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Importance: Rhinovirus infection in early life, particularly with allergic sensitization, is associated with higher risks of developing recurrent wheeze and asthma. While emerging evidence links different rhinovirus species (eg, rhinovirus C) to a higher severity of infection and asthma exacerbation, to our knowledge, little is known about longitudinal associations of rhinovirus C infection during infancy with subsequent morbidities., Objective: To examine the association of different viruses (respiratory syncytial virus [RSV], rhinovirus species) in bronchiolitis with risks of developing recurrent wheeze., Design, Setting, and Participants: This multicenter prospective cohort study of infants younger than 1 year who were hospitalized for bronchiolitis was conducted at 17 hospitals across 14 US states during 3 consecutive fall to winter seasons (2011-2014)., Exposures: Major causative viruses of bronchiolitis, including RSV (reference group) and 3 rhinovirus species (rhinovirus A, B, and C)., Main Outcomes and Measures: Development of recurrent wheeze (as defined in national asthma guidelines) by age 3 years., Results: This analytic cohort comprised 716 infants who were hospitalized for RSV-only or rhinovirus bronchiolitis. The median age was 2.9 months (interquartile range, 1.6-3.8 months), 541 (76%) had bronchiolitis with RSV only, 85 (12%) had rhinovirus A, 12 (2%) had rhinovirus B, and 78 (11%) had rhinovirus C infection. Overall, 231 (32%) developed recurrent wheeze by age 3 years. In the multivariable Cox model, compared with infants with RSV-only infection, the risk of recurrent wheeze was not significantly different in those with rhinovirus A or B (rhinovirus A: hazard ratio [HR], 1.27; 95% CI, 0.86-1.88; rhinovirus B: HR, 1.39; 95% CI, 0.51-3.77; both P > .10). By contrast, infants with rhinovirus C had a significantly higher risk (HR, 1.58; 95% CI, 1.08-2.32). There was a significant interaction between virus groups and IgE sensitization on the risk of recurrent wheeze (P for interaction < .01). Only infants with both rhinovirus C infection and IgE sensitization (to food or aeroallergens) during infancy had significantly higher risks of recurrent wheeze (HR, 3.03; 95% CI, 1.20-7.61). Furthermore, compared with RSV-only, rhinovirus C infection with IgE sensitization was associated with significantly higher risks of recurrent wheeze with subsequent development of asthma at age 4 years (HR, 4.06; 95% CI, 1.17-14.1)., Conclusions and Relevance: This multicenter cohort study of infants hospitalized for bronchiolitis demonstrated between-virus differences in the risk of developing recurrent wheeze. Infants with rhinovirus C infection, along with IgE sensitization, had the highest risk. This finding was driven by the association with a subtype of recurrent wheeze: children with subsequent development of asthma.

Background: Studies suggest an effect of nebulized hypertonic saline solution on air-flow limitation in subjects with respiratory syncytial virus (RSV) bronchiolitis, but results are based on subjective scores of clinical severity and are not clear. In this observational study, we used a noninvasive computerized tool to quantify wheezing before and after nebulization with hypertonic saline in children admitted for RSV infection., Methods: Twenty-seven children (≤ 24 months old) admitted to the pediatric ward of the Medical Center Leeuwarden with polymerase chain reaction-confirmed RSV bronchiolitis were included. Subjects were simultaneously assessed both clinically and by computerized acoustic monitoring before and 15 min after treatment with nebulized hypertonic saline solution., Results: Clinical assessment, defined by the Respiratory Distress Assessment Instrument score, did not change after nebulization (n = 27, 5.0 vs 4.7, P = .17). Computerized acoustic monitoring showed no improvement in wheezing (n = 27, 3.4% vs 2.0%, P = .05) or inspiration/expiration ratio (0.85 vs 0.85, P = .93) after nebulization., Conclusions: Hypertonic saline nebulization does not improve air flow, as assessed by both clinical and computerized acoustic scores, in children admitted for RSV., (Copyright © 2015 by Daedalus Enterprises.)

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.)

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.

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.)

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.

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.

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.

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.

Unlabelled: The objective of this study was to investigate the association hypothesis that outcome following respiratory syncytial virus (RSV) induced bronchiolitis (RSVB) and RSV induced wheeze (RSVW) are different. At 3 years respiratory symptoms were more common in those with RSV infection than the control group but there was no increase in allergic sensitisation (11% vs 10%). Those with RSVW were more likely to have evidence of allergic sensitisation when compared with RSVB subjects (22% vs 7%), and have increased symptoms and increased use of inhaled steroids., Conclusion: The data argue that RSV infection during infancy does not induce allergic asthma and that host factors rather than the virus determine long-term outcomes.

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.

Background: Acute viral bronchiolitis is one of the most common causes of hospitalisation during infancy in our region with respiratory syncytial virus (RSV) historically being the major causative agent. Many infants with early-life RSV bronchiolitis have sustained bronchial hyperreactivity for many years after hospitalisation and the reasons for this are probably multifactorial. The principal aim of the present study was to investigate if children hospitalised for any acute viral bronchiolitis during infancy in our region, and not only those due to RSV, had more episodes of subsequent wheezing up to age seven years and reduced lung function at that age compared to children not hospitalised for acute bronchiolitis during infancy. A secondary aim was to compare the hospitalised infants with proven RSV bronchiolitis (RS+) to the hospitalised infants with non-RSV bronchiolitis (RS-) according to the same endpoints., Methods: 57 infants hospitalised at least once with acute viral bronchiolitis during two consecutive winter seasons in 1993-1994 were examined at age seven years. An age-matched control group of 64 children, who had not been hospitalised for acute viral bronchiolitis during infancy, were recruited from a local primary school. Epidemiological and clinical data were collected retrospectively from hospital discharge records and through structured clinical interviews and physical examinations at the follow-up visit., Results: The children hospitalised for bronchiolitis during infancy had decreased lung function, more often wheezing episodes, current medication and follow-up for asthma at age seven years than did the age matched controls. They also had lower average birth weight and more often first order family members with asthma. We did not find significant differences between the RSV+ and RSV- groups., Conclusion: Children hospitalised for early-life bronchiolitis are susceptible to recurrent wheezing and reduced pulmonary function by seven years compared to age-matched children not hospitalised for early-life bronchiolitis. We propose that prolonged bronchial hyperreactivity could follow early-life RSV negative as well as RSV positive bronchiolitis.

Background: Respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) is often followed by recurrent wheezing episodes during childhood. The effect of postbronchiolitis wheezing on the well-being of the child is not known. This study aimed to determine the impact of RSV LRTI hospitalization before age 13 months on health-related quality of life (HRQoL) at age 3 years., Methods: HRQoL was measured in a previously described cohort of children with a history of RSV infection and compared with control term children from the open population. HRQoL was determined during the winter season in index and control children. We used a validated questionnaire, which measures the health status of children in 13 domains weighted by the impact of the health status problems on well-being. The lung domain was the focus of this study. In addition daily respiratory symptoms of the index children were recorded prospectively up to age 3 years and correlated with HRQoL scores., Results: HRQoL was lower in index children (n = 128) than in control children (n = 340) for the lung, gastrointestinal tract and sleeping domains. HRQoL scores for social and developmental domains were similar for index and control children. As anticipated the largest difference between index and control children was found in the lung domain (77.6 +/- 2.2 vs. 93.9 +/- 0.8, P < 0.01). HRQoL in the lung domain was lower during the winter than during the summer season (77.6 +/- 2.2 vs. 85.6 +/- 1.9, P < 0.01), which was explained by increased airway morbidity during the winter season. We found a high correlation between lung HRQoL scores and total number of wheezing days during follow-up., Conclusions: Postbronchiolitis wheezing has broad implications for long-term well-being of children. Decreased HRQoL was attributed to postbronchiolitis wheezing, but not to preexistent risk factors, such as premature birth. This study underscores the importance of developing new strategies to prevent and treat long term airway morbidity after RSV LRTI.

Severe respiratory syncytial virus (RSV) infection has been hypothesised to be a risk factor for the development of allergy and asthma, but epidemiological studies in older children have been inconclusive. The current study hypothesises that the effect of RSV bronchiolitis might be most prominent during the first year after bronchiolitis. Forty-two infants had experienced RSV bronchiolitis severe enough to cause hospitalisation. For each child with RSV infection, two controls were acquired from a birth cohort and matched for date of birth and sex. All the children were followed prospectively and underwent a follow-up examination at a mean age of 1 yr, which included physical examination, and serum immunoglobulin (Ig) E tests for common food and inhaled allergens. Risk factors for the development of recurrent wheezing and IgE antibodies were analysed for the whole group of 126 children. A positive test for IgE antibodies was noted in 14 of 42 (33%) RSV children and in 2 of 84 (2.3%) children in the control group. RSV bronchiolitis was the most important risk factor for allergic sensitisation. Likewise, 13 children (15.5%) of the RSV group and three (3.6%) children of the control group suffered from recurrent wheezing, and RSV bronchiolitis posed a considerable risk for recurrent wheezing. Severe respiratory syncytial virus bronchiolitis during the first year of life is an important risk factor for the development of recurrent wheezing and sensitisation to common allergens during the subsequent year.

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.

Background: There is some information about wheeze characteristics in infants, however it is not clear whether the different wheeze patterns relates to prognosis and evolution during the first two years of life., Objectives: To characterize wheezing and spectral pattern of lung sounds in infants with acute bronchiolitis (AB) and in infants with recurrent wheeze (RW) as well as to compare these parameters with the clinical evolution 2 years after admission., Methods: Seventy six AB infants (48 boys), aged 5.5 +/- 0.7 months (mean +/- SD), 62 RSV (+) and 32 RW infants (20 boys), aged 11.4 +/- 2 months were studied during the first week of admission at the hospital. Patients were studied during spontaneous sleep, breathing with a face mask connected to a pneumotachograph at flows of 0.1 +/- 0.02 L/s. Sounds were registered at baseline and 20 minutes after salbutamol using 2 contact sensors placed at both lower lobes levels. Signals were low-pass filtered, amplified and a Fourier analysis was applied to sounds within a target flow range. Spectral analysis was done between 100 and 1000 HZ., Results: In 40/76 (53%) AB vs 30/34 (88%) RW sinusoidal wheezing (p < 0.01; chi 2) were observed and a positive bronchodilator response was obtained in 37/76 (49%) AB vs 32/34 (94%) RW (p < 0.01; chi 2). Patients with sinusoidal wheezing (s-w) had more wheezing episodes in follow-up, 26/40 vs 8/36 in complex wheezing (c-w), (p < 0.01: chi 2) and 30/34 in RW (p < 0.01; chi 2). IgE values at 18 months were higher in s-w compared to c-w (63 +/- 7 vs 24 +/- 5 Iu/mL (p < 0.01) and 96 +/- 11 Iu/mL in RW (p < 0.01)., Conclusions: a) Wheezing characteristics in acute bronchiolitis vs recurrent wheezing are different; b) Bronchodilator response relates to wheeze characteristics and c) Higher IgE and more recurrent wheezing episodes are seen in acute bronchiolitis with sinusoidal wheezing. These findings suggest that lung sounds analysis is useful in assessing wheezy patients and have a value to identify infants on risk of developing asthma.

Despite differences in study design, follow-up studies consistently show that approximately half of the infants with respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) go on to have recurrent wheezing episodes during childhood. Respiratory symptoms are associated with abnormal lung function, including bronchial hyper-responsiveness. Wheezing symptoms following RSV LRTI gradually decrease, and it appears that during school age airway morbidity is no longer related to RSV LRTI during infancy. Mechanisms underlying the association between RSV LRTI and long-term airway morbidity are poorly understood. On the one hand, abnormal airway function that is congenitally present or acquired before RSV LRTI occurs could be the cause of both RSV LRTI and subsequent recurrent wheezing. On the other hand, it is possible that RSV LRTI causes changes in the lower airways or the immune system that result in long-term airway morbidity. Animal models suggest that RSV infection can promote the development of allergic sensitization, but most studies in humans do not indicate a role for atopy in the development of recurrent wheezing following RSV LRTI.

Respiratory syncytial virus (RSV) bronchiolitis is associated with subsequent recurrent wheezing episodes. To determine whether cytokine responses during infection can be of predictive value for the development of recurrent wheezing, we performed a follow-up study in 50 hospitalized children with RSV bronchiolitis. Monocyte and lymphocyte cytokine responses in vitro were studied during the acute phase of disease, and again during the convalescent phase, 3 to 4 wk later. Monocyte cytokine responses, including interleukin-10 (IL-10), were measured in whole blood cultures, stimulated with lipopolysaccharide and interferon-gamma (LPS + IFN-gamma). In addition, T-cell cytokine responses, including IFN-gamma and IL-4 production, were measured in whole-blood cultures stimulated with phytohemagglutinin (PHA) or alphaCD2 + alphaCD28. Cytokine responses were analyzed in relation to the development of recurrent episodes of wheezing, documented by parents in a diary during a 1-yr follow-up period. IL-10 responses during the acute phase of RSV bronchiolitis were comparable to those in healthy control subjects. During the convalescent phase, IL-10 responses were significantly increased in patients as compared with those in healthy control subjects (p < 0.001). At follow-up, 27 children (58%) had recurrent episodes of wheezing. IL-10 levels, measured during the convalescent phase, were significantly higher in patients who developed recurrent wheezing during the year after RSV bronchiolitis than in patients without recurrent episodes of wheezing (p = 0.006). Moreover, IL-10 responses during the convalescent phase correlated significantly with the number of wheezing episodes (r = 0.42, n = 46, p = 0.004). Interestingly, no association was found between IFN-gamma responses, IL-4 responses, or IFNgamma/IL-4 ratios and recurrent wheezing. We conclude that monocyte IL-10 responses in vitro upon stimulation with nonspecific stimuli may have predictive value for the development of recurrent wheezing after RSV bronchiolitis. Moreover, our results indicate that not only allergen-driven Th2 cytokine responses can lead to asthmatic symptoms but also virus-induced changes in cytokine responses may result in asthmatic symptoms.

Background: Previous studies suggest that recurrent episodes of coughing and wheezing occur in up to 75% of infants after acute viral bronchiolitis., Aim: To assess the efficacy of budesonide given by means of a metered dose inhaler, spacer, and face mask in reducing the incidence of coughing and wheezing episodes up to 12 months after acute viral bronchiolitis., Methods: Children under the age of 12 months admitted to hospital with acute viral bronchiolitis were randomised to receive either budesonide or placebo (200 microg or one puff twice daily) for the next eight weeks. Parents kept a diary card record of all episodes of coughing and wheezing over the next 12 months., Results: Full follow up data were collected for 49 infants. There were no significant differences between the two study groups for the number of infants with symptom episodes up to six months after hospital discharge. At 12 months, 21 infants in the budesonide group had symptom episodes compared with 12 of 24 in the placebo group. The median number of symptom episodes was 2 (range, 0-13) in those who received budesonide and 1 (range, 0-11) in those who received placebo. Because there is no pharmacological explanation for these results, they are likely to be caused by a type 1 error, possibly exacerbated by there being more boys in the treatment group., Conclusion: Routine administration of budesonide by means of a metered dose inhaler, spacer, and face mask system immediately after acute viral bronchiolitis cannot be recommended.

Objective: To determine whether abnormalities of cellular immunity are present and linked to early wheezing after bronchiolitis., Methods: We prospectively studied 26 infants hospitalized for a first episode of bronchiolitis and without any prior immune, cardiac, or respiratory disease. Blood was obtained at the time of enrollment and 5 months later for the assessment of the total cellular and differential counts, CD4+ (helper) and CD8+ (suppressor/cytotoxic) lymphocytes, and the activation markers CD23 (low-affinity immunoglobulin E receptor) and CD25 (interleukin-2 (IL-2) receptor). The cytokines interferon gamma (T-helper (TH) type-1 cytokine) and IL-4 (TH-2) were measured in plasma and in vitro after stimulation with IL-2 or with the house-dust mite (Dermatophagoides farinae) antigen. A daily log of episodes of wheezing was kept by parents after discharge., Results: We found an increase in blood eosinophils, an increased percentage of CD4+, CD25+, and CD23+ lymphocytes in subjects at 5 months compared with the time of bronchiolitis and with healthy subjects of the same age (p < 0.05). Plasma IL-4 levels, although not different from those of healthy subjects, also increased significantly. Peripheral blood lymphocytes from infants who wheezed produced more IL-4 in vitro, 5 months after bronchiolitis, in response to D. farinae antigen. In babies who wheezed, a positive correlation was found between the total number of days that wheezing occurred and the blood eosinophil count. Babies who wheezed more often (> 20 days) had more peripheral blood basophils and eosinophils, and peripheral blood lymphocytes obtained from these subjects at the time of bronchiolitis produced less interferon gamma on stimulation with IL-2., Conclusions: Bronchiolitis is followed by activation of cellular immunity, and early wheezing in infants is associated with a TH-2 response.

As part of a long term prospective study, 73 children who had been admitted to hospital with viral bronchiolitis as infants, were reviewed 5.5 years later and compared with a carefully matched control group. In the postbronchiolitis group, there was a highly significant increase in respiratory symptoms including wheezing (42.5% v 15.0%, relative risk = 2.8). Although atopy in the family was not significantly increased in the index group, personal atopy was more prevalent. However, personal atopy was not significantly more prevalent in the symptomatic postbronchiolitis, compared with those who were symptom free, and so did not account for the high prevalence of postbronchiolitis wheezing in this cohort. In addition, in a stepwise logistic regressional model, bronchiolitis remained a significant predictor of wheezing after adjusting for potential confounding variables, including atopy. Bronchial responsiveness to histamine was significantly increased in the index group. However, no significant relationship of positive tests to wheezing could be demonstrated, and a high rate of positive responses was noted in the controls.

It has been suggested that thoracic gas volume (TGV) measured in infants in a plethysmograph most accurately represents true lung volume when calculated from end-inspiratory airway occlusions. The rationale proposed is that pressure measured at the mouth underestimates alveolar pressure more at end-expiration than at end-inspiration, presumably due to small airway closure, and this results in greater overestimation of TGV. To investigate this possibility we calculated TGV in 40 wheezy infants from occlusions at both end-inspiration (TGVei) and end-expiration (TGVee) using a 60 L whole body plethysmograph. TGV was corrected for equipment dead space and tidal volume. When a significant change in TGV was defined as lying outside the 95% confidence interval of the TGVee measurements, 8 of the 40 infants tested had significantly higher TGV values measured from occlusions made at end-expiration, while two infants had significantly lower TGV values measured from occlusions made at end-expiration. This trend was not more common in infants with "concave" flow-volume curves. Although it is technically easier to make occlusions at end-expiration, occluding at end-inspiration may minimize errors of TGV measures in a few individuals due to small airway closure at low lung volumes.

Partial expiratory flow-volume curves are commonly used in infant pulmonary function testing. The flow measurements are volume dependent and thoracic gas volume (TGV) is often measured in conjunction with forced expiratory maneuvers. Since it is not possible to make continuous, simultaneous measurements of TGV during forced expiration, it is assumed that lung volume returns to its original value after forced expiration. To test this assumption we measured TGV using a whole body plethysmograph in 14 wheezy infants before and after a series of forced expirations produced with an inflatable jacket. Forced expiration did not cause a significant change in group mean TGV measurements. Examination of individual data did not show any systematic difference between TGV measured before and after forced expiration. These results suggest that repeated forced expirations do not alter TGV within the time scale of usual pulmonary function testing protocols.

Lung function was measured in nine infants, ages 15-36 weeks, who had persistent wheezing, apparently following acute bronchiolitis, before and after 2 weeks of treatment with either inhaled nebulized beclomethasone dipropionate (BDP) or placebo in a randomized, double blind, crossover trial. The effect of nebulized albuterol (Salbutamol) was measured before and after the steroid treatment. Thoracic gas volume (TGV) and specific airway conductance (SGaw) were determined using a whole body plethysmograph, and forced expiratory flow at resting lung volume (VmaxFRC) was determined with a thoracoabdominal compression jacket. All infants had marked airways obstruction before treatment with mean +/- SE VmaxFRC of 24 +/- 4% predicted and SGaw of 37 +/- 5% predicted. Two weeks of placebo treatment had no significant effect on lung function, but after 2 weeks of BDP inhalation there was a significant rise in SGaw to 61 +/- 7% (P less than 0.005). VmaxFRC increased to 42 +/- 13% but the difference did not reach significance. Respiratory rate and clinical score for retractions and wheezing also fell significantly with BDP therapy (P less than 0.01 and P less than 0.001 respectively). Albuterol had no effect on lung function either before or during steroid therapy. Steroids may have a role in the management of persistent wheezing following bronchiolitis.

A historical cohort study was performed in order to assess the hypothesis that even mild bronchiolitis in infancy in a predictor of wheezing later in childhood. Subjects who had experienced bronchiolitis and a matched control group were compared in terms of reported wheezing 8 years later. A highly significant difference was found between the bronchiolitis group and the control group in terms of current wheezing (P less than .0001, relative risk 3.24). This difference was maintained after adjusting for many potentially confounding variables including family history of allergy and other allergic manifestations in the child. Results suggested that 13.6% of a normal practice population in the age range 6 to 9 years currently wheeze, but that 44.1% of children who experienced bronchiolitis currently wheeze. Based on the incidence of bronchiolitis (4.27/100 children in their first 2 years of life) and the relative odds for wheezing derived from a logistic regression model including variables that measured passive smoking, genetic tendency to wheeze, and bronchiolitis, calculations of attributable risk suggested that wheezing in 9.4% of the population of children who currently wheeze was attributable to bronchiolitis.

To determine whether the magnitude of the respiratory syncytial virus (RSV)-specific IgE response at the time of an episode of RSV bronchiolitis in infancy accurately predicts the development of subsequent wheezing episodes, we observed 38 infants prospectively from the time of an episode of infantile bronchiolitis through 48 months of age. Peak RSV-IgE titers were measured at the time of the bronchiolitis episode using an ELISA procedure. Notation was made of both the number of subsequent wheezing episodes reported by parents and the number documented by a physician. Subsequent wheezing was documented by a physician in 20% of infants who did not develop an RSV-IgE response at the time of the bronchiolitis episode and in 70% of those with the highest responses (P less than 0.025). These results suggest that the magnitude of the RSV-IgE response at the time of RSV bronchiolitis is a useful prognostic indicator for recurrent wheezing.