Association of Pseudomonas aeruginosa infection stage with lung function trajectory in children with cystic fibrosis.

BACKGROUND: Pseudomonas aeruginosa (Pa) infection in cystic fibrosis (CF) is characterized in stages: never (prior to first positive culture) to incident (first positive culture) to chronic. The association of Pa infection stage with lung function trajectory is poorly understood and the impact of age on this association has not been examined. We hypothesized that FEV1 decline would be slowest prior to Pa infection, intermediate after incident infection and greatest after chronic Pa infection. METHODS: Participants in a large US prospective cohort study diagnosed with CF prior to age 3 contributed data through the U.S. CF Patient Registry. Cubic spline linear mixed effects models were used to evaluate the longitudinal association of Pa stage (never, incident, chronic using 4 different definitions) with FEV1 adjusted for relevant covariates. Models contained interaction terms between age and Pa stage. RESULTS: 1,264 subjects born 1992-2006 provided a median 9.5 (IQR 0.25 to 15.75) years of follow up through 2017. 89% developed incident Pa; 39-58% developed chronic Pa depending on the definition. Compared to never Pa, incident Pa infection was associated with greater annual FEV1 decline and chronic Pa infection with the greatest FEV1 decline. The most rapid FEV1 decline and strongest association with Pa infection stage was seen in early adolescence (ages 12-15). CONCLUSIONS: Annual FEV1 decline worsens significantly with each Pa infection stage in children with CF. Our findings suggest that measures to prevent chronic infection, particularly during the high-risk period of early adolescence, could mitigate FEV1 decline and improve survival.

Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole-Genome Analysis of 7,840 Patients.

Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome-wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 (SLC9A3/CEP72) and chr11p13 (EHF/APIP) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.

Strategies to increase uptake of voluntary medical male circumcision among men aged 25-39 years in Nyanza Region, Kenya: Results from a cluster randomized controlled trial (the TASCO study).

INTRODUCTION: Voluntary medical male circumcision (VMMC) for HIV prevention began in Nyanza Region, Kenya in 2008. By 2014, approximately 800,000 VMMCs had been conducted, and 84.9% were among males aged 15-24 years. We evaluated the impact of interpersonal communication (IPC) and dedicated service outlets (DSO) on VMMC uptake among men aged 25-39 years in Nyanza Region. MATERIALS AND METHODS: We conducted a cluster randomized controlled trial in 45 administrative Locations (clusters) in Nyanza Region between May 2014 and June 2016 among uncircumcised men aged 25-34 years. In arm one, an IPC toolkit was used to address barriers to VMMC. In the second arm, men were referred to DSO that were modified to address their preferences. Arm three combined the IPC and DSO arms, and arm four was standard of care (SOC). Randomization was done at Location level (11-12 per arm). The primary outcome was the proportion of enrolled men who received VMMC within three months. Generalized estimating equations were used to evaluate the effect of interventions on the outcome. RESULTS: At baseline, 9,238 households with men aged 25-39 years were enumerated, 9,679 men were assessed, and 2,792 (28.8%) were eligible. For enrollment, 577 enrolled in the IPC arm, 825 in DSO, 723 in combined IPC + DSO, and 667 in SOC. VMMC uptake among men in the SOC arm was 3.2%. In IPC, DSO, and combined IPC + DSO arms, uptake was 3.3%, 4.5%, and 4.4%, respectively. The adjusted odds ratio (aOR) of VMMC uptake in the study arms compared to SOC were IPC aOR = 1.03; 95% CI: 0.50-2.13, DSO aOR = 1.31; 95% CI: 0.67-2.57, and IPC + DSO combined aOR = 1.31, 95% CI: 0.65-2.67. DISCUSSION: Using these interventions among men aged 25-39 years did not significantly impact VMMC uptake. These findings suggest that alternative demand creation strategies for VMMC services are needed to reach men aged 25-39 years. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02497989.

Airway Disease in Children with Primary Ciliary Dyskinesia: Impact of Ciliary Ultrastructure Defect and Genotype.

Rationale: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance, recurrent respiratory infections, progressive airway damage, and obstructive lung disease. Although the association of ciliary ultrastructure defect/genotype with the severity of airflow obstruction has been well characterized, their association with airway abnormalities on chest computed tomography (CT) has been minimally evaluated. Objectives: We sought to delineate the association of ciliary defect class/genotype with chest CT scores in children with PCD. Methods: Cross-sectional analysis of children with PCD (N = 146) enrolled in a prospective multicenter observational study, stratified by defect type: outer dynein arm (ODA), ODA/inner dynein arm (IDA), IDA/microtubular disorganization (MTD), and normal/near normal ultrastructure with associated genotypes. CTs were scored using the MERAGMA-PCD (Melbourne-Rotterdam Annotated Grid Morphometric Analysis for PCD), evaluating airway abnormalities in a hierarchical order: atelectasis, bronchiectasis, bronchial wall thickening, and mucus plugging/tree-in-bud opacities. The volume fraction of each component was expressed as the percentage of total lung volume. The percentage of disease was computed as the sum of all components. Regression analyses were used to describe the association between clinical predictors and CT scores. Results: Acceptable chest CTs were obtained in 141 children (71 male): 57 ODA, 20 ODA/IDA, 40 IDA/MTD, and 24 normal/near normal. The mean (standard deviation) age was 8.5 (4.6) years, forced expiratory volume in 1 second (FEV1) percent predicted was 82.4 (19.5), and %Disease was 4.6 (3.5). Children with IDA/MTD defects had a higher %Disease compared with children with ODA defects (2.71% higher [95% confidence interval (CI), 1.37-4.06; P < 0.001]), driven by higher %Mucus plugging (2.35% higher [1.43-3.26; P < 0.001]). Increasing age, lower body mass index, and lower FEV1 were associated with a higher %Disease (0.23%; 95% CI, 0.11-0.35; P < 0.001 and 0.03%; 95% CI, 0.01-0.04; P = 0.008 and 0.05%; 95% CI, 0.01-0.08; P = 0.011, respectively). Conclusions: Children with IDA/MTD defects had significantly greater airway disease on CT, primarily mucus plugging, compared with children with ODA defects.

Systemic Corticosteroids in the Management of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

Rationale: Pulmonary exacerbation (PEx) events contribute to lung function decline in people with cystic fibrosis (CF). CF Foundation PEx guidelines note that a short course of systemic corticosteroids may offer benefit without contributing to long-term adverse effects. However, insufficient evidence exists to recommend systemic corticosteroids for PEx treatment. Objectives: To determine if systemic corticosteroids for the treatment of in-hospital pediatric PEx are associated with improved clinical outcomes compared with treatment without systemic corticosteroids. Methods: We conducted a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked database. People with CF were included if hospitalized for a PEx between 2006 and 2018 and were 6-21 years of age. Time to next PEx was assessed by Cox proportional hazards regression. Lung function outcomes were assessed by linear mixed-effect modeling and generalized estimating equations. To address confounding by indication, inverse probability treatment weighting was used. Results: A total of 3,471 people with CF contributed 9,787 PEx for analysis. Systemic corticosteroids were used in 15% of all PEx. In our primary analysis, systemic corticosteroids were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -0.36; 95% confidence interval [CI], -1.14, 0.42; P = 0.4) or a higher odds of returning to lung function baseline (odds ratio, 0.97; 95% CI, 0.84-1.12; P = 0.7) but were associated with a reduced chance of future PEx requiring intravenous antibiotics (hazard ratio, 0.91; 95% CI, 0.85-0.96; P = 0.002). When restricting the analysis to one PEx per person, lung function outcomes remained no different among PEx treated with or without systemic corticosteroids, but, in contrast to our primary analysis, the use of systemic corticosteroids was no longer associated with a reduced chance of having a future PEx requiring intravenous antibiotics (hazard ratio, 0.96; 95% CI, 0.86, 1.07; P = 0.42). Conclusions: Systemic corticosteroid treatment for in-hospital pediatric PEx was not associated with improved lung function outcomes. Prospective trials are needed to better evaluate the risks and benefits of systemic corticosteroid use for PEx treatment in children with CF.

Pleiotropic modifiers of age-related diabetes and neonatal intestinal obstruction in cystic fibrosis.

Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.

Performance and usability of a new mobile application for measuring respiratory rate in young children with acute lower respiratory infections.

OBJECTIVES: Respiratory rate (RR) measurement is critical to diagnosing pneumonia in resource-constrained settings, but accurate RR measurement is challenging. The acute lower respiratory illness treatment and evaluation (ALRITE) mobile phone application (app), designed to help healthcare workers (HCWs) manage pediatric respiratory illnesses, includes a semiautomated RR counter. This study aimed to evaluate the accuracy and usability of the ALRITE RR counter and a commercially available RR counter app, RRate, with a reference standard. METHODS: This was a cross-sectional observational study of HCWs. Participants used both apps to measure the RR of pediatric patients from standardized videos. The reference standard was determined by consensus of a manual 1-min count by two providers. We assessed agreement using Spearman's rank correlation coefficient and constructed Bland-Altman plots to determine bias and limits of agreement. Participants completed a usability survey. RESULTS: Thirty-nine HCWs participated. The agreement between the apps and reference standard (Spearman's coefficient) was 0.83 (95% confidence interval [CI]: 0.78-0.87) for ALRITE and 0.62 (95% CI: 0.52-0.70) for RRate. ALRITE had a bias of -2 breaths/min (lower limit of agreement [LoA] -16 to +12) and RRate had a bias of -0.4 breaths/min (LoA -24 to +23) compared to the reference standard. Both apps had a poorer agreement at higher RRs. Based on usability survey responses, 95% found ALRITE easy to use. CONCLUSIONS: The ALRITE RR counter has acceptable accuracy for counting RR in infants with respiratory distress, appears to be more accurate than a commercially available option, and was user-friendly. The ALRITE RR counter is a promising tool for meriting evaluation in real-world settings.

Clinical Outcomes of Antipseudomonal versus Other Antibiotics among Children with Cystic Fibrosis without Pseudomonas aeruginosa.

Rationale: Antibiotic selection for pulmonary exacerbation (PEx) management in children with cystic fibrosis is typically guided by prior respiratory culture results. Although antipseudomonal antibiotics are often used in children with chronic Pseudomonas aeruginosa (Pa) airway infection, no data exist to guide antibiotic selection in children who are culture negative for Pa for ≥1 year. Objectives: To determine among children classified as 1, 2, or 3 years' Pa negative if PEx treatment with at least one oral and/or intravenous antipseudomonal antibiotic is associated with improved clinical outcomes compared with treatment with antibiotics not effective against Pa. Methods: A retrospective cohort study was conducted using the linked Cystic Fibrosis Foundation Patient Registry-Pediatric Health Information System database. We included children 6-21 years old hospitalized between 2008 and 2018 consistently culture negative for Pa 1 year before a study PEx. Children were classified as 1 or 2 years' Pa negative if their last Pa-positive culture occurred in the 13-24 months or 25-36 months before a study PEx, respectively, with all subsequent cultures negative for Pa. Children classified as 3 years' Pa negative had no Pa-positive cultures in the 36 months before a study PEx. Inverse probability of treatment weighted linear or logistic regression models were used to compare clinical outcomes (pre- to post-PEx forced expiratory volume in 1 s, odds of returning to ≥90% of baseline lung function, and odds of having a future PEx) between antipseudomonal and non-antipseudomonal antibiotic strategies. Results: Among all children included in the linked data set, 1,290 children with 2,347 PExs were eligible for analysis. Among all study PExs, 530, 326, and 1,491 were classified as 1, 2, and 3 years' Pa negative, respectively, and antipseudomonal antibiotics were administered in 79%, 67%, and 66% of all PExs classified as 1, 2, and 3 years' Pa negative, respectively. For all Pa-negative groups, when compared with non-antipseudomonal antibiotic regimens, antipseudomonal antibiotic treatment was not associated with greater improvement in any studied clinical outcome. Conclusions: Despite their common use, including antibiotics effective against Pa may provide no additional benefit for PEx treatment among children who are Pa negative for at least 1 year prior. Prospective trials are warranted to directly test this hypothesis.

CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor.

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[Cl-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% ± 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE41o-) cells, F312del-CFTR demonstrated residual function (50.9% ± 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis.

Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.S. cohorts spanning decades of CF care. We found that an annualized chronic Pa definition requiring at least 1 Pa+ culture in 3 of 4 consecutive years ("Green 3/4") resulted in chronic Pa metrics similar to established encounter-based modified Leeds criteria definitions, including a similar age at and proportion who fulfilled chronic Pa criteria, and a similar proportion with sustained Pa infection after meeting the chronic Pa definition. The Green 3/4 chronic Pa definition will be valuable for longitudinal analyses in cohorts with limited culture frequency.

Impact of guideline-recommended dietitian assessments on weight gain in infants with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF)-specialized nutrition care strives to meet normal infant growth, but the relationship of dietitian assessments to weight outcomes is unknown. We characterize nutrition management for inadequate weight gain and assess association of dietitian assessments and center-level weight-for-age Z-scores (WAZ). METHODS: We used encounter data from 226 infants across 28 US CF Centers from the Baby Observational Nutritional study between January 2012 through December 2017. We identified dietitian assessments and consensus guideline-recommended responses to inadequate weight gain: calorie increases, pancreatic enzyme replacement therapy (PERT) increases, or shortened time to next visit. We compared center assessments by funnel plot and summarize median WAZ by center. RESULTS: Of 2,527 visits, 808 (32%) visits had identified inadequate weight gain, distributed in 216 infants. Assessments occurred in 1953 visits (77%), but varied widely between centers (range 17% - 98%). For inadequate weight gain, most and least common responses were calorie increase (64%) and PERT increase (21%). Funnel plot analysis identified 4 high-performers for frequent dietitian assessments (range 92% - 98%) and 4 under-performers (range 17% - 56%). High-performers treated inadequate weight gain more often with adequate calories (24/30, 80% v. 12/23, 52%) and closer follow up (104/164, 63% v. 60/120, 49%) compared to under-performers. Three of 4 high-performing sites met center nutrition goals for positive median WAZ at 2 years old unlike 3 under-performers (WAZHigh 0.33 v. WAZLow -0.15), despite similar patient characteristics. CONCLUSION: We characterized multicenter variation in dietitian assessments, identifying opportunities to improve care delivery to target early nutrition outcomes.

Racial and Language Disparities in Pediatric Emergency Department Triage.

OBJECTIVE: The aim of this study was to assess the impact race and language have on emergency department (ED) triage scores while accounting for illness severity. We hypothesized that non-White and non-English-speaking patients were assigned lower-acuity triage scores compared with White and English-speaking patients, respectively. METHODS: We used a chart review-based retrospective cohort study design, examining patients aged 0 to 17 years at our pediatric ED from July 2015 through June 2016. Illness severity was measured using a truncated Modified Pediatric Early Warning Score calculated from patient vital signs. We used univariate and multivariate multinomial logistic regression to assess the association between race and language with Emergency Severity Index scores. RESULTS: Our final data set consisted of 10,815 visits from 8928 patients. Non-Hispanic (NH) White patients accounted for 34.6% of patients. In the adjusted analyses, non-White patients had significantly reduced odds of receiving a score of 2 (emergency) (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.33-0.49) or 3 (urgent) (OR, 0.5; 95% CI, 0.45-0.56) and significantly higher odds of receiving a score of 5 (minor) (OR, 1.34; 95% CI, 1.07-1.69) versus a score of 4 (nonurgent). We did not find a consistent disparity in Emergency Severity Index scores when comparing English- and non-English-speaking patients. CONCLUSIONS: We confirm that non-White patients receive lower triage scores than White patients. A more robust tool is required to account for illness severity and will be critical to understanding whether the relationship we describe reflects bias within the triage system or differences in ED utilization by racial groups.

Influence of gender and sexual identity on adolescent skin health.

BACKGROUND/OBJECTIVE: Studies have identified dermatologic conditions and relevant skin-related behaviors that distinctly or disproportionately impact sexual and gender minority (SGM) adults compared with their cisgender/heterosexual counterparts, but whether these observations apply to SGM adolescents remains unknown. We aimed to describe the nature and frequency of skin conditions in SGM youth relative to their cisgender/heterosexual peers and explore adolescents' attitudes toward their skin health and accessing dermatologic care. METHODS: SGM and cisgender/heterosexual youth aged 13-21 years seen at Seattle Children's Hospital Adolescent Medicine and Gender clinics from June to December 2019 were invited to participate in this cross-sectional survey study, with subsequent statistical analysis. RESULTS: One-hundred and eighteen subjects were included in the study. Sexual orientation did not affect how participants personally felt about and cared for their skin, though gender identity did influence this relationship. (P = .012) Both sexual and gender minority youth demonstrated a preference for a dermatologist who identified as SGM and would be more likely to actively seek care from these providers. (P < .001) There was no difference in the reported prevalence of most dermatologic conditions among groups based on sexual orientation or gender identity. CONCLUSION: Dermatologists should inquire with adolescent and young adult patients how their sexual orientation and gender identities influence how they view their skin, in an effort to guide counseling and demonstrate holistic support for adolescents. Therapeutic alliances with SGM youth may be strengthened by providers who openly identify as SGM.

Influence of Blood Pressure Percentile Reporting on the Recognition of Elevated Blood Pressures.

OBJECTIVES: To explore the impact of displaying blood pressure (BP) percentiles with BP readings in the electronic health record (EHR) on the recognition of children with elevated blood pressures (EBPs). METHODS: This was a retrospective cohort study of children (ages 1-17), including inpatients and outpatients, with at least 1 EHR noninvasive BP recording. In phase 1, BP percentiles were calculated, stored, and not displayed to clinicians. In phase 2, percentiles were displayed adjacent to the EHR BP. Encounters with 1 BP ≥95th percentile were classified as elevated. EBP recognition required the presence of at least 1 EBP-related International Classification of Diseases, Ninth Revision or International Classification of Diseases, 10th Revision code. We compared recognition frequencies across phases with logistic regression. RESULTS: In total, 45 504 patients in 115 060 encounters were included. Inpatient recognition was 4.1% (238 of 5572) in phase 1 and 5.5% (338 of 5839) in phase 2. The adjusted odds ratio (OR) associated with the intervention was 1.22 (95% confidence interval [CI]: 0.90-1.66). Outpatient recognition rates were 8.0% (1096 of 13 725 EBP encounters) in phase 1 and 9.7% (1442 of 14 811 encounters) in phase 2. The adjusted OR was 1.296 (95% CI: 0.999-1.681). Overall, recognition rates were higher in boys (outpatient OR: 1.51; 95% CI: 1.15-1.98) and older children (outpatient/inpatient OR: 1.08/1.08; 95% CI: 1.05-1.11/1.05-1.11) and lower for those on a surgical service (outpatient/inpatient: OR: 0.41/0.38; 95% CI: 0.30-0.58/0.27-0.52). CONCLUSIONS: Addition of BP percentiles to the EHR did not significantly change EBP recognition as measured by the addition of an EBP diagnosis code. Girls, younger children, and patients followed on a surgical service were less likely to have their EBP recognized by providers.

Association Between Number of Intravenous Antipseudomonal Antibiotics and Clinical Outcomes of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

BACKGROUND: Pulmonary exacerbations (PEx) in people with cystic fibrosis (PwCF) are associated with significant morbidity. While standard PEx treatment for PwCF with Pseudomonas aeruginosa infection includes two IV antipseudomonal antibiotics, little evidence exists to recommend this approach. This study aimed to compare clinical outcomes of single versus double antipseudomonal antibiotic use for PEx treatment. METHODS: Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System dataset. PwCF were included if hospitalized between 2007 and 2018 and 6-21 years of age. Regression modeling accounting for repeated measures was used to compare lung function outcomes between single versus double IV antipseudomonal antibiotic regimens using propensity-score weighting to adjust for relevant confounding factors. RESULTS: Among 10,660 PwCF in the dataset, we analyzed 2,578 PEx from 1,080 PwCF, of which 455 and 2,123 PEx were treated with 1 versus 2 IV antipseudomonal antibiotics, respectively. We identified no significant differences between PEx treated with 1 versus 2 IV antipseudomonal antibiotics either in change between pre- and post-PEx percent predicted forced expiratory volume in one second (ppFEV1) (-0.84%, [95% CI -2.25, 0.56]; P = 0.24), odds of returning to ≥90% of baseline ppFEV1 within 3 months following PEx (Odds Ratio 0.83, [95% CI 0.61, 1.13]; P = 0.24) or time to next PEx requiring IV antibiotics (Hazard Ratio 1.04, [95% CI 0.87, 1.24]; P = 0.69). CONCLUSIONS: Use of 2 IV antipseudomonal antibiotics for PEx treatment in young PwCF was not associated with greater improvements in measured respiratory and clinical outcomes compared to treatment with 1 IV antipseudomonal antibiotic.

Association of Intensity of Antipseudomonal Antibiotic Therapy With Risk of Treatment-Emergent Organisms in Children With Cystic Fibrosis and Newly Acquired Pseudomonas Aeruginosa.

BACKGROUND: While Pseudomonas aeruginosa (Pa) eradication regimens have contributed to a decline in Pa prevalence in people with cystic fibrosis (CF), this antibiotic exposure might increase the risk of acquisition of drug-resistant organisms. This study evaluated the association between antipseudomonal antibiotic exposure intensity and acquisition risk of drug-resistant organisms among children with CF and new Pa infection. METHODS: We utilized data from the Early Pseudomonas Infection Control Clinical Trial (EPIC CT), a randomized controlled trial comparing Pa eradication strategies in children with CF and new Pa. The exposure was the number of weeks of oral or inhaled antipseudomonal antibiotics or ever versus never treatment with intravenous antipseudomonal antibiotics during the 18 months of EPIC CT participation. Primary outcomes were risks of acquisition of several respiratory organisms during 5 years of follow-up after EPIC CT estimated using Cox proportional hazards models separately for each specific organism. RESULTS: Among 249 participants, there was no increased acquisition risk of any organism associated with greater inhaled antibiotic exposure. With each additional week of oral antibiotics, there was an increased hazard of Achromobacter xylosoxidans acquisition (HR, 1.24; 95% CI: 1.02-1.50; P = .03). Treatment with intravenous antibiotics was associated with an increased hazard of acquisition of multidrug-resistant Pa (HR, 2.47; 95% CI: 1.28-4.78; P = .01) and MRSA (HR, 1.57; 95% CI: 1.03-2.40; P = .04). CONCLUSIONS: Results from this study illustrate the importance of making careful antibiotic choices to balance the benefits of antibiotics in people with CF while minimizing risk of acquisition of drug-resistant organisms.

Effect of Concomitant Azithromycin and Tobramycin Use on Cystic Fibrosis Pulmonary Exacerbation Treatment.

Rationale: Pulmonary exacerbations (PExs) are associated with significant morbidity in people with cystic fibrosis (CF). Severe PExs are treated with intravenous antibiotics, including tobramycin. CF care guidelines recommend continuing chronic maintenance medications during PEx treatment. Azithromycin (AZM) is one of the most widely prescribed chronic medications for CF in the United States. Recent evidence has identified a potential antagonistic relationship between AZM and tobramycin.Objectives: To determine whether, among PEx treated with intravenous tobramycin, concomitant AZM use is associated with worse clinical outcomes.Methods: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System (CFFPR-PHIS)-linked dataset. People with CF age 6-21 years were included if they were hospitalized between 2006 and 2016 for a PEx. Inverse probability of treatment weighing was used to minimize the effects of confounders, including indication bias. Associations of concomitant treatment with AZM and lung function outcomes were determined using linear mixed-effect models and generalized estimating equations. Cox proportional hazard regression models were used to evaluate associations with time to next PEx.Results: Among the 10,660 people with CF included in the CFFPR-PHIS-linked dataset, 2,294 children and adolescents with 5,022 PExs that had intravenous tobramycin use were identified. A little less than half (n = 2,247; 45%) of all PExs were treated concomitantly with AZM and intravenous tobramycin. AZM use both at the most recent outpatient clinic encounter and during PEx treatment in combination with intravenous tobramycin was associated with a significantly lower absolute improvement in percentage-predicted forced expiratory volume in 1 second (ppFEV1) (-0.93%; 95% confidence interval [CI], -1.78 to -0.07; P = 0.033), a lesser odds of returning to 90% or more of baseline ppFEV1 (odds ratio, 0.79; 95% CI, 0.68-0.93; P = 0.003), and a shorter time to next PEx requiring intravenous antibiotics (hazard ratio, 1.22; 95% CI, 1.14-1.31; P < 0.001) compared with intravenous tobramycin use without concomitant AZM.Conclusions: Concomitant AZM and intravenous tobramycin use for in-hospital PEx treatment was associated with poorer clinical outcomes than treatment with intravenous tobramycin without AZM. These results support the hypothesis that an antagonistic relationship between these two medications might exist.

Association of Inhaled Antibiotics in Addition to Standard Intravenous Therapy and Outcomes of Pediatric Inpatient Pulmonary Exacerbations.

Rationale: Considerable morbidity and disease progression in people with cystic fibrosis (CF) result from pulmonary exacerbations (PExs). PEx guidelines note insufficient evidence to recommend for or against the concomitant use of inhaled and intravenous antibiotics.Objectives: We hypothesize that the addition of inhaled antibiotics for PEx therapy is associated with improvements in lung function and a longer time to next PEx compared with standard intravenous antibiotics alone.Methods: We performed a retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System linked dataset. People with CF were included if they were hospitalized for PEx between 2006 and 2016 and 6 to 21 years of age. Lung function outcomes were assessed by linear mixed effect modeling and generalized estimating equations. The time to next PEx was assessed by Cox proportional hazards regression. To estimate independent causal effects while accounting for indication bias and other confounders, inverse probabilities of treatment weights were calculated based on covariates believed to influence the likelihood of inhaled antibiotic use during PEx treatment.Results: A total of 3,253 children and adolescents contributed 9,040 PEx events for analysis. Inhaled antibiotics were used in 23% of PEx events but were not associated with better pre- to post-PEx percent predicted forced expiratory volume in 1 second responses (mean difference, -1.11%; 95% confidence interval [CI], -1.83 to -0.38; P = 0.003), higher odds of returning to lung function baseline (odds ratio, 0.94; 95% CI, 0.82 to 1.07; P = 0.34), or longer time to next PEx (hazard ratio, 1.05; 95% CI, 0.99 to 1.12; P = 0.098).Conclusions: The addition of inhaled antibiotics to standard intravenous antibiotic PEx treatment was not associated with improved lung function outcomes or a longer time to next PEx.

Knowledge acquisition and retention after a high flow training programme in Peru: a quasi-experimental single group pre-post design.

OBJECTIVE: Respiratory infections remain the leading infectious cause of death in children under 5 and disproportionately affect children in resource-limited settings. Implementing non-invasive respiratory support can reduce respiratory-related mortality. However, maintaining competency after deployment can be difficult. Our objective was to evaluate the effectiveness of a comprehensive multidisciplinary high-flow training programme in a Peruvian paediatric intensive care unit (PICU). DESIGN: Quasi-experimental single group pre-post intervention study design. SETTING: Quaternary care PICU in a resource-constrained setting in Lima, Peru. PARTICIPANTS: Attending physicians, fellows, paediatric residents, registered nurses, respiratory therapists and medical technicians working in the PICU were invited to participate. INTERVENTIONS: Concurrent with initial high-flow deployment, we implemented a training programme consisting of lectures, case-based discussion and demonstrations with baseline, 3-month and 12-month training sessions. Pre-training and post-training assessment surveys were distributed surrounding all training sessions. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was achieving minimum competency (median score of 80%) on the high flow training assessment tool. Secondary outcomes included knowledge acquisition (differences in pre-baseline and post-baseline training assessments), short-term retention (differences in post-baseline and pre-3-month refresher training assessments) and long-term retention (differences in post-3-month refresher and pre-12-month refresher training assessments). RESULTS: Eighty participants (50% nurses, 15% ICU physicians and 34% other providers) completed the baseline assessment. Participants showed improvement in overall score and all subtopics except the clinical application of knowledge after baseline training (p<0.001). Participants failed to retain minimum competency at 3-month and 12-month follow-up assessments (70% (IQR: 57-74) and 70% (IQR: 65-74), respectively). After repeat training sessions, overall knowledge continued to improve, exceeding baseline performance (78% (IQR: 70-87), 83% (IQR: 74-87) and 87% (IQR: 83-91) at baseline, 3 and 12 months, respectively). CONCLUSION: This study suggests the need for repeat training sessions to achieve and maintain competency after the implementation of new technology.

Genital Shedding of Human Immunodeficiency Virus Type-1 (HIV) When Antiretroviral Therapy Suppresses HIV Replication in the Plasma.

BACKGROUND: During antiretroviral treatment (ART) with plasma HIV RNA below the limit of quantification, HIV RNA can be detected in genital or rectal secretions, termed discordant shedding (DS). We hypothesized that proliferating cells produce virions without HIV replication. METHODS: ART-naive Peruvians initiating ART were observed for DS over 2 years. HIV env and pol genomes were amplified from DS. Antiretrovirals and cytokines/chemokines concentrations were compared at DS and control time points. RESULTS: Eighty-two participants had ART suppression. DS was detected in 24/82 (29%) participants: 13/253 (5%) cervicovaginal lavages, 20/322 (6%) seminal plasmas, and 6/85 (7%) rectal secretions. HIV RNA in DS specimens was near the limit of quantification and not reproducible. HIV DNA was detected in 6/13 (46%) DS cervicovaginal lavages at low levels. Following DNase treatment, 5/39 DS specimens yielded HIV sequences, all without increased genetic distances. Women with and without DS had similar plasma antiretroviral levels and DS in 1 woman was associated with inflammation. CONCLUSIONS: HIV RNA and DNA sequences and therapeutic antiretroviral plasma levels did not support HIV replication as the cause of DS from the genital tract. Rather, our findings infer that HIV RNA is shed due to proliferation of infected cells with virion production.