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OBJECTIVES: Although recent evidence suggests that management of viral bronchiolitis requires something other than guidelines-guided therapy, there is a lack of evidence supporting the economic benefits of phenotypic-guided bronchodilator therapy for treating this disease. The aim of the present study was to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. METHODS: A decision analysis model was developed to compare the cost-effectiveness of phenotypic-guided versus guidelines-guided bronchodilator therapy in infants with viral bronchiolitis. Phenotypic-guided bronchodilator therapy was defined as the administration of albuterol in infants exhibiting a profile of increased likelihood of response to bronchodilators. The effectiveness parameters and costs of the model were obtained from systematic reviews of the literature with meta-analyses and electronic medical records. The main outcome was the avoidance of hospital admission after initial care in the emergency department. RESULTS: Compared to guidelines-guided strategy, treating patients with viral bronchiolitis with the phenotypic-guided bronchodilator therapy strategy was associated with lower total costs (US$250.99; 95% uncertainty interval [UI]: US $184.37 to $336.51 vs. US$263.46; 95% UI: US$189.81 to $349.19 average cost per patient) and a higher probability of avoidance of hospital admission (0.7902; 95% UI: 0.7315–0.8356 vs. 0.7638; 95% UI: 0.7062–0.8201), thus leading to dominance. Results were robust to deterministic and probabilistic sensitivity analyses. CONCLUSIONS: Compared to guidelines-guided strategy, treating infants with viral bronchiolitis using the phenotypic-guided bronchodilator therapy strategy is a more cost-effective strategy, because it involves a lower probability of hospital admission at lower total treatment costs.

In persons with cystic fibrosis (CF), decreased airway microbial diversity is associated with lower lung function. Conflicting data exist on the impact of short-term antibiotics for treatment of acute pulmonary exacerbations. However, whether differences in antibiotic exposure impacts airway microbiome changes has not been studied. We hypothesized that subtherapeutic beta-lactam antibiotic exposure, determined by the pharmacokinetics and pharmacodynamics (PK/PD) after intravenous (IV) antibiotic administration, would be associated with different patterns of changes in CF airway microbial diversity. Eligible children were enrolled when well; study assessments were performed around the time of pulmonary exacerbation. Plasma drug concentrations and bacterial minimum inhibitory concentrations (MICs) were used to determine therapeutic versus subtherapeutic beta-lactam antibiotic exposure. Respiratory samples were collected from children, and extracted bacterial DNA was amplified for the V4 region of the 16S rRNA gene. Twenty children experienced 31 APEs during the study; 45% (n = 14) of antibiotic courses were deemed therapeutic. Those in the therapeutic group had more significant decreases in alpha diversity at end of treatment and post-recovery compared to baseline than those in the subtherapeutic group. Therapeutic and subtherapeutic beta-lactam use is associated with different patterns of changes in CF airway microbial diversity following antibiotic administration.

Background: Early rhinovirus (RV) infection is a strong risk factor for asthma development. Airway remodeling factors play a key role in the progression of the asthmatic condition. We hypothesized that RV infection in young children elicits the secretion of growth factors implicated in airway remodeling and asthma progression.Methods: We examined the nasal airway production of remodeling factors in children ( ≤ 2 years old) hospitalized due to PCR-confirmed RV infection. Airway remodeling proteins included: MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, TIMP-2, EGF, Angiopoietin-2, G-CSF, BMP-9, Endoglin, Endothelin-1, Leptin, FGF-1, Follistatin, HGF, HB-EGF, PLGF, VEGF-A, VEGF-C, VEGF-D, FGF-2, TGF-β1, TGF-β2, TGF-β3, PDGF AA, PDGF BB, SPARC, Periostin, OPN, and TGF-α.Results: A total of 43 young children comprising RV cases (n = 26) and uninfected controls (n = 17) were included. Early RV infection was linked to (1) enhanced production of several remodeling factors (e.g., HGF, TGFα), (2) lower MMP-9/TIMP-2 and MMP-2/TIMP-2 ratios, and (3) increased MMP-10/TIMP-1 ratios. We also found that relative to term infants, severely premature children had reduced MMP-9/TIMP-2 ratios at baseline.Conclusion: RV infection in young children elicits the airway secretion of growth factors implicated in angiogenesis, fibrosis, and extracellular matrix deposition. Our results highlight the potential of investigating virus-induced airway remodeling growth factors during early infancy to monitor and potentially prevent chronic progression of respiratory disorders in all ages.

INTRODUCTION: IFN-lambda (type III-IFN-λ1) is a molecule primarily produced by epithelial cells that provides an important first-line defense against viral respiratory infections and has been linked to the pathogenesis of viral induced wheezing in early life. The goal of this study was to better understand the regulation of innate IFN-lambda responses in vitro in primary human infant airway epithelial cells (AECs) and in vivo using nasal aspirates during viral respiratory infections. METHODS: IFN-lambda protein levels were quantified: I) in human infant AECs exposed to (poly(I:C) dsRNA) under different experimental conditions (n=8 donors); and II) in nasal aspirates of young children (≤3 years) hospitalized with viral respiratory infection (n=138) and in uninfected controls (n= 74). In vivo IFN-lambda airway levels during viral infections were correlated with individual characteristics and respiratory disease parameters. RESULTS: Our in vitro experiments showed that the poly(I:C)-induced innate production of IFN-lambda in human infant AECs is regulated by: I) p38-MAPK/NF-kB dependent mechanism; and II) exposure to pro-inflammatory signals such as IL1β. Our in vivo studies demonstrated that: I) infants (90(th) percentile) had higher viral loads and were more likely to have respiratory sick visits within 12-months of discharge (OR= 5.8). CONCLUSION: IFN-lambda responses to dsRNA in the human infant airway epithelium are regulated by p38-MAPK and NF-kB signaling. High in vivo IFN-lambda production is influenced by virus type and associated with recurrent respiratory sick visits in young children.

OBJECTIVE Initiation of continuous positive airway pressure (CPAP) in children with severe obstructive sleep apnea syndrome (OSAS) is challenging and the distinct features of the subset of children requiring CPAP are poorly defined. Asthma often coexists with OSAS in children. The goal of this study was to explore the influence of asthma in the need for CPAP therapy in children with severe OSAS. HYPOTHESIS Asthmatic children with severe OSAS have higher probability of needing CPAP than children with severe OSAS without asthma. METHODS Cross-sectional study of clinical presentation, individual risk factors, and initial overnight polysomnogram (PSG) parameters in children with severe OSAS. Severe OSAS was defined as an obstructive apnea hypopnea index ≥10/h. The association between asthma and CPAP initiation was studied individually and adjusted by pertinent covariates. RESULTS Four hundred eligible children (mean age 7 years, ±SD 5.3) with severe OSAS were enrolled and 133 individuals (33%) were identified to have asthma. The proportion of children needing CPAP was significantly higher in asthmatics with severe OSAS (29%) compared to those with OSAS alone (14%) (P

Introduction: Viral bronchiolitis is a term often used to group all infants with the first episode of severe viral respiratory infection. However, this term encompasses a collection of different clinical and biological processes. We hypothesized that the first episode of severe viral respiratory infection in infants can be subset into clinical phenotypes with distinct outcomes and underlying airway disease patterns. Methods: We included children (≤2 years old) hospitalized for the first time due to PCR-confirmed viral respiratory infection. All cases were categorized based on primary manifestations (wheezing, sub-costal retractions and hypoxemia) into mild, hypoxemia or wheezing phenotypes. We characterized these phenotypes using lung-X-rays, respiratory outcomes and nasal protein levels of antiviral and type 2 cytokines (IFNγ, IL-10, IL-4, IL-13, IL-1β, and TNFα). Results: A total of 50 young children comprising viral respiratory infection cases (n = 41) and uninfected controls (n = 9) were included. We found that 22% of viral respiratory infection cases were classified as mild (n = 9), 39% as hypoxemia phenotype (n = 16) and 39% as wheezing phenotype (n = 16). Individuals in the hypoxemia phenotype had more lung opacities, higher probability of PICU admission and prolonged hospitalizations. Subjects in the wheezing phenotype had higher probability of recurrent sick visits. Nasal cytokine profiles showed that individuals with recurrent sick visits in the wheezing phenotype had increased nasal airway levels of type 2 cytokines (IL-13/IL-4). Conclusion: Clinically-based classification of the first episode of severe viral respiratory infection into mild, hypoxemia or wheezing phenotypes provides critical information about respiratory outcomes, lung disease patterns and underlying airway immunobiology.

Background Human Rhinovirus (HRV) has been identified as the most common cause of acute respiratory infections and hospitalizations in premature children. It is unclear if premature children are more susceptible to HRV due to their decreased pulmonary reserve or because they have enhanced lower airway reactivity to HRV. Methods We conducted a retrospective analysis of the clinical respiratory presentation of all PCR-confirmed HRV infections in full-term and premature children aged ≤3 years in our institution. Standardized respiratory distress scores were developed to examine lower airway obstruction (i.e., wheezing, hyperinflation, and sub-costal retractions) along with markers of decreased pulmonary reserve (hypoxemia and tachypnea) in young children with HRV infections. Demographic and clinical variables were obtained from reviewing electronic medical records (EMR). Results This study included a total of 205 children; 71% of these children were born full-term (>37 weeks gestation), 10% preterm (32–37 weeks) and 19% severely premature (

Viral respiratory infections are often grouped as a single respiratory syndrome named ‘viral bronchiolitis’, independently of the viral etiology or individual risk factors. Clinical trials and guidelines have used a more stringent definition of viral bronchiolitis, including only the first episode of wheezing in children less than 12 months of age without concomitant respiratory comorbidities. There is increasing evidence suggesting that this definition is not being followed by pediatric care providers, but it is unclear to what extent viral respiratory infections are currently misclassified as viral bronchiolitis using standard definitions. We conducted a retrospective analysis of hospitalized young children (≤3 years) due to viral respiratory infections. Bronchiolitis was defined as the first wheezing episode less than 12 months of age. Demographic variables and comorbidities were obtained by electronic medical record review. The study comprised a total of 513 hospitalizations (n=453). Viral bronchiolitis was diagnosed in 144 admissions (28.1%). Notably, we identified that the majority of children diagnosed with bronchiolitis (63%) were misclassified as they had prior episodes of wheezing. Many children with bronchiolitis misclassification had significant comorbidities, including prematurity (51%), neuromuscular conditions (9.8%), and congenital heart disease (9.8%). Misclassification of bronchiolitis is a common problem that may lead to inappropriate management of viral respiratory infections in young children. A comprehensive approach that takes into consideration viral etiology and individual risk factors may lead to a more accurate clinical assessment of this condition and would potentially prevent bronchiolitis misclassification.

OBJECTIVES: To determine the antibiotic prescribing practices of pediatric residents and assess how they acquire knowledge leading to prescribing behaviors. METHODS: We performed a cross-sectional electronic survey of all pediatric residents at the Children’s National Medical Center and Nicklaus Children’s Hospital, assessing antibiotic prescribing patterns for common pediatric infections, use of antibiograms, and factors influencing antibiotic choice. RESULTS: Eighty-five surveys (45%) were returned complete and included in the analysis. Increased deviations from clinical guideline recommendations were observed for antibiotic treatments of sinusitis and community-acquired pneumonia as compared with otitis media and group A streptococcal pharyngitis. Only 57% of residents reported having used antibiograms. General pediatric inpatient attending physicians were identified as the most influential source for house staff antibiotic knowledge. CONCLUSIONS: Results illustrate the need for better promotion and integration of clinical guidelines with antibiograms when developing antibiotic education programs for residents in training. In addition, pediatric hospitalists should play an active role in the implementation of these programs and can provide valuable insight into the development of educational programs in conjunction with graduate medical education divisions.

We need a better risk stratification system for the increasing number of survivors of extreme prematurity suffering the most severe forms of bronchopulmonary dysplasia (BPD). However, there is still a paucity of studies providing scientific evidence to guide future updates of BPD severity definitions. Our goal was to validate a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks postmenstrual age (PMA). We hypothesized that this approach improves BPD risk assessment, particularly in extremely premature infants. This is a longitudinal cohort of premature infants (≤32 weeks PMA, n = 188; Washington D.C). We performed receiver operating characteristic analysis to define optimal BPD severity levels using the duration of supplementary O2 as predictor and respiratory hospitalization after discharge as outcome. Internal validation included lung X-ray imaging and phenotypical characterization of BPD severity levels. External validation was conducted in an independent longitudinal cohort of premature infants (≤36 weeks PMA, n = 130; Bogota). We found that incorporating the total number of days requiring O2 (without restricting at 36 weeks PMA) improved the prediction of respiratory outcomes according to BPD severity. In addition, we defined a new severity category (level IV) with prolonged exposure to supplemental O2 (≥120 days) that has the highest risk of respiratory hospitalizations after discharge. We confirmed these findings in our validation cohort using ambulatory determination of O2 requirements. In conclusion, a new predictive model for BPD severity that incorporates respiratory assessments beyond 36 weeks improves risk stratification and should be considered when updating current BPD severity definitions.

Infants requiring hospitalization due to a viral lower respiratory tract infection (LRTI) have a high risk of developing recurrent respiratory illnesses in early life and asthma beyond childhood. Notably, all validated clinical scales for viral LRTI have focused on predicting acute severity instead of recurrence. We present a novel clinical approach combining individual risk factors with bedside clinical parameters to predict recurrence after viral LRTI hospitalization in young children. A retrospective longitudinal cohort of young children (≤3 years) designed to define clinical predictive factors of recurrent respiratory illnesses within 12 months after hospitalization due to PCR-confirmed viral LRTI. Data collection was through electronic medical record. We included 138 children hospitalized with viral LRTI. Using automatic stepwise logistic model selection, we found that the strongest predictors of recurrence in infants hospitalized for the first time were severe prematurity (≤32 weeks’ gestational age, OR=5.19; 95% CI 1.76 to 15.32; p=0.002) and a clinical score that weighted hypoxemia, subcostal retractions and wheezing (OR=3.33; 95% CI 1.59 to 6.98; p

Patients with neuromuscular disease (NMD) experience weakened cough due to progressive respiratory muscle weakness. Peak cough flow (PCF) measurements derived from adult populations are used to recommend initiation of assisted cough therapies. The objective of this study was to characterize PCF values among pediatric patients with NMD. Retrospective chart review was performed for patients seen in the multidisciplinary pediatric muscular dystrophy clinic from 2010 to 2016. Clinical and demographic variables included age, gender, ambulation status, and PCF measurements. 366 patients with an established diagnosis of NMD (median age 11.8 years) were included in this study. 102 (27.8%) out of the 366 patients were affected by Duchenne muscular dystrophy (DMD), 42 (11.5%) by congenital muscular dystrophy (CMD), 42 (11.5%) by Charcot Marie Tooth disease (CMT) and 24 (6.5%) by Becker’s muscular dystrophy (BMD). The mean PCF values in DMD (255.8 L/min) and CMD (249.1 L/min) were lower than CMT (321.5 L/min) with p-values of 0.007 and 0.02, respectively. The mean PCF of BMD (333.3 L/min) was higher than that of DMD and CMD but the difference was not statistically significant. PCFs were not statistically different between ambulatory and non-ambulatory status (263.0 L/min versus 290.8 L/min, p = 0.12). Children under 10 years of age had lower PCF relative to older subjects (179.5 L/min versus 300.9 L/min, p

BackgroundTo carry out a complete clinical, pathological, genetic and microbiological characterization of pediatric patients with molecular confirmed cystic fibrosis (CF) attending the Carlos Andrade Marín Hospital (HCAM) within the study period.MethodsA cross-sectional analysis of the pediatric population with a confirmed diagnosis of CF disease who attended HCAM, one of the largest tertiary-level hospitals in Ecuador, between 2017 and 2018 was performed. All demographic, clinical and genetic variables were obtained from the electronic medical records (EMR) stored by the hospital.ResultsForty seven patients with CF were included in the study. Gender distribution was similar between male (48.9%,n = 23) and female patients (51.1%,n = 24). The Tiffeneau-Pinelli index (FEV1/FVC) changed significantly after nine months post-diagnosis (85.55 ± 13.26;p n = 19); H609R, found in 36.11% (n = 13); g.204099A > C, found in 14.1% (n = 7), followed by G85E and the N1303K with 11.11% (n = 3) each.ConclusionsTo our best knowledge, this is the first study exploring the clinical, genetic and bacteriological profile of CF’s patients in Ecuador. Within the cohort of patients, an important and unique genetic feature was characterized by the presence of the g.204099A > C and the c.206359C > A homozygous polymorphism as well as the presence of the H609R variant, a mutation only reported among Ecuadorians.

Background Culture-independent next generation sequencing has identified diverse microbial communities within the cystic fibrosis (CF) airway. The study objective was to test for differences in the upper airway microbiome of children with CF and healthy controls and age-related differences in children with CF. Methods Oropharyngeal swabs and clinical data were obtained from 25 children with CF and 50 healthy controls aged ≤6 years. Bacterial DNA was amplified and sequenced for the V4 region of 16S rRNA marker-gene. Alpha diversity was measured using operational taxonomic units (OTUs), Shannon diversity, and the inverse Simpson's index. Beta diversity was measured using Morisita-Horn and Bray-Curtis and Jaccard distances. General linear models were used for comparison of alpha diversity measures between groups to account for differences in demographics and exposures. Mixed effects general linear models were used for longitudinal comparisons 1) between children with CF of different ages and 2) between children with CF receiving CF transmembrane conductance regulator (CFTR) modulators, children with CF not receiving CFTR modulators, and healthy controls to adjust for repeated measures per subject. Results Children with CF were more likely to have received antibiotics in the prior year than healthy controls (92% vs 24%, p < 0.001). Controlling age, race, ethnicity, length of breastfeeding, and having siblings, children with CF had a lower richness than healthy controls: OTUs 62.1 vs 83, p = 0.022; and trended toward lower diversity: Shannon 2.09 vs 2.35, p = 0.057; inverse Simpson 5.7 vs 6.92, p = 0.118. Staphylococcus, three Rothia OTUs, and two Streptococcus OTUs were more abundant in CF children versus healthy controls (all p < 0.05). Bray-Curtis and Jaccard distances, which reflect overall microbial community composition, were also significantly different (both p = 0.001). In longitudinally collected samples from children with CF, Morisita-Horn trended toward more similarity in those aged 0–2 years compared to those aged 3–6 years (p = 0.070). In children >2 years of age, there was a significant trend in increasing alpha diversity measures between children with CF not receiving CFTR modulators, children with CF receiving CFTR modulators, and healthy controls: OTUs 63.7 vs 74.7 vs 97.6, p < 0.001; Shannon 2.11 vs 2.34 vs 2.56, p < 0.001; inverse Simpson 5.78 vs 7.23 vs 7.96, p < 0.001. Conclusions Children with CF have lower bacterial diversity and different composition of organisms compared with healthy controls. This appears to start in early childhood, is possibly related to the use of antibiotics, and may be partially corrected with the use of CFTR modulators., Health sciences; Respiratory system; Infectious disease; Microbiology; Epidemiology; Pediatrics; Cystic fibrosis; Human microbiome; Pulmonary medicine.

Background: Tracheostomy in infants is primarily required for long-term ventilatory support due to lung disease or neuromuscular weakness, and/or to bypass severe upper airway obstruction. Objective: To determine whether the course of respiratory disease changes after tracheostomy, depending on the primary indication for the procedure. Methods: Retrospective review of electronic medical records of infants who underwent tracheostomy. Clinical variables included among others demographics, perinatal history, age at tracheostomy and length of hospital stay. Results: Forty-six infants (29 male) underwent tracheostomy; 30 for ventilatory support (group A) and 16 due to upper airway obstruction (group B). Mean gestational age and birth weight were significantly lower in group A (29±6 vs. 35±6 weeks, p Conclusions: Infants who undergo tracheostomy represent two distinct populations. The clinical course after tracheostomy appears to be determined primarily by the underlying condition, especially prematurity and severe BPD. However, tracheostomy appears to facilitate patients’ rehabilitation.

Summary Objective To characterize the epidemiology and the clinical, pathological, microbiological and genetical profile of children with cystic fibrosis treated in Ecuador. Methods We conducted a cross-sectional analysis of the pediatric population with a confirmed diagnosis of cystic fibrosis (CF) attending to one of the biggest III-level hospitals in Ecuador. All demographic, clinical and genetical variables were obtained from the electronic medical records (EMR) from 2017-2018. Results 47 patients with CF were observed and followed for more than a year. Gender distribution was similar between male (48.9%, n = 23) and female patients (51.1%, n = 24). The Tiffeneau-Pinelli index (FEV1/FVC) changed significantly after 9 months post-diagnosis (85.55 ± 13.26; p C, which has only been reported among Ecuadorians. Conclusions This is the first study carried out in Ecuador exploring the clinical, genetical and bacteriological analysis of patients with CF. Children with CF are often colonized by four species of gram-positive bacteria (S. aureus, Coagulase-Negative Staphylococcus, Streptococcus pneumoniae and M. catarrhalis) were the most predominant this condition atients were hospitalized for complications related to cystic fibrosis, with an average of 19 days of stay.

Spinal muscular atrophy is one of the most common fatal autosomal recessive disorders. Children diagnosed with SMA Type 1 (SMAT1) demonstrate severe oral motor weakness and flaccid dysarthria progressing to complete anarthria. A review of literature illustrates that little has been described regarding augmentative and alternative communication (AAC) use among these children, although communication has a critical impact on quality of life and participation in daily activities. Responses to an investigator-developed parent survey were obtained to appraise communication skills and opportunities among children diagnosed with SMA1. Results illustrate parent perception of greater receptive than expressive language ability and highlight the benefits of implementing speech-generating devices (SGD). Barriers to SGD acquisition and implementation, including access and funding, are reported and described. Overall, families indicated that SGD increases quality of life and provides valued improvements through expanded functional communication.

Background: Human metapneumovirus (HMPV) is a recently discovered respiratory pathogen of the family Paramyxoviridae, the same family as that of respiratory syncytial virus (RSV). Premature children are at high risk of severe RSV infections, however, it is unclear whether HMPV infection is more severe in hospitalized children with a history of severe prematurity. Methods: We conducted a retrospective analysis of the clinical respiratory presentation of all polymerase chain reaction-confirmed HMPV infections in preschool-age children ( 5 years) with and without history of severe prematurity (

Background MicroRNAs (miRs) control gene expression and the development of the immune system and antiviral responses. MiR-155 is an evolutionarily-conserved molecule consistently induced during viral infections in different cell systems. Notably, there is still an unresolved paradox for the role of miR-155 during viral respiratory infections. Despite being essential for host antiviral TH1 immunity, miR-155 may also contribute to respiratory disease by enhancing allergic TH2 responses and NFkB-mediated inflammation. The central goal of this study was to define how airway miR-155 production is related to TH1, TH2, and pro-inflammatory cytokine responses during naturally occurring viral respiratory infections in young children. Methods Normalized nasal airway levels of miR-155 and nasal protein levels of IFN-γ, TNF-α, IL-1β, IL-13, IL-4 were quantified in young children (≤2 years) hospitalized with viral respiratory infections and uninfected controls. These data were linked to individual characteristics and respiratory disease parameters. Results A total of 151 subjects were included. Increased miR-155 levels were observed in nasal samples from patients with rhinovirus, RSV and all respiratory viruses analyzed. High miR-155 levels were strongly associated with high IFN-γ production, increased airway TH1 cytokine polarization (IFN-γ/IL-4 ratios) and increased pro-inflammatory responses. High airway miR-155 levels were linked to decreased respiratory disease severity in individuals with high airway TH1 antiviral responses. Conclusions The airway secretion of miR-155 during viral respiratory infections in young children is associated with enhanced antiviral immunity (TH1 polarization). Further studies are needed to define additional physiological roles of miR-155 in the respiratory tract of human infants and young children during health and disease.

OBJECTIVES To determine the frequency of subtherapeutic exposure to intravenously administered β-lactam antibiotics in a cohort of cystic fibrosis (CF) patients who were treated for a pulmonary exacerbation, and its impact on pulmonary function. METHODS Nineteen CF patients between the ages of 5 and 21 years treated at Children's National Health System for a pulmonary exacerbation were followed between March 2015 and August 2016 in a prospective, longitudinal study. Pharmacokinetic modeling and minimum inhibitory concentrations (MICs) of the involved pathogens were used to determine therapeutic or subtherapeutic β-lactam antibiotic exposure based on the time the antibiotic concentration was above the MIC. Clinical outcomes were measured by spirometry values. RESULTS The 19 participants were treated with a total of 29 courses of antibiotics. The most common β-lactam antibiotics used in a treatment course were ceftazidime (62%) and meropenem (45%). There was no difference in age, CF genotype, or creatinine clearance between the 9 participants (47%) who reached therapeutic concentrations versus the 10 (53%) who did not. Those who achieved sufficiently high antibiotic exposure had more significant improvement of their pulmonary function tests. CONCLUSIONS We found that sufficient antibiotic exposure during treatment of CF pulmonary exacerbations was associated with improved pulmonary function. Moreover, it was impossible to predict, solely from the dosing regimen used, which patients were going to reach therapeutic β-lactam antibiotic serum concentrations. This suggests that CF patients may benefit from closer monitoring of their β-lactam exposure and bacterial MIC for optimal clinical outcomes.

Background Cystic fibrosis (CF) is associated with significant morbidity and early mortality due to recurrent acute and chronic lung infections. The chronic use of multiple antibiotics increases the possibility of multidrug resistance (MDR). Antibiotic susceptibility determined by culture-based techniques may not fully represent the resistance profile. The study objective was to detect additional antibiotic resistance using molecular methods and relate the presence of MDR to airway microbiome diversity and pulmonary function. Methods Bacterial DNA was extracted from sputum samples and amplified for the V4 region of the 16S rRNA gene. An qPCR array was used to detect antibiotic resistance genes. Clinical culture results and pulmonary function were also noted for each encounter. Results Six study participants contributed samples from 19 encounters. Those samples with MDR (n = 7) had significantly lower diversity measured by inverse Simpson's index than those without (n = 12) (2.193 ± 0.427 vs 6.023 ± 1.564, p = 0.035). Differential abundance showed that samples with MDR had more Streptococcus (p = 0.002) and Alcaligenaceae_unclassified (p = 0.002). Pulmonary function was also decreased when MDR was present (FEV1, 51 ± 22.9 vs 77 ± 26.7, p = 0.054; FVC, 64.5 ± 22.7 vs 91.6 ± 27.7, p = 0.047). Conclusions The presence of MDR within the CF airway microbiome was associated with decreased microbial diversity, the presence of Alcaligenes, and decreased pulmonary function.

Cystic fibrosis (CF) is an autosomal recessive disease associated with recurrent lung infections that can lead to morbidity and mortality. The impact of antibiotics for treatment of acute pulmonary exacerbations on the CF airway microbiome remains unclear with prior studies giving conflicting results and being limited by their use of 16S ribosomal RNA sequencing. Our primary objective was to validate the use of true single molecular sequencing (tSMS) and PathoScope in the analysis of the CF airway microbiome. Three control samples were created with differing amounts of Burkholderia cepacia, Pseudomonas aeruginosa, and Prevotella melaninogenica, three common bacteria found in cystic fibrosis lungs. Paired sputa were also obtained from three study participants with CF before and >6 days after initiation of antibiotics. Antibiotic resistant B. cepacia and P. aeruginosa were identified in concurrently obtained respiratory cultures. Direct sequencing was performed using tSMS, and filtered reads were aligned to reference genomes from NCBI using PathoScope and Kraken and unique clade-specific marker genes using MetaPhlAn. A total of 180–518 K of 6–12 million filtered reads were aligned for each sample. Detection of known pathogens in control samples was most successful using PathoScope. In the CF sputa, alpha diversity measures varied based on the alignment method used, but similar trends were found between pre- and post-antibiotic samples. PathoScope outperformed Kraken and MetaPhlAn in our validation study of artificial bacterial community controls and also has advantages over Kraken and MetaPhlAn of being able to determine bacterial strains and the presence of fungal organisms. PathoScope can be confidently used when evaluating metagenomic data to determine CF airway microbiome diversity.

A 9-year-old male patient, previously healthy, presented with acute-onset chest pain. The pain was on the right lateral chest, 10/10 in severity and non-reproducible. The patient had 1-week history of cough that had been improving; no fever, weight loss, dyspnoea, palpitations or night sweats were reported. He had positive sick contacts. Examination was remarkable for slight decrease in breath sounds at the right lower lung field posteriorly. Initial chest radiograph showed a well-circumscribed opacity in the right lower lobe posteriorly with adjacent consolidation seen on the lateral view. The lesion appeared to be distinct from the cardiomediastinal silhouette (figure 1). Sonography was performed to characterise the nature of the lesion; however, it was difficult to visualise and only revealed mixed echotexture (figure 2). Contrast-enhanced CT scan of the thorax was then obtained. CT …

Background Rhinovirus (RV ) has been linked to the pathogenesis of asthma. Prematurity is a risk factor for severe RV infection in early life, but is unknown if RV elicits enhanced pro‐asthmatic airway cytokine responses in premature infants. This study investigated whether young children born severely premature (

Background Rhinitis and obstructive sleep apnea (OSA) often coexist during childhood. To delineate this clinical association, we examined OSA severity and polysomnogram (PSG) features in children with rhinitis and OSA. Given that rapid-eye-movement (REM) sleep is characterized by nasal congestion, we hypothesized that children with rhinitis have more REM-related breathing abnormalities. Methods We conducted a retrospective cross-sectional analysis of 145 children with PSG-diagnosed A. Outcomes included PSG parameters and obstructive apnea–hypopnea index (OAHI) during REM and non-REM. Linear multivariable models examined the joint effect of rhinitis and OSA parameters with control for potential confounders. Results Rhinitis was present in 43% of children with OSA (n = 63) but overall OAHI severity was unaffected by the presence of rhinitis. In contrast, OAHI during REM sleep in children with moderate-severe OSA was significantly increased subjects with rhinitis and OSA (44.1/hr; SE = 6.4) compared with those with OSA alone (28.2/hr; SE = 3.8). Conclusion Rhinitis is highly prevalent in children with OSA. Although OSA is not more severe in children with rhinitis, they do have a distinct OSA phenotype characterized by more REM-related OSA. Further research is needed to delineate the link between REM-sleep and the physiology of the nose during health and disease.

Background Next-generation sequencing has shown the cystic fibrosis (CF) lung microbiome to be a complex polymicrobial community. Anaerobic bacteria decrease in relative abundance with older age and disease progression, and may impact host inflammatory state. Persons with CF suffer from recurrent pulmonary exacerbations (PEs) that are treated with broad-spectrum antibiotics. Our objectives were to examine the effect of broad-spectrum (BS) vs narrow-spectrum (NS) anaerobic antibacterial treatment on bacterial diversity, and on pulmonary function recovery. Methods Pulmonary function tests (PFTs) and respiratory samples were collected as part of a prospective 18 month longitudinal study in CF patients at 4 time points, baseline (B), pulmonary exacerbation (E), end of exacerbation treatment (T), and follow-up (F). Treatment antibiotics were classified as broad or narrow based on anaerobic activity. 16S rRNA sequencing generated operational taxonomic units for analysis. Alpha diversity (relative abundance) was calculated via Shannon Index and Inverse Simpson formulas and β diversity (similarity in community composition) by Morisita-Horn (MH). Differences in diversity indices and PFTs were compared with regard to BS vs NS anaerobic activity, and statistical significance determined by GLS regression. Results Changes in alpha diversity for BS vs NS were not significantly different (P > 0.05) (Figures 1 and 2). Community composition measured by MH was consistently more similar for NS than BS (T-B: 0.66 vs. 0.45, P = 0.04; F-B: 0.75 vs. 0.47, P < 0.01) (Figure 3). Recovery of forced expiratory volume in 1 second (FEV1) from E to F was significantly higher in the NS group (25.4 vs. 21.0, P < 0.01) (Figure 4). Conclusion While antibiotic spectrum did not influence bacterial abundance, BS therapy led to higher changes in community composition from B and E onset following antibiotic administration compared with NS therapy. The differences in β diversity suggest BS therapy can have a lasting impact on community composition. As those receiving NS therapy had similar or better recovery of pulmonary function than those with BS, there is no indication that NS therapy leads to worse clinical outcomes. A limitation may be that children receiving BS therapy tended to have more severe disease. Disclosures All authors: No reported disclosures.

We report a significant complication after tracheocutaneous fistula (TCF) excision with closure by secondary intention in a 4-year-old boy who had been tracheostomy dependent since infancy. He had a persistent 3 mm TCF one year after decannulation. On postoperative day 2 the patient developed profound subcutaneous emphysema and pneumomediastinum. He was extubated after 2 days and discharged from the hospital on postoperative day 7. At follow up he had complete resolution of subcutaneous emphysema and complete closure of the TCF. The main methods of TCF closure and management of subcutaneous emphysema are discussed along with the lessons learned from this case.

Rhinovirus (RV) infections account for most asthma exacerbations among children and adults, yet the fundamental mechanism responsible for why asthmatics are more susceptible to RV than otherwise healthy individuals remains largely unknown. Nonetheless, the use of models to understand the mechanisms of RV-induced airway disease in asthma has dramatically expanded our knowledge about the cellular and molecular pathogenesis of the disease. For instance, ground-breaking studies have recently established that the susceptibility to RV in asthmatic subjects is associated with a dysfunctional airway epithelial inflammatory response generated after innate recognition of viral-related molecules, such as double-stranded RNA. This review summarizes the novel cardinal features of the asthmatic condition identified in the past few years through translational and experimental RV-based approaches. Specifically, we discuss the evidence demonstrating the presence of an abnormal innate antiviral immunity (airway epithelial secretion of types I and III interferons), exaggerated production of the master Th2 molecule thymic stromal lymphopoietin, and altered antimicrobial host defense in the airways of asthmatic individuals with acute RV infection.

To the Editor: Rhinovirus wheezing illnesses during early childhood are strongly linked with development of asthma later in life [1]. Indeed, rhinovirus infection in the first 3 years of life is associated with an almost 10-fold increase in risk for asthma at age 6 years [1]. The exact mechanism by which rhinovirus elicits a pro-asthmatic propensity in young children is largely unknown, but is purportedly related to a viral-induced T-helper cell (Th)2 airway inflammatory response [2]. Interestingly, the discovery of interactions between epithelial innate immunity and adaptive allergic responses has unveiled new potential links between rhinovirus and asthma. Of particular interest is the epithelial-derived cytokine thymic stromal lymphopoietin (TSLP), which is considered a “master Th2 cytokine” because it primes the differentiation of naive T0 cells into Th2 lymphocytes via activation of antigen presenting cells [3]. TSLP is induced by rhinovirus infection or by exposure to double stranded (ds)RNA (viral surrogate) in the lungs of allergic mice [4], and in human bronchial epithelial cells (HBEC) [5]. Together, these data suggest that TSLP may be the missing link between innate antiviral epithelial immunity and the Th2 immune response characteristic of asthma. This cross-sectional preliminary study aimed to investigate whether rhinovirus infections that occur naturally during the first 3 years of life are associated with elevated airway TSLP levels and enhanced Th2 responses, which may potentially facilitate the establishment of rhinovirus-induced pro-asthmatic changes during early childhood. We measured nasal airway TSLP, Th2 cytokines and antiviral responses in nasal washes obtained from newborns, infants and toddlers (≤3 years) with PCR-confirmed acute …

Cytomegalovirus (CMV) is a prevalent pathogen in the immunocompromised host and invasive pneumonia is a feared complication of the virus in this population. In this pediatric case series we characterized CMV lung infection in 15 non-HIV infected children (median age 3 years; IQR 0.2–4.9 years), using current molecular and imaging diagnostic modalities, in combination with respiratory signs and symptoms. The most prominent clinical and laboratory findings included cough (100%), hypoxemia (100%), diffuse adventitious breath sounds (100%) and increased respiratory effort (93%). All patients had abnormal lung images characterized by ground glass opacity/consolidation in 80% of cases. CMV was detected in the lung either by CMV PCR in bronchoalveolar lavage (82% detection rate) or histology/immunohistochemistry in lung biopsy (100% detection rate). CMV caused respiratory failure in 47% of children infected and the overall mortality rate was 13.3%. Conclusion: CMV pneumonia is a potential lethal disease in non-HIV infected children that requires a high-index of suspicion. Common clinical and radiological patterns such as hypoxemia, diffuse adventitious lung sounds and ground-glass pulmonary opacities may allow early identification of CMV lung infection in the pediatric population, which may lead to prompt initiation of antiviral therapy and better clinical outcomes.

Rationale. The sleep-related factors that modulate the nocturnal worsening of asthma in children are poorly understood. This study addressed the hypothesis that asthmatic children have a REM sleep-related vulnerability trait that is independent of OSA.Methods. We conducted a retrospective cross-sectional analysis of pulse-oximetry signals obtained during REM and NREM sleep in control and asthmatic children (n=134). Asthma classification was based on preestablished clinical criteria. Multivariate linear regression model was built to control for potential confounders (significance levelP≤0.05).Results. Our data demonstrated that (1) baseline nocturnal respiratory parameters were not significantly different in asthmatic versus control children, (2) the maximal % of SaO2desaturation during REM, but not during NREM, was significantly higher in asthmatic children, and (3) multivariate analysis revealed that the association between asthma and REM-related maximal % SaO2desaturation was independent of demographic variables.Conclusion. These results demonstrate that children with asthma have a REM-related vulnerability trait that impacts oxygenation independently of OSA. Further research is needed to delineate the REM sleep neurobiological mechanisms that modulate the phenotypical expression of nocturnal asthma in children.