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Background: Viral bronchiolitis is a common condition and a leading cause of hospitalization in young children., Objective: This article provides readers with an update on the evaluation, diagnosis, and treatment of viral bronchiolitis, primarily due to RSV., Methods: A PubMed search was conducted in December 2021 in Clinical Queries using the key terms "acute bronchiolitis" OR "respiratory syncytial virus infection". The search included clinical trials, randomized controlled trials, case control studies, cohort studies, meta-analyses, observational studies, clinical guidelines, case reports, case series, and reviews. The search was restricted to children and English literature. The information retrieved from the above search was used in the compilation of this article., Results: Respiratory syncytial virus (RSV) is the most common viral bronchiolitis in young children. Other viruses such as human rhinovirus and coronavirus could be etiological agents. Diagnosis is based on clinical manifestation. Viral testing is useful only for cohort and quarantine purposes. Cochrane evidence-based reviews have been performed on most treatment modalities for RSV and viral bronchiolitis. Treatment for viral bronchiolitis is mainly symptomatic support. Beta-agonists are frequently used despite the lack of evidence that they reduce hospital admissions or length of stay. Nebulized racemic epinephrine, hypertonic saline and corticosteroids are generally not effective. Passive immunoprophylaxis with a monoclonal antibody against RSV, when given intramuscularly and monthly during winter, is effective in preventing severe RSV bronchiolitis in high-risk children who are born prematurely and in children under 2 years with chronic lung disease or hemodynamically significant congenital heart disease. Vaccines for RSV bronchiolitis are being developed. Children with viral bronchiolitis in early life are at increased risk of developing asthma later in childhood., Conclusion: Viral bronchiolitis is common. No current pharmacologic treatment or novel therapy has been proven to improve outcomes compared to supportive treatment. Viral bronchiolitis in early life predisposes asthma development later in childhood., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Our main objective was to compare the lung function, the rate of allergic sensitization and the prevalence of asthma at 7-9 years in children hospitalized for bronchiolitis with viral coinfection versus single viral infection. Observational study in children with previous bronchiolitis and current age 7-9 years. Clinical data were collected. Fraction of exhaled nitric oxide (FeNO) determination, spirometry and skin prick test for common aeroallergens were performed. A total of 181 children hospitalized for bronchiolitis (40 coinfections and 141 single infections), with median age of 8.3 years (IQR:7.5-9.1) were included. Single-HRV-infections showed lower basal FEV1(%) than coinfections (p = 0.04) and lower z-score FEV 1 than single-RSV-infections (p = 0.04) or coinfections (p = 0.02). Also, single-HRV-infections had lower post-bronchodilator FEV1(%) and z-score FEV 1 values than coinfections (p = 0.03 and p = 0.03). Single-HRV-bronchiolitis was an independent risk factor for FEV 1  < 80% (p = 0.007). FeNO value > 25 ppb was detected in 21(12.5%) cases, without differences between viral groups (p = 0.768). The prevalence of allergic sensitization was similar in coinfections (31.4%) versus single infections (38.7%), (p = 0.428). The highest frequency of allergic rhinitis was observed in single-HRV patients (p = 0.004). The respiratory morbidity at 7-9 years of coinfected patients was similar to the single-HRV ones. In contrast, the likelihood of current asthma was up to 5 times higher in RSV/HRV coinfections than in the single-RSV-infections ones (p = 0.012). The respiratory morbidity at 7-9 years of age after severe bronchiolitis is significantly higher in single-HRV or viral coinfection patients that in single-RSV ones. Single-HRV-bronchiolitis is independently associated with lower lung function at school-age., (© 2022. The Author(s).)

Respiratory syncytial virus (RSV) bronchiolitis is not only the leading cause of hospitalization in U.S. infants, but also a major risk factor for asthma development. While emerging evidence suggests clinical heterogeneity within RSV bronchiolitis, little is known about its biologically-distinct endotypes. Here, we integrated clinical, virus, airway microbiome (species-level), transcriptome, and metabolome data of 221 infants hospitalized with RSV bronchiolitis in a multicentre prospective cohort study. We identified four biologically- and clinically-meaningful endotypes: A) clinical classic microbiome M. nonliquefaciens inflammation IFN-intermediate , B) clinical atopic microbiome S. pneumoniae/M. catarrhalis inflammation IFN-high , C) clinical severe microbiome mixed inflammation IFN-low , and D) clinical non-atopic microbiome M.catarrhalis inflammation IL-6 . Particularly, compared with endotype A infants, endotype B infants-who are characterized by a high proportion of IgE sensitization and rhinovirus coinfection, S. pneumoniae/M. catarrhalis codominance, and high IFN-α and -γ response-had a significantly higher risk for developing asthma (9% vs. 38%; OR, 6.00: 95%CI, 2.08-21.9; P = 0.002). Our findings provide an evidence base for the early identification of high-risk children during a critical period of airway development.

Background: Viral respiratory infections, especially acute bronchiolitis, play a key role in the development of asthma in childhood. However, most studies have focused on respiratory syncytial virus or rhinovirus infections and none of them have compared the long-term evolution of single versus double or multiple viral infections., Objective: Our aim was to compare the frequency of asthma development at 6-8 years in children with previous admission for bronchiolitis associated with single versus double or multiple viral infection., Patients & Methods: A cross-sectional study was performed in 244 children currently aged 6-8 years, previously admitted due to bronchiolitis between September 2008 and December 2011. A structured clinical interview and the ISAAC questionnaire for asthma symptoms for 6-7-year-old children, were answered by parents by telephone. Specimens of nasopharyngeal aspirate for virological study (polymerase chain reaction) and clinical data were prospectively taken during admission for bronchiolitis., Results: Median current age at follow-up was 7.3 years (IQR: 6.7-8.1). The rate of recurrent wheezing was 82.7% in the coinfection group and 69.7% in the single-infection group, p = 0.06. The number of wheezing-related admissions was twice as high in coinfections than in single infections, p = 0.004. Regarding the ISAAC questionnaire, 30.8% of coinfections versus 15% of single infections, p = 0.01, presented "wheezing in the last 12 months", data that strongly correlate with current prevalence of asthma. "Dry cough at night" was also reported more frequently in coinfections than in single infections, p = 0.02. The strongest independent risk factors for asthma at 6-8 years of age were: age > 9 months at admission for bronchiolitis (OR: 3.484; CI95%: 1.459-8.317, p:0.005), allergic rhinitis (OR: 5.910; 95%CI: 2.622-13.318, p<0.001), and viral coinfection-bronchiolitis (OR: 3.374; CI95%: 1.542-7.386, p:0.01)., Conclusions: Asthma at 6-8 years is more frequent and severe in those children previously hospitalized with viral coinfection-bronchiolitis compared with those with single infection. Allergic rhinitis and older age at admission seem also to be strong independent risk factors for asthma development in children previously hospitalised because of bronchiolitis.

Objective: To verify whether the occurrence of acute viral bronchiolitis in the first year of life constitutes a risk factor for asthma at age 6 considering a parental history of asthma., Methods: Cross-sectional study in a cohort of live births. A standardized questionnaire of the International Study of Asthma and Allergies in Childhood was applied to the mothers to identify asthma in children at the age of 6 years. Acute viral bronchiolitis diagnosis was performed by maternal report of a medical diagnosis and/or presence of symptoms of coryza accompanied by cough, tachypnea, and dyspnea when participants were 3, 6, 9, and 12 months. Socioeconomic, environmental data, parental history of asthma, and data related to pregnancy were collected in the first 72h of life of the newborn and in prospective home visits by trained interviewers. The association between acute viral bronchiolitis and asthma was evaluated by logistic regression analysis and potential modifier effect of parental history was verified by introducing an interaction term into the adjusted logistic regression model., Results: Prevalence of acute viral bronchiolitis in the first year of life was 68.6% (461). The occurrence of acute viral bronchiolitis was a risk factor for asthma at 6 years of age in children with parental history of asthma OR: 2.66, 95% CI (1.10-6.40), modifier effect p=0.002. Parental history of asthma OR: 2.07, 95% CI (1.29-3.30) and male gender OR: 1.69, 95% CI, (1.06-2.69) were other identified risk factors for asthma., Conclusion: Acute viral bronchiolitis in the first year of life is a risk factor for asthma in children with parental history of asthma., (Copyright © 2016. Published by Elsevier Editora Ltda.)

Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.

Acute bronchiolitis is a common paediatric disease of infancy. Its association with subsequent asthma development has puzzled clinicians and epidemiologists for decades. This article reviews the current state of knowledge regarding the role of acute bronchiolitis in the inception of asthma. There is little doubt that acute bronchiolitis is associated with an increased risk of recurrent wheezing throughout the primary school years although the direction of causality--i.e. whether bronchiolitis in infancy leads to asthma or it merely represents the first clinical presentation of predisposition to asthma--is uncertain. Existing evidence suggests that both host factors (e.g. prematurity, atopic predisposition) and acute viral infection characteristics (e.g. type of virus, severity) are operating in this relationship, perhaps with variable involvement in different individuals. Further clarification of these issues will help paediatricians provide evidence-based information regarding the long-term prognosis of this common disease to the families, and at the same time, it will facilitate prophylactic approaches and therapeutic strategies., (© 2014 Asian Pacific Society of Respirology.)

Viral bronchiolitis is a major cause of hospitalization in infancy, with increased asthma risk in later childhood. However, the principal mechanisms behind post-bronchiolitic asthma have remained unclear. Previously, different cytokine polymorphisms have been associated with asthma occurrence, but no previous follow-up study has investigated cytokine polymorphisms in relation to post-bronchiolitic asthma. We hypothesized that former bronchiolitis patients with cytokine gene variants associating with Th2 cell up-regulation are at asthma risk at preschool age. Our emphasis was in IL10 rs1800896, since IL-10 has an important role in immune tolerance, and lower production of IL-10 has been associated with Th2-type immunology, and accordingly, with increased asthma risk. IL10 rs1800896, IFNG rs2430561, and IL18 rs1872387 polymorphims and their associations with asthma and allergy were studied in 135 preschool-aged children hospitalized for bronchiolitis at age 0-6 months. Parents were interviewed to record asthma and allergy from infancy to present. At age 6.4 years (mean), asthma was present in 17(12.6%), atopic eczema in 47(34.8%) and allergic rhinitis in 36(26.7%) children. IL10 rs1800896 SNP associated significantly with asthma; only 1/32 (3.1%) of those with G/G genotype had asthma (P = 0.04). In logistic regression adjusted for gender, age and atopy, the carriage of allele A (rs1800896) was a significant risk factor for preschool asthma. IFNG rs2430561 or IL18 rs1872387 SNP's had no associations with asthma or allergy. In conclusion, IL10 rs1800896 SNP was significantly associated with preschool asthma after severe lower respiratory tract infection in early infancy., (© 2013 Wiley Periodicals, Inc.)

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.)

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.)

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.)

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.

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.

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.)

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.)

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.

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.

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.

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.

Respiratory syncytial virus (RSV) bronchiolitis in early life is a risk factor for later development of asthma and atopy. Ribavirin is the only effective drug currently available against acute RSV bronchiolitis. However, the long-term effects of ribavirin remain unclear. We investigated a cohort of children hospitalized with RSV bronchiolitis from when they were under 2 yr old until they reached a mean age of 6.2 yr. In total, we enrolled 175 children in this study. Both the group treated with ribavirin and the group not treated with ribavirin included high-risk young children with congenital heart disease or chronic lung disease. Their respective age-matched controls, that we labeled groups A and B, both without ribavirin treatment, consisted of previously healthy subjects. Wheezing was either verified by physicians or estimated by a questionnaire. Allergen sensitization was judged by serum allergen-specific IgE levels. The cumulative incidence of physician-diagnosed asthma or recurrent wheezing in the ribavirin group (15%) was significantly lower than its incidence in the non-ribavirin-treated group (34%, p = 0.049), and in the control A group (43%, p = 0.005). Allergen sensitization was also least frequent in the ribavirin group. Ribavirin therapy was an independent factor in reducing the risk of developing asthma, asthma/recurrent wheezing, and sensitization to D. pteronyssinus/D. farinae. The long-term value of ribavirin for acute RSV bronchiolitis and its underlying mechanisms deserves further research.

Background: Recent studies have stressed the influence of other viruses than respiratory syncytial virus (RSV) in the development of asthma in later childhood after bronchiolitis in infancy. However, the virus-specific prognosis until adulthood has remained obscure, due to lack of sufficiently long follow-up studies. The aim of the present study was to evaluate adult respiratory morbidity after bronchiolitis in infancy, focused on cases not caused by RSV., Methods: A total of 54 children hospitalized for bronchiolitis at age <2 years were re-studied at median age 19 years; 22 with RSV bronchiolitis and 22 with non-RSV bronchiolitis outside RSV epidemic were included. RSV etiology was studied by antigen and antibody assays on admission. Adult asthma was defined by two ways, based on written questionnaire, clinical examination and home peak expiratory flow monitoring. Lung function was evaluated by flow-volume spirometry (FVS), bronchial reactivity by methacholine inhalation challenge (MIC), and atopy by skin prick tests (SPT)., Results: In the non-RSV group, asthma by two definitions was present in 41-50% (vs 18-27% in RSV group). In logistic regression, adjusted for gender, age on admission, current atopy and smoking, non-RSV etiology of bronchiolitis, compared with RSV etiology, increased asthma risk by both strict (odds ratio [OR], 8.34; 95% confidence interval [CI], 1.18-58.69) and less strict (OR, 7.93; 95% CI, 1.14-55.41) criteria. An abnormal result in FVS was present in 32-41% and in MIC in 48-52% of cases in non-RSV and RSV groups, respectively., Conclusions: Infants with non-RSV bronchiolitis requiring treatment in hospital are at an increased risk for subsequent asthma in adulthood.

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.

Viral infections are important causes of asthma exacerbations in children, and lower respiratory tract infections (LRTIs), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis are at significantly increased risk for both recurrent wheezing and childhood asthma. To date, studies addressing the incidence of asthma after bronchiolitis severe enough to warrant hospitalization have focused almost exclusively on RSV, but a number of recent studies suggest that other respiratory pathogens, including RV, may contribute as well. It is not known whether viral bronchiolitis directly contributes to asthma causation or simply identifies infants at risk for subsequent wheezing, as from an atopic predisposition or preexisting abnormal lung function. Alternatively, the properties of the infecting virus may be important. Thus, many possible determinants exist that may contribute to the severity of bronchiolitis and the subsequent development of asthma. One such determinant is the potential involvement of genetic susceptibility loci to asthma after viral bronchiolitis, a critical area that is just beginning to be evaluated. By clarifying the roles of both host- (genetic) and virus- (environment) specific factors that contribute to the frequency and severity of viral LRTI, it may be possible to determine if severe LRTIs cause asthma, or if asthma susceptibility predisposes patients to severe LRTI in response to viral infection. Characterizing these relationships offers the potential of identifying at-risk hosts in whom preventing or delaying infection could alter the phenotypic expression of asthma.

Respiratory viral infections have been implicated in the origin of, protection from and exacerbation of allergy-related symptoms in a variety of ways. Viral infections are closely linked to infantile wheezing. Severe bronchiolitis in early infancy may predispose to chronic childhood asthma as well as allergic sensitization; alternatively it could represent a marker of susceptible individuals. In contrast, repeated mild infections in early life may have a protective role in the development of asthma or atopy by driving the immune system towards Th1 responses. However, evidence on this hypothesis is not consistent as far as respiratory viruses are concerned. Several factors, including the presence of an atopic environment, timing of exposure and severity of the infection, interactively contribute to the allergy-infection relationship. In the present report, recent data on the role of viral infections in the development and progression of allergy and asthma are reviewed.

Background: The relationship between early infections due to respiratory syncytial virus (RSV), particularly bronchiolitis in infancy, and the subsequent development of asthma, bronchial hyper-responsiveness, and/or other allergic manifestations, seems increasingly certain, even if the mechanisms involved are not yet quite clear., Objectives: The objectives of this work were to determine the prevalence of, and risk factors for, asthma and allergy in 5 to 6 year-old children who five years previously, had experienced their first episode of bronchiolitis before the age of twelve months, and to define the possible effect of the age at which the bronchiolitis occurred on the subsequent development of asthma., Method: A retrospective cohort survey was conducted, based on the registers of two hospital paediatric emergency units (Unit A: the Ambroise Pare teaching hospital at Boulogne, France and unit B: the General Hospital of Cherbourg, France). The cohort comprised 5-6 years old children who had consulted or been admitted to emergency unit A or B between October 1993 and March 1994 for a first attack of bronchiolitis before the age of 12 months., Results: One hundred and twenty eight children were included in the two centres (centre A: 78; centre B: 50). A familial history of allergy was found in 92 children (71.8%). Fifty-two (40.6%) were exposed to tobacco smoke. One hundred and five children (81.2%) had been hospitalised during the first episode of bronchiolitis, but none had been placed in intensive care. Their mean age at admission was 5.1 months, and 29 children were less than three months old. Ninety seven children (75.8%) had experienced at least one episode of wheezing at some time of their life. In the twelve months before the telephone interview, 40 children (31.3%) had had at least one such episode, 47 (36.7%) an attack of asthma, 32 (25.0%) wheezing after an effort, 43 (39.4%) a dry cough at night, 52 children (40.6%) had exhibited allergic rhinitis signs, and 32 (25.0%) eczema. Among the 47 children who had experienced at least one attack of asthma during the previous twelve months, 27 (57.4%) had a history of familial asthma (p<0.04). This was the only significant relationship observed in this study with regard to risk factors for asthma. No relationship was observed between asthma or recent wheezing on the one hand, and on the others age less than three months during the first bronchiolitis episode (p=0.6), initial hospital admission (p=0.6) tobacco smoke exposure (p=0.27), sex (p=0.10) or day care management until age three (p=0.73)., Discussion: This study showed a high prevalence of asthma and other allergic manifestations in children who five years previously, had experienced their first bronchiolitis episode before the age of twelve months. The only risk factor for asthma or chest wheezing identified in this study was a familial history of allergy. These data support the idea that for most children, early acute bronchiolitis, even if severe, is a transient event, with no or very few consequences in the middle or long term. Nevertheless it may be the expression of an interaction between viral infection and atopic familial predisposition leading to lasting bronchial hyper-responsiveness.

Background: Viral respiratory tract infections cause significant morbidity and mortality. Respiratory viruses are suspected to play a role in the inception of asthma early in life. Respiratory syncytial virus (RSV) is the most common cause of infant bronchiolitis, which is associated with the development of childhood wheezing and asthma. However, it is not clear whether this association is "causal" or "circumstantial.", Methods: Animal models have been pivotal in studying the pathophysiology of viral respiratory infections. Various approaches to assessing airway inflammation and function have been used to define the mechanisms of virus-induced airway dysfunction and to address clinically relevant questions regarding the role of RSV in wheezing and asthma after bronchiolitis., Results: Viral lower respiratory tract infections alter airway function in humans and animals. The extent and duration of the alterations may depend on the virus itself, host factors and environmental factors. Animal studies demonstrated that viral infection induces airway hyperresponsiveness and enhances this alteration in the allergen-sensitized and exposed host. This altered airway function is mediated by immune and neurogenic inflammatory mechanisms. Recent studies in mice show that neonatal RSV infection sensitizes the newborn to develop an asthma-like phenotype on reinfection, providing further opportunities to investigate the role of RSV in postbronchiolitis wheezing and asthma in this animal model., Conclusions: Further studies are needed to fully establish the mechanisms underlying the pathophysiology of viral respiratory tract infections and to clarify their role in the inception and/or progression of chronic airway diseases such as asthma. The results of ongoing therapeutic studies promise to minimize the impact of such viral infections.

Objective: The purpose of the study was to evaluate asthma at >13 y of age in children with infantile bronchiolitis or pneumonia., Methods: In 1981-1982, 127 children at <2 y of age were hospitalized for bronchiolitis (n = 81) or pneumonia (n = 46). Respiratory syncytial virus (RSV) infection, eosinophilia and markers of atopy were assessed and recorded on admission. At a median age of 14.9 y, atopic and asthmatic symptoms were screened by a written questionnaire in 98/127 (77%) study subjects., Results: Asthma was present, according to two definitions, in 14% to 23% in the original bronchiolitis and in 12% to 15% in the original pneumonia group. The figures were 8% to 17% in the RSV infection and 16% to 23% in the non-RSV infection group. Early asthma-predictive factors were repeated wheezing, atopic dermatitis and elevated blood eosinophils. All but one of the teenage asthmatics had allergic rhinitis., Conclusion: An increased risk for asthma persists until the teenage period after bronchiolitis and pneumonia in infancy. Both early and later atopy were significant risk factors. The present study was unable to demonstrate the association between early RSV infection and teenage asthma.

Background: Viral bronchiolitis in infancy has been identified in previous studies as a potential precursor to the development of lower respiratory tract illness in later childhood and beyond., Objective: To evaluate the long-term respiratory repercussions of acute infantile viral bronchiolitis., Methods: We studied 71 individuals aged 19 to 24 years with a history of a viral bronchiolitis in infancy and 32 controls. All participants underwent the following evaluation: medical history, forced spirometry, methacholine challenge, and skin prick testing., Results: The bronchiolitis group had a higher prevalence of respiratory symptoms (P = .03) and bronchial hyperresponsiveness (P = .003) than controls. The bronchiolitis group also had a lower peak expiratory flow rate (P = .02). Skin prick test responses were similar in both groups., Conclusions: The findings from this study support and extend those from previous studies by suggesting that viral bronchiolitis may be a predisposing factor for lower respiratorytract problems in young adulthood.

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.

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.

Infants who recover from respiratory syncytial virus (RSV)-induced bronchiolitis are at high risk of developing asthma and recurrent wheezing. It is not known whether severe RSV infection itself causes persistent effects or is a marker of a "wheezy" predisposition. To determine the long-term immunological correlates of infantile bronchiolitis, interleukin (IL)-4 and interferon (IFN)-gamma responses to a panel of antigens were studied in a well-characterised cohort of 7-8-yr-old children with a history of severe RSV bronchiolitis in infancy. Peripheral blood lymphocytes from 37 children who were hospitalised with RSV bronchiolitis in infancy and from 69 age-, sex- and location-matched controls were stimulated in vitro with RSV, house-dust mite, birch and cat antigens. Cellular proliferation, and enzyme-linked immunoSPOT IFN-gamma and IL-4 production were measured. IL-4 producing T-cells responding to RSV and cat antigens were significantly more frequent in exbronchiolitics. Other responses (including the IFN-gamma response to RSV) were equally strong in exbronchiolitics and controls. Respiratory syncytial virus infection primes memory T-cells that make interferon-gamma, but virus and aeroallergen-specific and interleukin-4 producing T-cells are also frequently primed in bronchiolitics. Respiratory syncytial virus bronchiolitis in infancy may increase the risk of allergic sensitisation by providing a local interleukin-4-rich environment, in which airborne allergens are first encountered.

Relationships between lower respiratory diseases with wheezing during infancy and asthma at school-age remain debatted. Indeed, although epidemiologic studies show that wheezy infants most often become asymptomatic before entry to school, they also demonstrate that severe bronchiolitis during infancy is a significant risk factor for persistence of wheezing episodes at school-age. One of the most important factors demonstrated to enhance the risk for persistence of asthma is an early allergic sensitization.