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.

Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis.

BACKGROUND AND AIMS: It is not known why severe cystic fibrosis (CF) liver disease (CFLD) with portal hypertension occurs in only ~7% of people with CF. We aimed to identify genetic modifiers for severe CFLD to improve understanding of disease mechanisms. APPROACH AND RESULTS: Whole-genome sequencing was available in 4082 people with CF with pancreatic insufficiency (n = 516 with severe CFLD; n = 3566 without CFLD). We tested ~15.9 million single nucleotide polymorphisms (SNPs) for association with severe CFLD versus no-CFLD, using pre-modulator clinical phenotypes including (1) genetic variant ( SERPINA1 ; Z allele) previously associated with severe CFLD; (2) candidate SNPs (n = 205) associated with non-CF liver diseases; (3) genome-wide association study of common/rare SNPs; (4) transcriptome-wide association; and (5) gene-level and pathway analyses. The Z allele was significantly associated with severe CFLD ( p = 1.1 × 10 -4 ). No significant candidate SNPs were identified. A genome-wide association study identified genome-wide significant SNPs in 2 loci and 2 suggestive loci. These 4 loci contained genes [significant, PKD1 ( p = 8.05 × 10 -10 ) and FNBP1 ( p = 4.74 × 10 -9 ); suggestive, DUSP6 ( p = 1.51 × 10 -7 ) and ANKUB1 ( p = 4.69 × 10 -7 )] relevant to severe CFLD pathophysiology. The transcriptome-wide association identified 3 genes [ CXCR1 ( p = 1.01 × 10 -6 ) , AAMP ( p = 1.07 × 10 -6 ), and TRBV24 ( p = 1.23 × 10 -5 )] involved in hepatic inflammation and innate immunity. Gene-ranked analyses identified pathways enriched in genes linked to multiple liver pathologies. CONCLUSION: These results identify loci/genes associated with severe CFLD that point to disease mechanisms involving hepatic fibrosis, inflammation, innate immune function, vascular pathology, intracellular signaling, actin cytoskeleton and tight junction integrity and mechanisms of hepatic steatosis and insulin resistance. These discoveries will facilitate mechanistic studies and the development of therapeutics for severe CFLD.

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.

Molecular networks in atopic mothers impact the risk of infant atopy.

BACKGROUND: The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease. METHODS: Pregnant women and their infants with (n = 174, high-risk) or without (n = 126, low-risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non-atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome-wide transcriptomic analyses were performed in paired atopic (n = 20) and non-atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation-gene expression relationships. RESULTS: Atopic dermatitis was more prevalent in high-risk compared to low-risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non-atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non-atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans-acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non-atopic mothers and high-risk and low-risk children. CONCLUSION: These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy.

Physical activity and social interaction assessments in schoolyard settings using the System for Observing Outdoor Play Environments in Neighborhood Schools (SOOPEN).

BACKGROUND: The schoolyard environment provides key opportunities to promote physical activity and socioemotional development for children. Schoolyards can also serve as a community park resource outside of school hours. We aimed to: (i) implement and evaluate reliability of the System for Observing Outdoor Play Environments in Neighborhood Schools (SOOPEN), (ii) assess schoolyard use by children during recess and community members of all ages outside of school hours, and (iii) investigate relationships of schoolyard and children´s group characteristics with physical activity levels and prosocial interactions. METHODS: In this cross-sectional study, we observed student and community visitor behavior using SOOPEN at three urban elementary schoolyards in Tacoma, Washington, USA, prior to renovations intended to expand each facility's use as a community park in neighborhoods with poor park access. We assessed interrater reliability using intraclass correlation coefficients and described current levels of schoolyard use (at the group level), physical activity, and prosocial behavior. Physical activity was assessed on a five-point scale and dichotomized to indicate moderate-to-vigorous physical activity (MVPA). Social interactions were coded as prosocial, antisocial, or neutral. We examined associations of selected schoolyard features and group characteristics with group MVPA and prosocial behavior during recess using modified Poisson regression to estimate prevalence ratios (PR) and 95% confidence intervals (CI). RESULTS: We observed a total of 981 activity-defined, informal groups in the schoolyards, and achieved good to excellent interrater reliability using SOOPEN. Community use of the schoolyards during evenings and weekends was limited (n = 56 groups). During 26, 25-50 min recess periods (n = 833 groups), 19% of groups were engaged in MVPA. Schoolyard areas with paved surfaces were associated with more MVPA (PR = 1.52, 95% CI: 1.04, 2.23) compared to field/grass areas; supervised groups were associated with less MVPA than groups not directly supervised by an adult (PR = 0.59, 95% CI: 0.36, 0.96). Schoolyard characteristics were not associated with prosocial behavior. Mixed-gender groups were associated with more MVPA and more prosocial behavior. CONCLUSIONS: Our study using SOOPEN, a reliable new activity observation tool, highlights the multi-dimensional dynamics of physical activity and social interactions in schoolyards, which could be leveraged to promote healthy behaviors during and outside of school hours.

Can Use of Default Dispensing Quantities in Electronic Medical Record Lower Opioid Prescribing?

OBJECTIVES: Leftover opioids can contribute to misuse and abuse. Recommended dosing quantities in the electronic medical record can guide prescribing patterns. We hypothesized that decreasing the default from 30 doses to 12 doses would decrease the overall number of opioids prescribed without increasing second opioid prescriptions or additional health utilization. METHODS: We performed a single-center retrospective study of children with forearm and elbow fractures who presented to the emergency department for evaluation and subsequent orthopedic follow-up between January 15, and September 19, 2017. The default dispensing quantity was decreased on June 1, 2016 from 30 doses to 12 doses. Patients were categorized to preintervention and postintervention groups. We compared the number of opioids prescribed, second opioid prescriptions, emergency department visits, and pain-related telephone calls and orthopedic visits with χ2 and logistic regression analyses. RESULTS: There were 1107 patients included. Rates of opioid prescribing were similar preintervention and postintervention (61% vs 56%, P = 0.13). After the change to the default quantity, the median number of doses decreased from 18 to 12 doses, with opioid prescriptions of 30 or more doses dropping from 35% to 11%. No significant association was found between preintervention versus postintervention, opioid prescription at discharge, and having 1 or more pain-related or unexpected follow-up visits. CONCLUSIONS: Lowering the default dispensing quantity of opioids in the electronic medical record decreases the number of opioids prescribed without increasing second prescriptions or additional health care utilization. These findings suggest that a further reduction in the number of opioids prescribed for upper-extremity fractures may be possible.

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.

African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study.

PURPOSE: In a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification. MATERIALS AND METHODS: The Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men. RESULTS: Of the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99). CONCLUSIONS: Of men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.

Use of Automated Office Blood Pressure Measurement in the Evaluation of Elevated Blood Pressures in Children and Adolescents.

OBJECTIVES: To determine the level of agreement between automated office blood pressures (AOBP), auscultated or manual office BP (manual office blood pressure), and 24-hour ABPM, and to explore the ability of AOBP and manual office blood pressure to correctly identify daytime ambulatory hypertension in children. STUDY DESIGN: We retrospectively compared BPs obtained by AOBP and manual office blood pressure to predict daytime hypertension on ABPM. Six BPs were taken by AOBP followed by manual office blood pressure. Office hypertension was defined by BPs ≥95th percentile for sex and height percentiles for those <13 years of age and a BP of ≥130/80 mm Hg for ages ≥13 years. Daytime ambulatory hypertension was diagnosed if mean wake BPs were ≥95th percentile and BP loads were ≥25%. Application of adult ABPM thresholds for daytime hypertension (130/80 mm Hg) was assessed in ages ≥13 years. Sensitivity and specificity were calculated considering ABPM as the reference. RESULTS: Complete data were available for 187 patient encounters. Overall, the best agreement was found if both AOBP and manual office blood pressure showed hypertension, but owing to low sensitivity up to 49% of children with hypertension would be misclassified. The use of adult thresholds for ABPM did not improve agreement. CONCLUSIONS: Neither AOBP nor manual office blood pressure confirm or exclude daytime ambulatory hypertension with confidence. These results suggest an ongoing role for ABPM in evaluation of hypertension in children.

Changes in Ambulatory Blood Pressure Phenotype over Time in Children and Adolescents with Elevated Blood Pressures.

OBJECTIVE: To determine the stability of ambulatory blood pressure monitoring (ABPM) over time in children referred for evaluation of elevated BPs and assess for factors predicting change. STUDY DESIGN: This retrospective chart review conducted at Seattle Children's Hospital and University of Pittsburgh Medical Center Children's Hospital of Pittsburgh identified 124 children referred for elevated BPs with 2 ABPM studies at least 6 months apart. All subjects received lifestyle counseling. Subjects with secondary hypertension (HTN) or on antihypertensive medication were excluded. ABPM phenotype was classified using American Heart Association guidelines as showing normal BP, prehypertension, and HTN. Generalized linear mixed effect regression models were used to regress stable, improving, or worsening HTN outcomes at study follow-up on baseline BP index and load variables. RESULTS: The median age of patients was 14.1 years (73% males) and the median interval between studies was 18 months. ABPM phenotype changed in 58 of 124 children, with 16% worsening and 31% improving. Older age was associated with persistence of HTN. Although not significant, decrease in body mass index z-score tracked with sustained normal ambulatory BPs. CONCLUSIONS: Although the sample size is small, our study suggests ABPM phenotype shows variability over time. Further study is required to identify factors supporting risk for progression of ABPM phenotype over time.

The Silverman Andersen respiratory severity score in the delivery room predicts subsequent intubation in very preterm neonates.

Treatment with mechanical ventilation is associated with chronic lung disease and poor neurologic outcomes in very premature neonates. Surfactant replacement in patients with respiratory distress syndrome reduces need for mechanical ventilation and may be most beneficial when performed early.

Continued 5α-Reductase Inhibitor Use after Prostate Cancer Diagnosis and the Risk of Reclassification and Adverse Pathological Outcomes in the PASS.

PURPOSE: Outcomes in patients who enroll in active surveillance programs for prostate cancer while receiving 5α-reductase inhibitors have not been well defined. We sought to determine the association of 5α-reductase inhibitor use with the risk of reclassification in the PASS (Canary Prostate Active Surveillance Study). MATERIALS AND METHODS: Participants in the multicenter PASS were enrolled between 2008 and 2016. Study inclusion criteria were current or never 5α-reductase inhibitors use, Gleason score 3 + 4 or less prostate cancer at diagnosis, less than a 34% core involvement ratio at diagnosis and 1 or more surveillance biopsies. Included in study were 1,009 men, including 107 on 5α-reductase inhibitors and 902 who had never received 5α-reductase inhibitors. Reclassification was defined as increase in the Gleason score and/or an increase to 34% or greater in the ratio of biopsy cores positive for cancer. Adverse pathology at prostatectomy was defined as Gleason 4 + 3 or greater and/or nonorgan confined disease (pT3 or N1). RESULTS: On multivariable analysis there was no difference in reclassification between men who had received and those who had never received 5α-reductase inhibitors (HR 0.81, p = 0.31). Patients who had received 5α-reductase inhibitors were less likely to undergo radical prostatectomy (8% vs 18%, p = 0.01) or any definitive treatment (19% vs 24%, p = 0.04). In the 167 participants who underwent radical prostatectomy there was no suggestion of a difference in the rate of adverse pathology findings at prostatectomy between 5α-reductase inhibitor users and nonusers. CONCLUSIONS: Continued 5α-reductase inhibitor use after an initial diagnosis of prostate cancer was not associated with the risk of reclassification on active surveillance in men in the PASS cohort.

Periimplant Breast Gas at High Altitudes: Prevalence, Significance, and Possible Associated Factors.

OBJECTIVE: The objective of our study was to confirm the suspected incidental nature of periimplant gas and characterize possible predisposing factors. MATERIALS AND METHODS: Three hundred twenty-one chest CT examinations of patients with breast implants over a 2-year period were identified using a research database query. Scans were evaluated for the qualitative presence of gas, the implant type, and the presence of implant rupture, capsular calcifications, and axillary clips. Subjects' self-reported home state address was included as a surrogate for recent airline travel or travel from lower altitudes to our center located in Denver, CO, which is 1 mile (1.6 km) above sea level. RESULTS: Of the 321 study subjects, 55 (17.1%) had periimplant gas present. No subject had CT signs or clinical evidence of chest wall infection. Periimplant breast gas was significantly associated with residence outside Colorado (odds ratio [OR], 28.32; 95% CI, 10.60-75.70), silicone implant type (OR, 14.56; 95% CI, 5.61-37.81), and implant rupture (OR, 4.21; 95% CI, 1.74-10.18). Capsular calcifications were associated with gas in backward elimination analysis only (OR, 2.15; 95% CI, 1.03-4.50). No association was found between periimplant gas and implant location, patient age, or the presence of axillary clips. CONCLUSION: Periimplant breast gas was relatively common in our patient population, and no association with infection was found. Our results suggest that the development of gas is related to atmospheric pressure, implant filler, and implant integrity. Gas around breast implants after airline travel or an altitude change can be safely dismissed in the absence of other associated findings.

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.

Seroprevalence and clinical characteristics of SARS-CoV-2 infection in children with cystic fibrosis.

BACKGROUND: People with cystic fibrosis (PwCF) have chronic lung disease and may be at increased risk of coronavirus disease 2019 (COVID-19)-related morbidity and mortality. This study aimed to determine seroprevalence and clinical characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children with cystic fibrosis (CF), and to assess antibody responses following SARS-CoV-2 infection or vaccination. METHODS: Children and adolescents with CF followed at Seattle Children's Hospital were enrolled between July 20, 2020 and February 28, 2021. SARS-CoV-2 serostatus was determined on enrollment at 6 and 11 months (±2 months) for nucleocapsid and spike IgG. Participants completed intake and weekly surveys inquiring about SARS-CoV-2 exposures, viral/respiratory illnesses, and symptoms. RESULTS: Of 125 PwCF enrolled, 14 (11%) had positive SARS-CoV-2 antibodies consistent with recent or past infection. Seropositive participants were more likely to identify as Hispanic (29% vs. 8%, p = 0.04) and have pulmonary exacerbations requiring oral antibiotics in the year prior (71% vs. 41%, p = 0.04). Five seropositive individuals (35.7%) were asymptomatic, while six (42.9%) reported mild symptoms, primarily cough and nasal congestion. Antispike protein IgG levels were approximately 10-fold higher in participants following vaccination compared with participants who had natural infection alone (p < 0.0001) and resembled levels previously reported in the general population. CONCLUSIONS: A majority of PwCF have mild or no symptoms of SARS-CoV-2 making it difficult to distinguish from baseline respiratory symptoms. Hispanic PwCF may be disproportionately impacted, consistent with racial and ethnic COVID-19 disparities among the general US population. Vaccination in PwCF generated antibody responses similar to those previously reported in the general population.

Antibiotic Regimen Changes during Cystic Fibrosis Pediatric Pulmonary Exacerbation Treatment.

Rationale/Objectives: Antibiotic selection for in-hospital treatment of pulmonary exacerbations (PEx) in people with cystic fibrosis (CF) is typically guided by previous respiratory culture results or past PEx antibiotic treatment. In the absence of clinical improvement during PEx treatment, antibiotics are frequently changed in search of a regimen that better alleviates symptoms and restores lung function. The clinical benefits of changing antibiotics during PEx treatment are largely uncharacterized. Methods: This was a retrospective cohort study using the Cystic Fibrosis Foundation Patient Registry Pediatric Health Information System. PEx were included if they occurred in children with CF from 6 to 21 years old who had been treated with intravenous antibiotics between January 1, 2006, and December 31, 2018. PEx with lengths of stay <5 or >21 days or for which treatment was delivered in an intensive care unit were excluded. An antibiotic change was defined as the addition or subtraction of any intravenous antibiotic between Hospital Day 6 and the day before hospital discharge. Inverse probability of treatment weighting was used to adjust for disease severity and indication bias, which might influence a decision to change antibiotics. Results: In all, 4,099 children with CF contributed 18,745 PEx for analysis, of which 8,169 PEx (43.6%) included a change in intravenous antibiotics on or after Hospital Day 6. The mean change in pre- to post-treatment percent predicted forced expiratory volume in 1 second (ppFEV1) was 11.3 (standard error, 0.21) among events in which an intravenous antibiotic change occurred versus 12.2 (0.18) among PEx without an intravenous antibiotic change (P = 0.001). Similarly, the odds of return to ⩾90% of baseline ppFEV1 were less for PEx with antibiotic changes than for those without changes (odds ratio [OR], 0.89 [95% confidence interval (CI), 0.80-0.98]). The odds of returning to ⩾100% of baseline ppFEV1 did not differ between PEx with versus without antibiotic changes (OR, 0.94 [95% CI, 0.86-1.03]). In addition, PEx treated with intravenous antibiotic changes were associated with higher odds of future PEx (OR, 1.17 [95% CI, 1.12-1.22]). Conclusions: In this retrospective study, changing intravenous antibiotics during PEx treatment in children with CF was common and not associated with improved clinical outcomes.

Polymicrobial infections and antibiotic treatment patterns for cystic fibrosis pulmonary exacerbations.

BACKGROUND: No data exist to guide antibiotic selection among people with CF (PwCF) with respiratory cultures positive for multiple CF-related bacteria (polymicrobial infections). This study aimed to describe the number of polymicrobial in-hospital treated pulmonary exacerbations (PEx), to determine the proportion of polymicrobial PEx where antibiotics were prescribed with activity against all bacteria detected (termed complete antibiotic coverage), and to determine clinical and demographic factors associated with complete antibiotic coverage. METHODS: Retrospective cohort study using the CF Foundation Patient Registry-Pediatric Health Information System dataset. Children aged 1-21 years with an in-hospital treated PEx from 2006 to 2019 were eligible for inclusion. Bacterial culture positivity was based on any positive respiratory culture in the 12 months prior to a study PEx. RESULTS: A total of 4,923 children contributed 27,669 total PEx of which 20,214 were polymicrobial; of these, 68% of PEx had complete antibiotic coverage. In regression modeling, a prior PEx with complete antibiotic coverage for MRSA was associated with a higher likelihood of having complete antibiotic coverage at a subsequent study PEx (OR (95% CI) 3.48 (2.50, 4.83)). CONCLUSIONS: The majority of children with CF hospitalized for polymicrobial PEx were prescribed complete antibiotic coverage. Prior PEx treatment with complete antibiotic coverage predicted complete antibiotic coverage at a future PEx for all bacteria studied. Studies are needed comparing outcomes of polymicrobial PEx treated with different antibiotic coverages to optimize PEx antibiotic selection.