 97) had eczema by age 6 years; 32% (n = 48 of 150) developed allergic sensitization by 3 years of age. Children with asthma had lower IL-13 expression at 6 years of age than those without (P = .001). IFN-gamma, IL-2, and IL-4 levels did not differ by asthma or eczema status during follow-up (all P > .05). Allergic sensitization was not associated with differences in cytokine levels during follow-up (all P > .05)., Conclusion: Severe RSV infection early in life is associated with a high incidence of asthma and eczema. Contrary to expectations, subsequent immunologic development in those who developed asthma, eczema, or allergic sensitization was not associated with a T(H)2 phenotype in the peripheral blood.

Viral respiratory infections are closely associated with wheezing illnesses and exacerbations of asthma throughout childhood, and yet there are a number of remaining questions pertaining to the specific nature of this relationship. Infection with an expanding list of respiratory viruses is an important cause of acute wheezing in infancy, and viruses are detected in most exacerbations of asthma throughout childhood. Furthermore, infants who develop severe viral respiratory infections are more likely to have asthma later in childhood. There has been progress in understanding the pathogenesis of viral respiratory illnesses, and this has led to new insights into how these processes might differ in asthma. Several host factors, including respiratory allergy and virus-induced interferon responses, modify the risk of virus-induced wheezing. In the absence of effective antiviral therapies, treatment of virus-induced wheezing and exacerbations of asthma can be challenging, and studies evaluating current treatment strategies are reviewed. Understanding the host-pathogen interactions that determine the severity of respiratory illnesses and long-term sequelae is likely to be of great help in identifying at-risk individuals, and in designing new and more effective treatments.

Objectives: The purpose of this study was to report the clinical features and outcome of all children with a laboratory proven diagnosis of respiratory virus infection admitted to a university Pediatric Intensive Care Unit (PICU)., Methods: Retrospective study between January 2003 and April 2007 was carried out in the PICU. Every child with a laboratory-confirmed viral infection was included., Results: 54 viruses were identified in 49 children (27 M, 22 F) over a 52-month period. The three respiratory virus species, respiratory syncytial virus (RSV) (n = 17), influenza (n = 13) and parainfluenza (n = 12), accounted for 86% of these 49 cases. PICU admissions due to influenza A (n = 10) were more common than influenza B (n = 3), whereas parainfluenza type 3 (n = 7) was the commonest subtype of parainfluenza infection. Comparing these three common viruses, the mean age of children admitted with RSV was lower than with influenza or parainfluenza (1.2 years vs. 5.6 years vs. 2.4 years, P = 0.003). Pre-existing conditions such as prematurity and chronic lung disease were only present in children with RSV infection. These respiratory viruses caused both upper (croup) and lower respiratory tract diseases (bronchiolitis, pneumonia). Extrapulmonary presentations were less prevalent and included encephalitis, seizures, cardiac arrest, coexisting diabetes ketoacidosis and acute lymphoblastic leukemia. One patient with RSV and another with influenza A died during their PICU stay. Nearly half of these patients required ventilatory support or received systemic corticosteroids, and 88% received initial broad spectrum antibiotic coverage. Approximately one in five of them had nebulised adrenaline, airway endoscopies or bacterial co-infections. Adenovirus was isolated in four patients and two (both with adenovirus type 3) died during the PICU stay., Conclusions: In PICU, respiratory viral infections were associated with significant morbidity and life-threatening conditions., ((c) 2008 Wiley-Liss, Inc.)