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Bronchiolitis is a leading cause of infant hospitalizations but its immunopathology remains poorly understood. Here we present data from 244 infants hospitalized with bronchiolitis in a multicenter prospective study, assessing the host response (transcriptome), microbial composition, and microbial function (metatranscriptome) in the nasopharyngeal airway, and associate them with disease severity. We investigate individual associations with disease severity identify host response, microbial taxonomical, and microbial functional modules by network analyses. We also determine the integrated relationship of these modules with severity. Several modules are significantly associated with risks of positive pressure ventilation use, including the host-type I interferon, neutrophil/interleukin-1, T cell regulation, microbial-branched-chain amino acid metabolism, and nicotinamide adenine dinucleotide hydrogen modules. Taken together, we show complex interplays between host and microbiome, and their contribution to disease severity., (© 2022. The Author(s).)

Background: Recent studies support the existence of several entities under the clinical diagnosis of bronchiolitis. Among infants with severe bronchiolitis, distinct profiles have been differentially associated with development of recurrent wheezing by age 3 years. However, their associations with actual asthma remain unclear., Objective: Our aim was to study the association between severe bronchiolitis profiles identified by using a clustering approach and childhood asthma., Methods: Among 408 children (aged <2 years) hospitalized with bronchiolitis in Finland (in 2008-2010), latent class analysis identified 3 bronchiolitis profiles: profile A (47%), characterized by history of wheezing and/or eczema, wheezing during acute illness, and rhinovirus infection; profile BC (38%), characterized by severe illness and respiratory syncytial virus infection; and profile D (15%), characterized by the least severely ill children, including mostly children without wheezing and with rhinovirus infection. The children were followed by questionnaire 4 years later (86% [n = 348]) and through a nationwide social insurance database 7 years later (99% [n = 403]). Current asthma at the 4- and 7-year follow-ups was defined by regular use (according to parental report and medical records) or purchase (according to the social insurance database) of asthma control medication., Results: Compared with risk of current asthma associated with profile BC, we observed increased risk of current asthma associated with profile A both at the 4-year follow-up (age- and sex-adjusted odds ratio = 2.42 [95% CI = 1.23-4.75]) and at the 7-year follow-up (age- and sex-adjusted odds ratio = 3.14 [95% CI = 1.33-7.42]). No significant difference in asthma risk was observed between profile D and profile BC., Conclusion: These longitudinal results provide further support for an association between a distinct severe bronchiolitis profile (characterized by a history of wheezing and/or eczema and rhinovirus infection) and risk of development childhood asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: In severe bronchiolitis, it is unclear if delayed clearance or sequential infection of respiratory syncytial virus (RSV) or rhinovirus (RV) is associated with recurrent wheezing., Methods: In a 17-center severe bronchiolitis cohort, we tested nasopharyngeal aspirates (NPA) upon hospitalization and 3 weeks later (clearance swab) for respiratory viruses using PCR. The same RSV subtype or RV genotype in NPA and clearance swab defined delayed clearance (DC); a new RSV subtype or RV genotype at clearance defined sequential infection (SI). Recurrent wheezing by age 3 years was defined per national asthma guidelines., Results: Among 673 infants, RSV DC and RV DC were not associated with recurrent wheezing, and RSV SI was rare. The 128 infants with RV SI (19%) had nonsignificantly higher risk of recurrent wheezing (hazard ratio [HR], 1.31; 95% confidence interval [CI], .95-1.80; P = .10) versus infants without RV SI. Among infants with RV at hospitalization, those with RV SI had a higher risk of recurrent wheezing compared to children without RV SI (HR, 2.49; 95% CI, 1.22-5.06; P = .01)., Conclusions: Among infants with severe bronchiolitis, those with RV at hospitalization followed by a new RV infection had the highest risk of recurrent wheezing., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Bronchiolitis is the leading cause of infant hospitalizations in the United States. Growing evidence supports the heterogeneity of bronchiolitis. However, little is known about the interrelationships between major respiratory viruses (and their species), host systemic metabolism, and disease pathobiology., Methods: In an ongoing multicenter prospective cohort study, we profiled the serum metabolome in 113 infants (63 RSV-only, 21 RV-A, and 29 RV-C) hospitalized with bronchiolitis. We identified serum metabolites that are most discriminatory in the RSV-RV-A and RSV-RV-C comparisons using sparse partial least squares discriminant analysis. We then investigated the association between discriminatory metabolites with acute and chronic outcomes., Results: In 113 infants with bronchiolitis, we measured 639 metabolites. Serum metabolomic profiles differed in both comparisons (P permutation  < 0.05). In the RSV-RV-A comparison, we identified 30 discriminatory metabolites, predominantly in lipid metabolism pathways (eg, sphingolipids and carnitines). In multivariable models, these metabolites were significantly associated with the risk of clinical outcomes (eg, tricosanoyl sphingomyelin, OR for recurrent wheezing at age of 3 years = 1.50; 95% CI: 1.05-2.15). In the RSV-RV-C comparison, the discriminatory metabolites were also primarily involved in lipid metabolism (eg, glycerophosphocholines [GPCs], 12,13-diHome). These metabolites were also significantly associated with the risk of outcomes (eg, 1-stearoyl-2-linoleoyl-GPC, OR for positive pressure ventilation use during hospitalization = 0.47; 95% CI: 0.28-0.78)., Conclusion: Respiratory viruses and their species had distinct serum metabolomic signatures that are associated with differential risks of acute and chronic morbidities of bronchiolitis. Our findings advance research into the complex interrelations between viruses, host systemic response, and bronchiolitis pathobiology., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Piedra provided bronchiolitis-related consultation for Gilead, Novavax, and Regeneron; the other authors have indicated they have no potential conflicts of interest to disclose.

We aimed to develop machine learning models to accurately predict bronchiolitis severity, and to compare their predictive performance with a conventional scoring (reference) model. In a 17-center prospective study of infants (aged < 1 year) hospitalized for bronchiolitis, by using routinely-available pre-hospitalization data as predictors, we developed four machine learning models: Lasso regression, elastic net regression, random forest, and gradient boosted decision tree. We compared their predictive performance-e.g., area-under-the-curve (AUC), sensitivity, specificity, and net benefit (decision curves)-using a cross-validation method, with that of the reference model. The outcomes were positive pressure ventilation use and intensive treatment (admission to intensive care unit and/or positive pressure ventilation use). Of 1,016 infants, 5.4% underwent positive pressure ventilation and 16.0% had intensive treatment. For the positive pressure ventilation outcome, machine learning models outperformed reference model (e.g., AUC 0.88 [95% CI 0.84-0.93] in gradient boosted decision tree vs 0.62 [95% CI 0.53-0.70] in reference model), with higher sensitivity (0.89 [95% CI 0.80-0.96] vs. 0.62 [95% CI 0.49-0.75]) and specificity (0.77 [95% CI 0.75-0.80] vs. 0.57 [95% CI 0.54-0.60]). The machine learning models also achieved a greater net benefit over ranges of clinical thresholds. Machine learning models consistently demonstrated a superior ability to predict acute severity and achieved greater net benefit.

Background: The role of the airway microbiome in the development of recurrent wheezing and asthma remains uncertain, particularly in the high-risk group of infants hospitalized for bronchiolitis., Objective: We sought to examine the relation of the nasal microbiota at bronchiolitis-related hospitalization and 3 later points to the risk of recurrent wheezing by age 3 years., Methods: In 17 US centers researchers collected clinical data and nasal swabs from infants hospitalized for bronchiolitis. Trained parents collected nasal swabs 3 weeks after hospitalization and, when healthy, during the summer and 1 year after hospitalization. We applied 16S rRNA gene sequencing to all nasal swabs. We used joint modeling to examine the relation of longitudinal nasal microbiota abundances to the risk of recurrent wheezing., Results: Among 842 infants hospitalized for bronchiolitis, there was 88% follow-up at 3 years, and 31% had recurrent wheezing. The median age at enrollment was 3.2 months (interquartile range, 1.7-5.8 months). In joint modeling analyses adjusting for 16 covariates, including viral cause, a 10% increase in relative abundance of Moraxella or Streptococcus species 3 weeks after day 1 of hospitalization was associated with an increased risk of recurrent wheezing (hazard ratio [HR] of 1.38 and 95% high-density interval [HDI] of 1.11-1.85 and HR of 1.76 and 95% HDI of 1.13-3.19, respectively). Increased Streptococcus species abundance the summer after hospitalization was also associated with a greater risk of recurrent wheezing (HR, 1.76; 95% HDI, 1.15-3.27)., Conclusions: Enrichment of Moraxella or Streptococcus species after bronchiolitis hospitalization was associated with recurrent wheezing by age 3 years, possibly providing new avenues to ameliorate the long-term respiratory outcomes of infants with severe bronchiolitis., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Respiratory syncytial virus (RSV)- and rhinovirus (RV)-induced bronchiolitis are associated with an increased risk of asthma, but more detailed information is needed on virus types., Objective: To study whether RSV or RV types are differentially associated with the future use of asthma control medication., Methods: Over 2 consecutive winter seasons (2008-2010), we enrolled 408 children hospitalized for bronchiolitis at age less than 24 months into a prospective, 3-center, 4-year follow-up study in Finland. Virus detection was performed by real-time reverse transcription PCR from nasal wash samples. Four years later, we examined current use of asthma control medication., Results: A total of 349 (86%) children completed the 4-year follow-up. At study entry, the median age was 7.5 months, and 42% had RSV, 29% RV, 2% both RSV and RV, and 27% non-RSV/-RV etiology. The children with RV-A (adjusted hazard ratio, 2.3; P = .01), RV-C (adjusted hazard ratio, 3.5; P < .001), and non-RSV/-RV (adjusted hazard ratio, 2.0; P = .004) bronchiolitis started the asthma control medication earlier than did children with RSV bronchiolitis. Four years later, 27% of patients used asthma control medication; both RV-A (adjusted odds ratio, 3.0; P = .03) and RV-C (adjusted odds ratio, 3.7; P < .001) etiology were associated with the current use of asthma medication. The highest risk was found among patients with RV-C, atopic dermatitis, and fever (adjusted odds ratio, 5.0; P = .03)., Conclusions: Severe bronchiolitis caused by RV-A and RV-C was associated with earlier initiation and prolonged use of asthma control medication. The risk was especially high when bronchiolitis was associated with RV-C, atopic dermatitis, and fever., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In 2 multicenter cohort studies of 2912 infants hospitalized for bronchiolitis during 2007-2014, the 5 most common pathogens were RSV (76.5%), rhinovirus (23.8%), coronavirus (6.9%), adenovirus (6.4%) and human metapneumovirus (6.0%). Hospitalization months significantly differed for these common pathogens (P ≤ 0.01), except for coronavirus (P = 0.30). There was a significant heterogeneity in temporal patterns by region in RSV-A and -B (both P < 0.001).

The relation of nasopharyngeal microbiota to the clearance of respiratory syncytial virus (RSV) in infants hospitalized for bronchiolitis is not known. In a multicenter cohort, we found that 106 of 557 infants (19%) hospitalized with RSV bronchiolitis had the same RSV subtype 3 weeks later (ie, delayed clearance of RSV). Using 16S ribosomal RNA gene sequencing and a clustering approach, infants with a Haemophilus-dominant microbiota profile at hospitalization were more likely than those with a mixed profile to have delayed clearance, after adjustment for 11 factors, including viral load. Nasopharyngeal microbiota composition is associated with delayed RSV clearance., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: A better understanding of bronchiolitis heterogeneity might help clarify its relationship with the development of recurrent wheezing and asthma., Objectives: We sought to identify severe bronchiolitis profiles using a clustering approach and to investigate for the first time their association with allergy/inflammatory biomarkers, nasopharyngeal microbiota, and development of recurrent wheezing by age 3 years., Methods: We analyzed data from a prospective, 17-center US cohort study of 921 infants (age <1 year) hospitalized with bronchiolitis (2011-2014 winters) with posthospitalization follow-up. Severe bronchiolitis profiles at baseline (hospitalization) were determined by using latent class analysis based on clinical factors and viral etiology. Blood biomarkers and nasopharyngeal microbiota profiles were determined by using samples collected within 24 hours of hospitalization. Recurrent wheezing by age 3 years was defined based on parental report of breathing problem episodes after discharge., Results: Three severe bronchiolitis profiles were identified: profile A (15%), which was characterized by a history of breathing problems/eczema during infancy and non-respiratory syncytial virus (mostly rhinovirus) infection; profile B (49%), which has the largest probability of respiratory syncytial virus infection and resembled classic respiratory syncytial virus-induced bronchiolitis; and profile C (36%), which was composed of the most severely ill group. Profile A infants had higher eosinophil counts, higher cathelicidin levels, and increased proportions of Haemophilus-dominant or Moraxella-dominant microbiota profiles. Compared with profile B, we observed significantly increased risk of recurrent wheezing in children with profile A (hazard ratio, 2.64; 95% CI, 1.90-3.68) and, to a lesser extent, with profile C (hazard ratio, 1.51; 95% CI, 1.14-2.01)., Conclusion: Although longer follow-up is needed, our results might help identify, among children hospitalized for bronchiolitis, subgroups with particularly increased risk of asthma., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Bronchiolitis, the leading cause of hospitalization among infants in the United States, is most commonly caused by respiratory syncytial virus (RSV), followed by rhinovirus (RV). Conventional perception is that bronchiolitis is a single entity, albeit with different viral etiologies and degrees of severity., Methods: We conducted a cross-sectional study of nasopharyngeal aspirates from 106 infants hospitalized with bronchiolitis due to either RSV only (80 patients) or RV only (26 patients). We performed metabolomics analysis and 16S ribosomal RNA gene sequencing on all samples and metagenomic sequencing on 58 of 106 samples., Results: Infants with RSV-only and RV-only infections had significantly different nasopharyngeal metabolome profiles (P < .001) and bacterial metagenome profiles (P < .05). RSV-only infection was associated with metabolites from a range of pathways and with a microbiome dominated by Streptococcus pneumoniae. By contrast, RV-only infection was associated with increased levels of essential and nonessential N-acetyl amino acids and with a high relative abundance of Haemophilus influenzae. These co-occurring species were associated with driving the bacterially derived metabolic pathways. Multi-omic analysis showed that both the virus and the microbiome were significantly associated with metabolic function in infants hospitalized with bronchiolitis., Conclusion: Although replication of these findings is necessary, they highlight that bronchiolitis is not a uniform disease between RSV and RV infections, a result with future implications for prevention and treatment.

BackgroundAlthough rhinovirus infection is associated with increased risks of acute and chronic respiratory outcomes during childhood compared with respiratory syncytial virus (RSV), the underlying mechanisms remain unclear. We aimed to determine the differences in nasal airway microRNA profiles and their downstream effects between infants with rhinovirus and RSV bronchiolitis.MethodsAs part of a multicenter cohort study of infants hospitalized for bronchiolitis, we examined nasal samples obtained from 16 infants with rhinovirus and 16 infants with RSV. We tested nasal airway samples using microarrays to profile global microRNA expression and determine the predicted regulation of targeted transcripts. We also measured gene expression and cytokines for NFκB pathway components.ResultsBetween the virus groups, 386 microRNAs were differentially expressed (false discovery rate (FDR)<0.05). In infants with rhinovirus, the NFκB pathway was highly ranked as a predicted target for these differentially expressed microRNAs compared with RSV. Pathway analysis using measured mRNA expression data validated that rhinovirus infection had upregulation of NFκB family (RelA and NFκB2) and downregulation of inhibitor κB family. Infants with rhinovirus had higher levels of NFκB-induced type-2 cytokines (IL-10 and IL-13; FDR<0.01).ConclusionIn infants with bronchiolitis, rhinovirus and RSV infections had different nasal airway microRNA profiles associated with NFκB signaling.

Background: The airway microbiome is a subject of great interest for the study of respiratory disease. Anterior nare samples are more accessible than samples from deeper within the nasopharynx. However, the correlation between the microbiota found in the anterior nares and the microbiota found within the nasopharynx is unknown. We assessed the anterior nares and nasopharyngeal microbiota to determine (1) the relation of the microbiota from these two upper airway sites and (2) if associations were maintained between the microbiota from these two sites and two bronchiolitis severity outcomes., Results: Among 815 infants hospitalized at 17 US centers for bronchiolitis with optimal 16S rRNA gene sequence reads from both nasal swab and nasopharyngeal aspirate samples, there were strong intra-individual correlations in the microbial communities between the two sample types, especially relating to Haemophilus and Moraxella genera. By contrast, we found a high abundance of Staphylococcus genus in the nasal swabs-a pattern not found in the nasopharyngeal samples and not informative when predicting the dominant nasopharyngeal genera. While these disparities may have been due to sample processing differences (i.e., nasal swabs were mailed at ambient temperature to emulate processing of future parent collected swabs while nasopharyngeal aspirates were mailed on dry ice), a previously reported association between Haemophilus-dominant nasopharyngeal microbiota and the increased severity of bronchiolitis was replicated utilizing the nasal swab microbiota and the same outcome measures: intensive care use (adjusted OR 6.43; 95% CI 2.25-20.51; P < 0.001) and hospital length-of-stay (adjusted OR 4.31; 95% CI, 1.73-11.11; P = 0.002). Additionally, Moraxella-dominant nasopharyngeal microbiota was previously identified as protective against intensive care use, a result that was replicated when analyzing the nasal swab microbiota (adjusted OR 0.30; 95% CI, 0.11-0.64; P = 0.01)., Conclusions: While the microbiota of the anterior nares and the nasopharynx are distinct, there is considerable overlap between the bacterial community compositions from these two anatomic sites. Despite processing differences between the samples, these results indicate that microbiota severity associations from the nasopharynx are recapitulated in the anterior nares, suggesting that nasal swab samples not only are effective sample types, but also can be used to detect microbial risk markers.

Background: Little is known about the relationship of airway microbiota with bronchiolitis in infants. We aimed to identify nasal airway microbiota profiles and to determine their association with the likelihood of bronchiolitis in infants., Methods: A case-control study was conducted. As a part of a multicenter prospective study, we collected nasal airway samples from 40 infants hospitalized with bronchiolitis. We concurrently enrolled 110 age-matched healthy controls. By applying 16S ribosomal RNA gene sequencing and an unbiased clustering approach to these 150 nasal samples, we identified microbiota profiles and determined the association of microbiota profiles with likelihood of bronchiolitis., Results: Overall, the median age was 3 months and 56% were male. Unbiased clustering of airway microbiota identified 4 distinct profiles: Moraxella-dominant profile (37%), Corynebacterium/Dolosigranulum-dominant profile (27%), Staphylococcus-dominant profile (15%) and mixed profile (20%). Proportion of bronchiolitis was lowest in infants with Moraxella-dominant profile (14%) and highest in those with Staphylococcus-dominant profile (57%), corresponding to an odds ratio of 7.80 (95% confidence interval, 2.64-24.9; P < 0.001). In the multivariable model, the association between Staphylococcus-dominant profile and greater likelihood of bronchiolitis persisted (odds ratio for comparison with Moraxella-dominant profile, 5.16; 95% confidence interval, 1.26-22.9; P = 0.03). By contrast, Corynebacterium/Dolosigranulum-dominant profile group had low proportion of infants with bronchiolitis (17%); the likelihood of bronchiolitis in this group did not significantly differ from those with Moraxella-dominant profile in both unadjusted and adjusted analyses., Conclusions: In this case-control study, we identified 4 distinct nasal airway microbiota profiles in infants. Moraxella-dominant and Corynebacterium/Dolosigranulum-dominant profiles were associated with low likelihood of bronchiolitis, while Staphylococcus-dominant profile was associated with high likelihood of bronchiolitis.

Background: LL-37 is a host defense peptide with antimicrobial and immunomodulatory properties. We examined the relation of serum LL-37 levels to the severity of bronchiolitis and viral etiology., Methods: We performed a 17-center prospective cohort study in infants hospitalized with bronchiolitis over 3 winters (2011-2014). Site teams collected clinical data, nasopharyngeal aspirates and serum. We used real-time polymerase chain reaction to test nasopharyngeal aspirates for 16 viruses. We tested serum for LL-37. Severity of bronchiolitis was defined by intensive care use and hospital length of stay. Viral etiology was defined as respiratory syncytial virus (RSV) or rhinovirus (RV), including coinfections with other viruses., Results: The median age of the 1005 enrolled infants was 3 months (interquartile range, 2-6 months). After adjustment for 12 variables, LL-37 levels in the lowest quartile, compared with the highest, were associated both with intensive care use (adjusted odds ratio [aOR], 1.97; P = .01) and longer hospital stay (1.34; P < .001). In separate multivariable models, infants with LL-37 levels in the lowest 3 quartiles, compared with the highest, were more likely to have RSV (eg, aOR, 2.6 [lowest quartile]; P < .001 [all quartiles]). By contrast, infants with the lowest 3 LL-37 quartiles were less likely to have RV (eg, aOR, 0.5 [lowest quartile]; Pall quartiles ≤ .03 [all quartiles])., Conclusions: In a large multicenter study of infants hospitalized with bronchiolitis, lower levels of serum LL-37 were associated with increased severity of illness. There was also an inverse relationship between LL-37 levels and the most common virus causing bronchiolitis, RSV. These findings highlight the role of LL-37 in the pathogenesis of bronchiolitis., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com)

Aim: Infants hospitalised for bronchiolitis undergo examinations and treatments not supported by current research evidence and we investigated practice variations with regard to Finnish children under the age of two., Methods: This prospective, multicentre cohort study was conducted in paediatric units in three university hospitals in Finland from 2008 to 2010. Hospital medical records were reviewed to collect data on clinical course, testing and treatment. Data were analysed separately for children meeting our strict definition of bronchiolitis, aged under 12 months without a history of wheezing, and a loose definition, aged 12-23 months or with a history of wheezing., Results: The median age of the 408 children was 8.1 months. Clinical management varied between the three hospitals when stratified by strict and loose bronchiolitis subgroup definitions: complete blood counts ranged from 15-95% vs 16-94%, respectively, and the other measures were chest x-ray (16-91% vs 14-72%), intravenous fluids (2-47% vs 2-41%), use of nebulised epinephrine (10-84% vs 7-50%), use of salbutamol (18-21% vs 13-84%) and use of corticosteroids (6-23% vs 60-76%)., Conclusion: The clinical management of bronchiolitis varied considerably with regard to the three hospitals and the two definitions of bronchiolitis. A stronger commitment to evidence-based bronchiolitis guidelines is needed in Finland., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

In this analysis of a prospective, multicenter study of children hospitalized with bronchiolitis, 925 had respiratory syncytial virus (RSV)-A and 649 had RSV-B. Overall, bronchiolitis severity did not differ by RSV subtype. However, among children with RSV-only bronchiolitis, those children with RSV-A had higher risk of intensive care treatment (odds ratio, 1.31; 95% confidence interval, 1.00-1.71; P = 0.048) when compared with those having RSV-B.

Respiratory syncytial virus (RSV) causes significant infant morbidity and mortality. For decades severe RSV-induced disease was thought to result from an uncontrolled host response to viral replication, but recent work suggests that a strong innate immune response early in infection is protective. To shed light on host-virus interactions and the viral determinants of disease, copy numbers of five RSV genes (NS1, NS2, N, G, F) were measured by quantitative real-time polymerase chain reaction (qPCR) in nasal wash samples from children with RSV-associated bronchiolitis. Correlations were sought with host cytokines/chemokines and biomarkers. Associations with disposition from the emergency department (hospitalized or sent home) and pulse oximetry O2 saturation levels were also sought. Additionally, RNase P copy number was measured and used to normalize nasal wash data. RSV gene copy numbers were found to significantly correlate with both cytokine/chemokine and biomarker levels; and RNase P-normalized viral gene copy numbers (NS1, NS2, N and G) were significantly higher in infants with less severe disease. Moreover, three of the normalized viral gene copy numbers (NS1, NS2, and N) correlated significantly with arterial O2 saturation levels. The data support a model where a higher viral load early in infection can promote a robust innate immune response that protects against progression into hypoxic RSV-induced lower respiratory tract illness.

Little is known about the relationship between the specific airway microbiota composition and severity of bronchiolitis. We aimed to identify nasopharyngeal microbiota profiles and link these profiles to acute severity in infants hospitalised for bronchiolitis.We conducted a multicentre prospective cohort study of 1005 infants (age <1 year) hospitalised for bronchiolitis over three winters, 2011-2014. By applying a 16S rRNA gene sequence and clustering approach to the nasopharyngeal aspirates collected within 24 h of hospitalisation, we determined nasopharyngeal microbiota profiles and their association with bronchiolitis severity. The primary outcome was intensive care use, i.e. admission to an intensive care unit or use of mechanical ventilation.We identified four nasopharyngeal microbiota profiles: three profiles were dominated by one of Haemophilus, Moraxella or Streptococcus, while the fourth profile had the highest bacterial richness. The rate of intensive care use was highest in infants with a Haemophilus-dominant profile and lowest in those with a Moraxella-dominant profile (20.2% versus 12.3%; unadjusted OR 1.81, 95% CI 1.07-3.11, p=0.03). After adjusting for 11 patient-level confounders, the rate remained significantly higher in infants with Haemophilus-dominant profiles (OR 1.98, 95% CI 1.08-3.62, p=0.03). These findings were externally validated in a separate cohort of 307 children hospitalised for bronchiolitis., (Copyright ©ERS 2016.)

Background: Bronchiolitis causes substantial disease in young children. Previous findings had indicated that a robust innate immune response was not associated with a poor clinical outcome in bronchiolitis. This study tested the hypothesis that increased concentrations of cytokines and chemokines in nasal wash specimens were associated with decreased severity in bronchiolitis., Methods: Children <24 months old who presented to the emergency department with signs and symptoms of bronchiolitis were eligible for enrollment. Nasal wash specimens were analyzed for viral pathogens and cytokine/chemokine concentrations. These results were evaluated with regard to disposition., Results: One hundred eleven children with bronchiolitis were enrolled. A viral pathogen was identified in 91.9% of patients (respiratory syncytial virus in 51.4%, human rhinovirus in 11.7%). Higher levels of cytokines and chemokines (interferon [IFN] γ; interleukin [IL] 4, 15, and 17; CXCL10; and eotaxin) were significantly associated with a decreased risk of hospitalization. IL-17, IL-4, IFN-γ, and IFN-γ-inducible protein 10 (CXCL10 or IP-10) remained statistically significant in the multivariate analyses., Conclusions: The cytokines and chemokines significantly associated with decreased bronchiolitis severity are classified in a wide range of functional groups (T-helper 1 and 2, regulatory, and chemoattractant). The involvement of these functional groups suggest that a broadly overlapping cytokine/chemokine response is required for control of virus-mediated respiratory disease in young children., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Objective: Although bronchiolitis is generally considered a single disease, recent studies suggest heterogeneity. We aimed to identify severe bronchiolitis profiles using a clustering approach., Methods: We analysed data from two prospective, multicentre cohorts of children younger than 2 years hospitalised with bronchiolitis, one in the USA (2007-2010 winter seasons, n=2207) and one in Finland (2008-2010 winter seasons, n=408). Severe bronchiolitis profiles were determined by latent class analysis, classifying children based on clinical factors and viral aetiology., Results: In the US study, four profiles were identified. Profile A (12%) was characterised by history of wheezing and eczema, wheezing at the emergency department (ED) presentation and rhinovirus infection. Profile B (36%) included children with wheezing at the ED presentation, but, in contrast to profile A, most did not have history of wheezing or eczema; this profile had the largest probability of respiratory syncytial virus infection. Profile C (34%) was the most severely ill group, with longer hospital stay and moderate-to-severe retractions. Profile D (17%) had the least severe illness, including non-wheezing children with shorter length of stay. Two of these profiles (A and D) were replicated in the Finnish cohort; a third group ('BC') included Finnish children with characteristics of profiles B and/or C in the US population., Conclusions: Several distinct clinical profiles (phenotypes) were identified by a clustering approach in two multicentre studies of children hospitalised for bronchiolitis. The observed heterogeneity has important implications for future research on the aetiology, management and long-term outcomes of bronchiolitis, such as future risk of childhood asthma., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Among children hospitalized with bronchiolitis, we examined the associations between in utero exposure to maternal cigarette smoking, postnatal tobacco smoke exposure, and risk of admission to the intensive care unit (ICU)., Methods: We performed a 16-center, prospective cohort study of hospitalized children aged <2 years with a physician admitting diagnosis of bronchiolitis. For 3 consecutive years, from November 1, 2007 until March 31, 2010, site teams collected data from participating families, including information about prenatal maternal smoking and postnatal tobacco exposure. Analyses used chi-square, Fisher's exact, and Kruskal-Wallis tests and multivariable logistic regression., Results: Among 2207 enrolled children, 216 (10%) had isolated in utero exposure to maternal smoking, 168 (8%) had isolated postnatal tobacco exposure, and 115 (5%) experienced both. Adjusting for age, sex, race, birth weight, viral etiology, apnea, initial severity of retractions, initial oxygen saturation, oral intake, and postnatal tobacco exposure, children with in utero exposure to maternal smoking had greater odds of being admitted to the ICU (adjusted odds ratio [aOR] 1.51, 95% confidence interval [CI] 1.14-2.00). Among children with in utero exposure to maternal smoking, those with additional postnatal tobacco exposure had a greater likelihood of ICU admission (aOR 1.95, 95% CI 1.13-3.37) compared to children without postnatal tobacco smoke exposure (aOR 1.47, 95% CI 1.05-2.04)., Conclusions: Maternal cigarette smoking during pregnancy puts children hospitalized with bronchiolitis at significantly higher risk of intensive care use. Postnatal tobacco smoke exposure may exacerbate this risk. Health care providers should incorporate this information into counseling messages., (Copyright © 2016 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about the association of gut microbiota, a potentially modifiable factor, with bronchiolitis in infants. We aimed to determine the association of fecal microbiota with bronchiolitis in infants., Methods: We conducted a case-control study. As a part of multicenter prospective study, we collected stool samples from 40 infants hospitalized with bronchiolitis. We concurrently enrolled 115 age-matched healthy controls. By applying 16S rRNA gene sequencing and an unbiased clustering approach to these 155 fecal samples, we identified microbiota profiles and determined the association of microbiota profiles with likelihood of bronchiolitis., Results: Overall, the median age was 3 months, 55% were male, and 54% were non-Hispanic white. Unbiased clustering of fecal microbiota identified 4 distinct profiles: Escherichia-dominant profile (30%), Bifidobacterium-dominant profile (21%), Enterobacter/Veillonella-dominant profile (22%), and Bacteroides-dominant profile (28%). The proportion of bronchiolitis was lowest in infants with the Enterobacter/Veillonella-dominant profile (15%) and highest in the Bacteroides-dominant profile (44%), corresponding to an odds ratio of 4.59 (95% confidence interval, 1.58-15.5; P = .008). In the multivariable model, the significant association between the Bacteroides-dominant profile and a greater likelihood of bronchiolitis persisted (odds ratio for comparison with the Enterobacter/Veillonella-dominant profile, 4.24; 95% confidence interval, 1.56-12.0; P = .005). In contrast, the likelihood of bronchiolitis in infants with the Escherichia-dominant or Bifidobacterium-dominant profile was not significantly different compared with those with the Enterobacter/Veillonella-dominant profile., Conclusions: In this case-control study, we identified 4 distinct fecal microbiota profiles in infants. The Bacteroides-dominant profile was associated with a higher likelihood of bronchiolitis., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: Our aim was to evaluate the association between viral findings during bronchiolitis and the use of asthma controller medication (primary outcome) and systemic corticosteroids (secondary outcome) during the first post-bronchiolitis year., Methods: We enrolled 408 children hospitalized for bronchiolitis at <24 months of age in a prospective, 3-center, 1-year follow-up study in Finland. Viruses were detected with polymerase chain reaction in nasopharyngeal aspirates. The parents underwent a structured interview during hospitalization. Twelve months later, the use of asthma medication was asked in a structured questionnaire. Multivariable logistic regression was used for statistical analysis., Results: In total, 365 (89%) children completed the 1-year follow-up. The use of long-term asthma controller medication was highest in the rhinovirus-positive group (61% vs. 15% in respiratory syncytial virus-positive group; adjusted odd ratios, 7.5; 95% confidence interval: 3.7-15.3), followed by children negative for both respiratory syncytial virus and rhinovirus (36%; adjusted odd ratios, 2.6; 95% confidence interval: 1.3-5.3). Likewise, rhinovirus etiology was associated with more courses of systemic corticosteroids during the follow-up. The main findings were similar in a subset of infants aged <12 months with first wheezing., Conclusions: Children hospitalized for rhinovirus-positive bronchiolitis used long-term asthma controller medication more often than those hospitalized for rhinovirus-negative bronchiolitis during first year after hospitalization.

In 169 Finnish infants hospitalized for bronchiolitis at age <6 months in 2008-2010, nasopharyngeal aspirates were tested by polymerase chain reaction for Bordetella pertussis and 16 viruses. Respiratory viruses were detected in 89% (71% with respiratory syncytial virus), but no infant had B. pertussis. The latter finding may reflect a positive effect from the broadening of the Finnish pertussis vaccination program in 2005.

In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95%CI: 28.5-41.7%). The decrease was largely driven by the restriction of eligibility to preterm infants with gestational age <29 weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed., (© 2015 Japan Pediatric Society.)

Background and Objectives: It remains unclear whether hyponatremia independently predicts a higher severity of bronchiolitis in children. The objective of this study was to investigate the association between hyponatremia and bronchiolitis severity in children hospitalized in the ICU for bronchiolitis., Methods: We conducted a 16-center, prospective cohort study of hospitalized children aged <2 years with bronchiolitis during the winters of 2007 through 2010. Patients were classified into 2 groups (normonatremic [135-145 mEq/L] and hyponatremic [<135 mEq/L]) based on the first-measured serum sodium concentration on the day of hospitalization. Outcomes were use of mechanical ventilation and ICU length of stay (LOS). To examine the association of sodium status with outcomes, we fit logistic and linear regression models with propensity score adjustment., Results: Of 231 children hospitalized in the ICU for bronchiolitis, 193 (84%) were categorized into the normonatremic group and 38 (16%) into the hyponatremic group. Compared with children with normonatremia, those with hyponatremia had higher risks of mechanical ventilation use (40% vs 58%; P = .04) and longer ICU LOS (median, 3 vs 6 days; P = .007). Likewise, in the adjusted analyses, children with hyponatremia had significantly higher risks of mechanical ventilation use (odds ratio, 2.14 [95% confidence interval, 1.03-4.48; P = .04) and longer ICU LOS (β-coefficient, 2.21 days [95% confidence interval, 0.68-3.73; P = .005])., Conclusions: In this prospective, multicenter study of children hospitalized for bronchiolitis, hyponatremia on the day of hospitalization was associated with a higher severity of disease. Our data support hyponatremia as a prognostic factor that might improve the ability of clinicians to predict the disease course of children with severe bronchiolitis., (Copyright © 2015 by the American Academy of Pediatrics.)

We compared the use of cough and cold medications in 2 multicenter studies of young children hospitalized with bronchiolitis before and after the 2008 Food and Drug Administration cough and cold medications advisory. Although cough and cold medication use decreased after the advisory, nearly 20% of children age 12-23.9 months with severe bronchiolitis received cough and cold medications., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In the United States (U.S.), Bordetella pertussis incidence has increased. Cough and apnea are common findings in pertussis and also in bronchiolitis, the most common cause of hospitalization in U.S. infants. The objective was to determine the prevalence of B. pertussis infection in children hospitalized with bronchiolitis and to describe its clinical course., Methods: Children hospitalized with bronchiolitis and age <2 years were eligible for a prospective, multicenter cohort study during 3 consecutive winter seasons (November-March) from 2007 to 2010. Sixteen sites in 12 states participated using a standardized enrollment protocol. Families were asked the 2010 Centers for Disease Control and Prevention pertussis classification questions. Nasopharyngeal aspirates were obtained and tested by real-time polymerase chain reaction for 16 viruses, Mycoplasma pneumoniae and B. pertussis., Results: Two thousand sixty-eight (94%) of 2207 children had 1 or more respiratory pathogens. B. pertussis was identified in 4 children [0.2%; 95% confidence interval (CI): 0.1-0.5%] with 3 having a viral co-infection. All 4 were younger than 4 months; 2 met the Centers for Disease Control and Prevention definition of probable pertussis; and 3 had received at least 1 dose of an acellular pertussis vaccine. During the hospitalization, 2 had paroxysmal cough, 1 required intensive care unit care and the median length of stay was 13 days., Conclusions: Our data support that B. pertussis is an uncommon pathogen in U.S. children hospitalized with bronchiolitis in the winter. Making a diagnosis of pertussis can be challenging because the disease can be atypical and may not meet the Centers for Disease Control and Prevention definition of probable infection.

Background: We investigated whether children with a higher respiratory syncytial virus (RSV) genomic load are at a higher risk of more-severe bronchiolitis., Methods: Two multicenter prospective cohort studies in the United States and Finland used the same protocol to enroll children aged <2 years hospitalized for bronchiolitis and collect nasopharyngeal aspirates. By using real-time polymerase chain reaction analysis, patients were classified into 3 genomic load status groups: low, intermediate, and high. Outcome measures were a length of hospital stay (LOS) of ≥3 days and intensive care use, defined as admission to the intensive care unit or use of mechanical ventilation., Results: Of 2615 enrolled children, 1764 (67%) had RSV bronchiolitis. Children with a low genomic load had a higher unadjusted risk of having a length of stay of ≥3 days (52%), compared with children with intermediate and those with high genomic loads (42% and 51%, respectively). In a multivariable model, the risk of having a length of stay of ≥3 days remained significantly higher in the groups with intermediate (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.20-1.69) and high (OR, 1.58; 95% CI, 1.29-1.94) genomic loads. Similarly, children with a high genomic load had a higher risk of intensive care use (20%, compared with 15% and 16% in the groups with low and intermediate genomic loads, respectively). In a multivariable model, the risk remained significantly higher in the group with a high genomic load (OR, 1.43; 95% CI, 1.03-1.99)., Conclusion: Children with a higher RSV genomic load had a higher risk for more-severe bronchiolitis., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the extent of variability in testing and treatment of children with bronchiolitis requiring intensive care., Methods: This prospective, multicenter observational study included 16 academic children's hospitals across the United States during the 2007 to 2010 fall and winter seasons. The study included children<2 years old hospitalized with bronchiolitis who required admission to the ICU and/or continuous positive airway pressure (CPAP) within 24 hours of admission. Among the 2207 enrolled patients with bronchiolitis, 342 children met inclusion criteria. Clinical data and nasopharyngeal aspirates were collected., Results: Respiratory distress severity scores and intraclass correlation coefficients were calculated. The study patients' median age was 2.6 months, and 59% were male. Across the 16 sites, the median respiratory distress severity score was 5.1 (interquartile range: 4.5-5.4; P<.001). The median value of the percentages for all sites using CPAP was 15% (range: 3%-100%), intubation was 26% (range: 0%-100%), and high-flow nasal cannula (HFNC) was 24% (range: 0%-94%). Adjusting for site-specific random effects (as well as children's demographic characteristics and severity of bronchiolitis), the intraclass correlation coefficient for CPAP and/or intubation was 21% (95% confidence interval: 8-44); for HFNC, it was 44.7% (95% confidence interval: 24-67)., Conclusions: In this multicenter study of children requiring intensive care for bronchiolitis, we identified substantial institutional variability in testing and treatment, including use of CPAP, intubation, and HFNC. These differences were not explained by between-site differences in patient characteristics, including severity of illness. Further research is needed to identify best practices for intensive care interventions for this major cause of pediatric hospitalization., (Copyright © 2015 by the American Academy of Pediatrics.)

Background: For children hospitalized with bronchiolitis, there is uncertainty about the expected inpatient clinical course and when children are safe for discharge., Objectives: Examine the time to clinical improvement, risk of clinical worsening after improvement, and develop discharge criteria., Design: Prospective multiyear cohort study., Setting: Sixteen US hospitals., Participants: Consecutive hospitalized children age <2 years with bronchiolitis., Measurement: We defined clinical improvement using: (1) retraction severity, (2) respiratory rate, (3) room air oxygen saturation, and (4) hydration status. After meeting improvement criteria, children were considered clinically worse based on the inverse of ≥1 of these criteria or need for intensive care., Results: Among 1916 children, the median number of days from onset of difficulty breathing until clinical improvement was 4 (interquartile range, 3-7.5 days). Of the total, 1702 (88%) met clinical improvement criteria, with 4% worsening (3% required intensive care). Children who worsened were age <2 months (adjusted odds ratio [AOR]: 3.51; 95% confidence interval [CI]: 2.07-5.94), gestational age <37 weeks (AOR: 1.94; 95% CI: 1.13-3.32), and presented with severe retractions (AOR: 5.55; 95% CI: 2.12-14.50), inadequate oral intake (AOR: 2.54; 95% CI: 1.39-4.62), or apnea (AOR: 2.87; 95% CI: 1.45-5.68). Readmissions were similar for children who did and did not worsen., Conclusions: Although children hospitalized with bronchiolitis had wide-ranging recovery times, only 4% worsened after initial improvement. Children who worsened were more likely to be younger, premature infants presenting in more severe distress. For children hospitalized with bronchiolitis, these data may help establish more evidence-based discharge criteria, reduce practice variability, and safely shorten hospital length-of-stay., (© 2015 Society of Hospital Medicine.)

Objective: To determine the variability between hospitals in diagnostic testing and management interventions for children with bronchiolitis admitted to inpatient wards and identify its association with patient characteristics., Methods: A prospective, multicenter (16 hospitals), multiyear (2007-2010) observational study of children (age <2 years) hospitalized with bronchiolitis. Outcomes included variability in diagnostic testing (complete blood count, chest radiographs) and medications or interventions (bronchodilator, systemic corticosteroid, antibiotic, IV placement) by hospital. A modified Respiratory Distress Severity Score was utilized to assess severity of illness. For all outcomes, intraclass correlation coefficient (ICC) was calculated from a model to estimate the random effects of hospital without added covariates and compared to ICCs from a second model that adjusted for demographic and clinical patient characteristics. A second unadjusted and adjusted model was created for age ≥ 2 months., Results: Of 2207 subjects, 1715 were identified as admitted to inpatient wards. We observed wide variations in the proportion of patients who received diagnostic testing (complete blood count 21-75%, chest radiograph 36-85%) and medications/interventions (bronchodilators 19-91%, systemic corticosteroids 8-44%, antibiotics 17-43%, IV placement 38-93%). Adjusting for demographic and clinical patient characteristics did not materially affect the proportion of variability attributable to hospitals (differences in ICCs with and without model adjustment <4%)., Conclusions: Wide variations in diagnostic test utilization and management interventions seen among children with bronchiolitis treated on the inpatient wards at 16 US hospitals were not attributable to demographic or clinical patient characteristics. These results further support efforts to standardize care for bronchiolitis through active quality improvement strategies., (Copyright © 2015 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Objective: To examine risk factors for transfer of bronchiolitis patients from the ward to the intensive care unit (ICU) and/or initiation of critical care interventions., Methods: We performed a 16-center, prospective cohort study of hospitalized children age <2 years with bronchiolitis. During the winters of 2007 to 2010, researchers collected clinical data and nasopharyngeal aspirates from study participants. The primary outcome was late intensive care use, defined as a transfer to the ICU and/or use of mechanical ventilation (regardless of location) after the child's first inpatient day., Results: Among 2104 children hospitalized with bronchiolitis, 1762 (84%) were identified as initial ward patients, comprising the analysis cohort. The median age was 4 months (interquartile range, 2-9 months), and 1048 (59%) were boys. The most frequently detected pathogens were respiratory syncytial virus (72%) and rhinovirus (25%). After the first inpatient day, 47 (3%; 95% confidence interval, 2-4) were subsequently transferred to the ICU or required mechanical ventilation. In the multivariable logistic regression model predicting subsequent transfer to the ICU or mechanical ventilation use, the significant predictors were birth weight <5 pounds (odds ratio, 2.28; 95% confidence interval, 1.30-4.02; P = .004) and respiratory rate high of ≥ 70 breaths/min on the first inpatient day (odds ratio, 4.64; 95% confidence interval, 2.86-7.53; P < .001)., Conclusions: In this multicenter study of children hospitalized with bronchiolitis, low birth weight and tachypnea were significantly associated with subsequent transfer to the ICU and/or use of mechanical ventilation., (Copyright © 2015 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background: Bronchiolitis is the leading cause of hospitalization in infants. Biomarkers of disease severity might help in clinical management., Objective: To determine the clinical predictiveness of NW-LDH, NW-caspase 3/7, and NW-LDH/NW-caspase 3/7 ratio in bronchiolitis., Methods: Previously healthy children less than 24 months of age with bronchiolitis were recruited from the Texas Children's emergency room and intensive care unit from October 2010 to April 2011. Demographic, clinical information, and NW samples were obtained at enrollment. NW samples were analyzed for respiratory viruses, caspase 3/7, and LDH., Results: A viral pathogen was detected in 91·6% of 131 children, with the most common being respiratory syncytial virus and human rhinovirus. A single infection was found in 61·8% of subjects and co-infection in 29·8%. Children admitted to ICU had significantly higher NW-LDH than children sent home from the ER or admitted to the general floor (P = 0·02). Children infected with RSV had the highest NW-LDH concentration (P = 0·03) compared with other viral infections. NW-LDH and NW-caspase were significantly correlated (r = 0·77, P < 0·0001). The univariate models showed NW-LDH and NW-LDH/NW- caspase 3/7 ratio were directly associated with hospitalization. Mutivariate regression analyses suggested a complex interaction between the biomarkers, demographics, and disposition., Conclusions: NW-LDH, NW-caspase 3/7 and NW-LDH/NW-caspase 3/7 ratio and their interactions with demographic factors are predictive of bronchiolitis severity and can help distinguish children requiring ICU-level care from those admitted to the general floor, or discharged home from the emergency center., (© 2014 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Background and Objective: Bronchiolitis is the leading cause of hospitalization for US infants and is associated with increased risk of childhood asthma. Although studies have shown differences in the presentation and management of asthma across race/ethnicity, it is unclear if such differences are present for bronchiolitis. We examined if racial/ethnic differences exist in the presentation and management of severe bronchiolitis., Methods: We performed a 16-center, prospective cohort study from 2007 to 2010. Children <2 years old hospitalized with a diagnosis of bronchiolitis were included. A structured interview, chart review, and 1-week phone follow-up were completed. Multivariable logistic regression was used to examine the independent association between race/ethnicity and diagnostic imaging, treatment (eg, albuterol, corticosteroids, and continuous positive airway pressure/intubation), management (eg, intensive care unit admission and length of stay), discharge on inhaled corticosteroids, and bronchiolitis relapse., Results: Among 2130 patients, 818 (38%) were non-Hispanic white (NHW), 511 (24%) were non-Hispanic black (NHB), and 801 (38%) were Hispanic. Compared with all groups, NHB children were most likely to receive albuterol before admission (odds ratio [OR]: 1.58; 95% confidence interval [CI]: 1.20-2.07) and least likely to receive chest x-rays during hospitalization (OR: 0.66; 95% CI: 0.49-0.90). Hispanic children were most likely to be discharged on inhaled corticosteroids (OR: 1.92; 95% CI: 1.19-3.10)., Conclusion: We observed differences between NHW and minority children regarding preadmission albuterol use, inpatient diagnostic imaging, and prescription of inhaled corticosteroids at discharge, practices that deviate from the American Academy of Pediatrics guidelines. The causes of these differences require further study, but they support implementation of care pathways for severe bronchiolitis., (© 2014 Society of Hospital Medicine.)

Objective: To determine whether hospital length-of-stay (LOS) for bronchiolitis is influenced by the causative virus: respiratory syncytial virus (RSV) or rhinovirus., Methods: This prospective study was carried out in 3 university hospitals in Finland during 2 consecutive winter seasons. We enrolled consecutive children <2 years of age hospitalized with an attending physician's diagnosis of bronchiolitis. All enrolled children were included in the primary analysis. A parallel analysis was also conducted using a stricter definition for bronchiolitis (age <12 months and no history of wheeze). Polymerase chain reaction was used to test the nasopharyngeal aspirate samples for multiple respiratory pathogens., Results: The median age of the 408 children was 8 months, 73% had no history of wheeze and their median hospital LOS was 2 days. 144 (35%) children had RSV only and 92 (23%) children rhinovirus only infections. Children with rhinovirus only had shorter duration of prehospital symptoms, higher disease severity score at entry and more often a history of wheezing (all P ≤ 0.001). Controlling for 7 demographic and clinical characteristics, those with rhinovirus only had shorter hospital LOS when compared with children with RSV only (adjusted odds ratio: 0.45; 95% confidence interval: 0.22-0.92; P = 0.03). The rhinovirus only finding was similar in the subset of 206 children with stricter diagnosis (adjusted odds ratio: 0.30; 0.06-1.49; P = 0.14)., Conclusions: Hospital LOS is associated with rhinovirus etiology of bronchiolitis. Our data call attention to the importance of both RSV and rhinovirus testing in clinical research.

Background: It is unclear whether the infectious etiology of severe bronchiolitis affects short-term outcomes, such as posthospitalization relapse. We tested the hypothesis that children hospitalized with rhinovirus (RV) bronchiolitis, either as a sole pathogen or in combination with respiratory syncytial virus (RSV), are at increased risk of relapse., Methods: We performed a 16-center, prospective cohort study of hospitalized children age <2 years with bronchiolitis. During the winters of 2007-2010, researchers collected clinical data and nasopharyngeal aspirates from study participants; the aspirates were tested using real-time polymerase chain reaction. The primary outcome was bronchiolitis relapse (urgent bronchiolitis visit or scheduled visit at which additions to the bronchiolitis medications were made) during the 2 weeks after hospital discharge., Results: Among 1836 enrolled children with 2-week, follow-up data, the median age was 4 months and 60% were male. Overall, 48% had sole RSV infection, 8% had sole RV infection, and 13% had RSV/RV coinfection. Compared with children with sole RSV infection, and adjusting for 10 demographic and clinical characteristics and clustering of patients within hospitals, children with sole RV infection did not differ in their likelihood of relapse (odds ratio: 0.99; 95% confidence interval: 0.52-1.90; P = 0.98), whereas those with RSV/RV coinfection were more likely to have relapse (odds ratio: 1.54; 95% confidence interval: 1.03-2.30; P = 0.03)., Conclusions: In this prospective, multicenter, multiyear study of children hospitalized with bronchiolitis, we found that RSV/RV coinfection was independently associated with a higher likelihood of bronchiolitis relapse. Present data support the concept that the infectious etiology of severe bronchiolitis affects short-term outcomes.

Objective: To identify risk factors for inpatient apnea among children hospitalized with bronchiolitis., Methods: We enrolled 2207 children, aged <2 years, hospitalized with bronchiolitis at 16 sites during the winters of 2007 to 2010. Nasopharyngeal aspirates (NPAs) were obtained on all subjects, and real-time polymerase chain reaction was used to test NPA samples for 16 viruses. Inpatient apnea was ascertained by daily chart review, with outcome data in 2156 children (98%). Age was corrected for birth <37 weeks. Multivariable logistic regression was performed to identify independent risk factors for inpatient apnea., Results: Inpatient apnea was identified in 108 children (5%, 95% confidence interval [CI] 4%-6%). Statistically significant, independent predictors of inpatient apnea included: corrected ages of <2 weeks (odds ratio [OR] 9.67) and 2 to 8 weeks (OR 4.72), compared with age ≥ 6 months; birth weight <2.3 kg (5 pounds; OR 2.15), compared with ≥ 3.2 kg (7 pounds); caretaker report of previous apnea during this bronchiolitis episode (OR 3.63); preadmission respiratory rates of <30 (OR 4.05), 30 to 39 (OR 2.35) and >70 (OR 2.26), compared with 40 to 49; and having a preadmission room air oxygen saturation <90% (OR 1.60). Apnea risk was similar across the major viral pathogens., Conclusions: In this prospective, multicenter study of children hospitalized with bronchiolitis, inpatient apnea was associated with younger corrected age, lower birth weight, history of apnea, and preadmission clinical factors including low or high respiratory rates and low room air oxygen saturation. Several bronchiolitis pathogens were associated with apnea, with similar apnea risk across the major viral pathogens.

We reexamined the finding of an inverse relationship between values of nasopharyngeal lactate dehydrogenase, a marker of the innate immune response, and bronchiolitis severity. In a prospective, multicenter study of 258 children, we found in a multivariable model that higher nasopharyngeal lactate dehydrogenase values in young children with bronchiolitis were independently associated with a decreased risk of hospitalization.

Objective: Because the decision to hospitalize an infant with bronchiolitis is often supported by subjective criteria and objective indicators of bronchiolitis severity are lacking, we tested the hypothesis that lactate dehydrogenase (LDH), which is released from injured cells, is a useful biochemical indicator of bronchiolitis severity., Patients and Methods: We retrospectively analyzed a study of children <24 months old presenting to the emergency department with bronchiolitis. Demographic, clinical information, nasal wash (NW), and serum specimens were obtained. NW samples were analyzed for respiratory viruses, caspase 3/7 activity, and a panel of cytokines and chemokines. Total LDH activity was tested in NW samples and sera., Results: Of 101 enrolled children (median age: 5.6 months), 98 had NW specimens available. A viral etiology was found for 82 patients (83.6%), with respiratory syncytial virus (RSV) (66%) and rhinovirus (19%) being the most common viruses detected. Concentrations of LDH in NW specimens were independent from those in sera and were higher in children with RSV infection or with dual infection. Significant correlations were found between NW LDH and NW cytokines/chemokines. Similarly, NW LDH correlated with NW-caspase 3/7 activity (r = 0.75; P < .001). In a multivariate analysis, NW LDH concentration in the upper quartile was significantly associated with a reduced risk of hospitalization (odds ratio: 0.19 [95% confidence interval: 0.05-0.68]; P = .011)., Conclusions: NW LDH levels in young children with bronchiolitis varied according to viral etiology and disease severity. Values in the upper quartile were associated with approximately 80% risk reduction in hospitalization, likely reflecting a robust antiviral response. NW LDH may be a useful biomarker to assist the clinician in the decision to hospitalize a child with bronchiolitis.