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Background: Vitamin D deficiency at birth has been reported as a risk factor for respiratory syncytial virus (RSV) lower respiratory tract infection during the first year of life. Limited data are available on whether an infant's vitamin D status is associated with the severity of acute RSV bronchiolitis., Methods: Infants < 1 year of age and hospitalized with their first episode of RSV bronchiolitis were enrolled into the RSV Bronchiolitis in Early Life II cohort. We investigated the relationships between vitamin D status at enrollment and the following indicators of bronchiolitis severity: duration of hospitalization, lowest oxygen saturation measured during hospitalization, and bronchiolitis severity score., Results: Among the 145 enrolled infants, the median (quartile 1 [Q1], Q3) serum 25-OH-VitD level was 36.8 (29.8, 42.3) ng/mL, with 14 infants (9.7%) having deficient serum vitamin D levels (25-OH-VitD <20 ng/mL). Vitamin D-deficient infants were younger than infants with 25-OH-VitD ≥ 20 ng/mL (2.8 vs 4.5 months, respectively; P = .04) and were less likely to consume infant's formula (42.9% vs 87.0%, respectively; P < .01). The following indicators of acute bronchiolitis severity did not differ between infants who were vitamin D-deficient and nondeficient: duration of hospitalization (P = .53), lowest oxygen saturation (P = .45), and bronchiolitis severity score (P = .97), even after adjusting for age, and for infant's formula consumption., Conclusions: Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not associated with indicators of acute bronchiolitis severity.

Background: Respiratory syncytial virus (RSV) bronchiolitis in infancy is a major risk factor for recurrent wheezing and asthma. Because azithromycin attenuated neutrophilic airway inflammation in a murine viral bronchiolitis model, demonstration of similar effects in human subjects might provide a strategy for the prevention of postbronchiolitis recurrent wheezing., Objectives: We sought to investigate whether azithromycin treatment during RSV bronchiolitis reduces serum and nasal lavage IL-8 levels and the occurrence of postbronchiolitis recurrent wheezing., Method: We performed a randomized, double-masked, placebo-controlled proof-of-concept trial in 40 otherwise healthy infants hospitalized with RSV bronchiolitis who were treated with azithromycin or placebo for 14 days. IL-8 levels were measured in nasal lavage fluid and serum on randomization, day 8, and day 15 (nasal lavage only). The occurrence of wheezing episodes was assessed monthly over the ensuing 50 weeks., Results: Compared with placebo, azithromycin treatment did not reduce serum IL-8 levels at day 8 (P = .6) but resulted in a greater decrease in nasal lavage fluid IL-8 levels by day 15 (P = .03). Twenty-two percent of azithromycin-treated participants experienced at least 3 wheezing episodes compared with 50% of participants in the placebo group (P = .07). Azithromycin treatment resulted in prolonged time to the third wheezing episode (P = .048) and in fewer days with respiratory symptoms over the subsequent year in comparison with placebo (36.7 vs 70.1 days, P = .01)., Conclusion: In this proof-of-concept study azithromycin treatment during RSV bronchiolitis reduced upper airway IL-8 levels, prolonged the time to the third wheezing episode, and reduced overall respiratory morbidity over the subsequent year., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

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.

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.

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.

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.

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.

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.

Although eosinophilia in wheezing infants predicts subsequent wheezing, it is not known how long the association persists. Our aim was to evaluate the connection between blood eosinophilia in infancy and later wheezing/asthma until adulthood, with special attention paid to infection-induced changes in blood eosinophils. We have prospectively followed up 83 infants until adulthood after hospitalization for bronchiolitis in 1981-1982. Blood eosinophils were determined in a counting chamber on admission and on convalescence 4-6 weeks later. Data on recurrent wheezing and asthma were registered prospectively at five follow-ups until the age of 18-20 years. The median (25th-75th percentile) eosinophil count was 0.100 x 10E9/L (0.028-0.321) on admission and 0.231 x 10E9/L (0.119-0.368) on convalescence. Eosinophils during bronchiolitis or infection-induced changes in eosinophils were not associated with subsequent wheezing/asthma at any age during the follow-up. The result was similar in univariate and multivariate analyses. Respiratory syncytial virus (RSV) bronchiolitis patients had lower eosinophils on admission than non-RSV cases, but the changes induced by RSV or other infection did not differ significantly. In univariate analyses, elevated eosinophils on convalescence predicted later wheezing until 3-4 years of age. In multivariate analysis, adjusted for RSV etiology, age on admission, and histories of earlier wheezing and atopy, elevated eosinophils on convalescence predicted increased asthma risk at 2-3 years (OR, 2.26; 95% CI, 1.29-3.95), at 3-4 years (OR, 2.24; 95% CI, 1.27-3.95), and at 8.5-10 years (OR, 2.16; 95% CI, 1.01-4.64). Eosinophilia outside, but not during, infection predicted recurrent wheezing until preschool and early school years but not thereafter.

This review examines the relationship between severe pulmonary disease caused by respiratory syncytial virus (RSV) infection in infancy and later development of asthma or reactive airway disease (RAD). RSV infection accounts for 70% or greater of all cases of infantile bronchiolitis and has been linked to subsequent asthma or RAD, either directly or through a shared common predisposition. Several studies suggest that RSV bronchiolitis is an important factor in the development of asthma and possibly atopy, although the association is lost by the age of 13 years. The mechanism is as yet unclear, but murine models of RSV disease have identified many plausible causal explanations. Further study is necessary to determine the relative roles of RSV infection and genetic predisposition in explaining the association between RSV infection and asthma/RAD.

Treatment of respiratory syncytial virus bronchiolitis rests primarily on supportive care with oxygen and fluid management. Other therapies commonly used include bronchodilators, corticosteroids and ribavirin, when considered appropriate. Small studies have also suggested that exogenous surfactant, helium/oxygen mixtures (heliox) and combination therapies may offer clinical benefit as well. Management of bronchiolitis can be facilitated by (1) recognizing the risks and benefits of various therapies, (2) understanding the markers of disease severity and (3) gaining familiarity with the time course of viral replication compared with presentation of symptoms. Although oxygen administration and judicious fluid replacement are the only interventions proved to be of reliable benefit to infants with bronchiolitis, newer studies support a role for adjunctive therapies aimed at relieving airway obstruction, especially when administered very early in the course of the illness or given to infants with more severe disease.

There is now convincing evidence that children who develop lower respiratory symptoms during infection with respiratory syncytial virus (RSV) in early life are at increased risk of developing asthma-like symptoms during the school years. What determines this association is not well-understood, but increased likelihood of allergic sensitization plays a minor role, if any, as a determinant of post-RSV wheeze. Current evidence suggests that both genetic and environmental factors determine the type of immune response to the acute RSV infection and that this response, in turn, may affect the development of the control mechanisms involved in the regulation of airway tone. Many different cytokines appear to play a role in this acute immune response, including interferon-gamma; interleukins 8, 10 and 12; and cytokines produced by T helper (Th) 1 and Th2 cells. Because asthma is a heterogeneous condition, future studies will need to determine the potentially different role of RSV infection as a risk factor for these different asthma phenotypes. It is likely, however, that strategies for the prevention of RSV infection may play a role in the prevention of the subsequent development of persistent wheezing and asthma-like symptoms in childhood.

Respiratory syncytial virus is an extremely common cause of childhood respiratory infections resulting in significant morbidity and mortality. Although apnea is a well-known complication in young infants with respiratory syncytial virus bronchiolitis, the encephalopathy associated with this infection is not well recognized. Our study reveals an incidence of encephalopathy of 1.8% in a total of 487 patients with respiratory syncytial virus bronchiolitis studied over a period of almost 4 years. Seizures were the presenting complication. Based on our study of a cohort of children with respiratory syncytial virus bronchiolitis, we believe that neurologic complications, although relatively uncommon, represent a significant component of this common childhood illness. Furthermore, respiratory syncytial virus has been shown to release several mediators that could directly or indirectly be neurotoxic and induce an encephalopathy associated with the respiratory illness.