Monoclonal antibodies derived from B cells in subjects with cystic fibrosis reduce Pseudomonas aeruginosa burden in mice.

Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across 3 donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.

A Pilot Randomized Clinical Trial of Pediatric Cystic Fibrosis Pulmonary Exacerbations Treatment Strategies.

Rationale: Despite the high prevalence and clear morbidity of cystic fibrosis (CF) pulmonary exacerbations (PEx), there have been no published clinical trials of outpatient exacerbation management. Objectives: To assess the feasibility of a pediatric clinical trial in which treatment of mild PEx is assigned randomly to immediate oral antibiotics or tailored therapy (increased airway clearance alone with oral antibiotics added only for prespecified criteria). The outcome on which sample size was based was the proportion of tailored therapy participants who avoided oral antibiotics during the 28 days after randomization. Methods: In this randomized, open-label, pilot feasibility study at 10 U.S. sites, children 6-18 years of age with CF were enrolled at their well baseline visits and followed through their first randomized PEx. Results: One hundred twenty-one participants were enrolled, of whom 94 (78%) reported symptoms of PEx at least once; of these, 81 (86%) had at least one exacerbation that met randomization criteria, of whom 63 (78%) were randomized. Feasibility goals were met, including enrollment, early detection of symptoms of PEx, and ability to randomize. Among the 33 participants assigned to tailored therapy, 10 (30%) received oral antibiotics, while 29 of 30 (97%) assigned to immediate antibiotics received oral antibiotics. The avoidance of oral antibiotics in 70% (95% confidence interval, 54-85%) was statistically significantly different from our null hypothesis that <10% of participants assigned to the tailored therapy arm would avoid antibiotics. Conclusions: Our pilot study demonstrates that conducting a randomized trial of oral antibiotic treatment strategies for mild PEx in children with CF is feasible and that assignment to a tailored therapy arm may reduce antibiotic exposure. Clinical trial registered with www.clinicaltrials.gov (NCT04608019).

The impact of elexacaftor/tezacaftor/ivacaftor on fat-soluble vitamin levels in people with cystic fibrosis.

BACKGROUND: While elexacaftor/tezacaftor/ivacaftor (ETI) has improved the pulmonary health of many people with cystic fibrosis (PwCF), less is known about ETI effectiveness for extra-pulmonary manifestations, including fat-soluble vitamin malabsorption. This study aims to evaluate ETI's impact on vitamin A, D, E, and international normalized ratio (INR, an indirect marker for Vitamin K) serum levels. METHODS: Retrospective cohort study of PwCF ≥12 years receiving ETI. Vitamin levels up to four years preceding and up to two years following ETI initiation were collected. Pairwise comparisons of vitamin levels pre/post-ETI initiation were made using Wilcoxon signed rank and McNemar's tests. Linear mixed effect models were used to regress vitamin levels on time since starting ETI, ETI use (yes/no), the interaction between time and ETI use, and age. RESULTS: Two hundred and sixty-four participants met study inclusion, and 169 (64%) had post-ETI initiation vitamin levels. Median vitamin A levels increased from 422.0 to 471.0 mcg/L (p < 0.001), median vitamin D levels increased from 28.5 to 30.8 ng/mL (p = 0.003), and there were no significant changes in median vitamin E or INR. Vitamin A levels rose at a rate of 40.7 mcg/L/year (CI 11.3, 70.2) after ETI start. CONCLUSIONS: ETI initiation is associated with increased median vitamin A and vitamin D levels, but no change in median vitamin E or INR levels. Ongoing monitoring of vitamin levels after ETI initiation is needed to screen for potential deficiencies and toxicities, particularly in light of case reports of hypervitaminosis A following ETI initiation.

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.

Transforming the nutrition care model for infants with cystic fibrosis: A qualitative study of clinicians' perspectives.

Clinician perspectives may inform health service strategies to meet optimal nutrition needs for infants with cystic fibrosis (CF). We conducted a qualitative study with CF-specialized dietitians (registered dietitians [RDs]) and physicians between July to December 2020 to characterize the current state of infant nutrition care delivery and organize input into a conceptual model to inform CF care program strategies. Among 42 participants, 36 completed survey responses and 6 completed interviews; 93% were RDs. Three global themes emerged in the current care model: nutrition management, family centered connections, and collaborative care delivery. Within nutrition management, clinicians emphasized providing education, setting goals, and maintaining adequate follow-up with families. Under family centered connections, clinicians expressed the need to foster relationships with families and link families to resources for assistance to social stressors such as food insecurity. Collaborative care delivery for clinicians interviewed was defined by sharing expertise from across the interdisciplinary team. Based on the timing of this study, clinicians reported compelling examples for various modes of telehealth and home weight monitoring to facilitate and support these domains of nutrition care, including potential advantages for education, supporting family needs, and communication. We integrate these themes to propose a conceptual model to organize complementary in-person and telehealth activities and enhance quality infant CF nutrition care delivery. Future implementation can refine this model through testing of practical telehealth interventions to optimize nutrition outcomes for infants with CF.

Sustained Reduction in Time to Data Entry in the Cystic Fibrosis Foundation Registry.

INTRODUCTION: Timely data entry into patient registries is foundational to learning health systems such as the Cystic Fibrosis Learning Network. The US Cystic Fibrosis Foundation Patient Registry (CFFPR) is an established registry that collects encounter data for clinical and research activities. Coordinators manually enter approximately 1,500 encounters annually at our institution, but there is limited evidence for interventions facilitating timely data entry. Our institution aimed to reduce the number of days between a clinical encounter and data entry into the CFFPR from an average of 43 days (range 0 to 183 days) to less than 30 days in a 3-month interval. METHODS: Data coordinators tested interventions to address barriers in four themes: accountability, work burden, communication, and visibility using plan-do-study-act cycles. We used statistical process control charts to assess progress on average time of entry. Coordinators provided feedback about acceptability and satisfaction for process changes. RESULTS: Initial interventions standardized process and reduced average time to data entry from 42.6 to 22.5 days in 3 months, but this process was not stable in the subsequent 6 months. Subsequent changes to increase metric visibility and improve team communication increased stability and decreased the average time to data entry to 23.0 days. Coordinators reported high satisfaction with process changes and have sustained improved time for over 2 years. CONCLUSIONS: This quality improvement project reduced and maintained data entry time by addressing significant barriers without additional personnel. Increased access to near real-time data in CFFPR accelerates learning for clinical care, quality improvement, and research.

Acute hyperglycaemia in cystic fibrosis pulmonary exacerbations.

Background: Hyperglycaemia may contribute to failure to recover from pulmonary exacerbations in cystic fibrosis (CF). We aimed to evaluate the prevalence and mechanism of hyperglycaemia during and post-exacerbations. Methods: Nine paediatric CF patients, not on insulin, hospitalized for intravenous antibiotics, underwent an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) upon admission (visit 1) and an OGTT 2 weeks (visit 2) and 6 weeks to 12 months later when at stable baseline (visit 3). Insulin and glucose levels were measured before, 30, 60 and 120 min after glucose ingestion during OGTT. Hyperglycaemia on OGTT was defined according to the American Diabetes Association criteria as abnormal OGTT or consistent with diabetes. Hyperglycaemia on CGM was defined as CGM time above 140 mg/dL > 4.5%. Results: At visit 1, 8/9 patients had hyperglycaemia on both CGM and OGTT (2 diabetes and 6 abnormal OGTT). At visit 2, 5/8 had hyperglycaemia (all abnormal OGTT). At visit 3, (median (IQR) time since visit 1, 4.9 (3.8-6.3) months), 5/7 had hyperglycaemia (2 diabetes and 3 abnormal OGTT). At visits 1, 2 and 3, respectively, mean (SD) 2-hour OGTT glucose was 175.8 (42.3), 146.3 (31.9) and 176.9 (51.7) mg/dL. CGM time above 140 mg/dL at visit 1 was 25.3% (16.9). Insulin AUC decreased from visit 2 (median (IQR) 5449 (3321-8123) mcIU-min/mL) to visit 3 (3234 (2913-3680) mcIU-min/mL). Conclusion: Hyperglycaemia is prevalent during paediatric CF exacerbations; it appears to improve with exacerbation treatment but to worsen later in association with decreased insulin secretion.

Repeated isolation of an antibiotic-dependent and temperature-sensitive mutant of Pseudomonas aeruginosa from a cystic fibrosis patient.

BACKGROUND: Bacteria adapt to survive and grow in different environments. Genetic mutations that promote bacterial survival under harsh conditions can also restrict growth. The causes and consequences of these adaptations have important implications for diagnosis, pathogenesis, and therapy. OBJECTIVES: We describe the isolation and characterization of an antibiotic-dependent, temperature-sensitive Pseudomonas aeruginosa mutant chronically infecting the respiratory tract of a cystic fibrosis (CF) patient, underscoring the clinical challenges bacterial adaptations can present. METHODS: Respiratory samples collected from a CF patient during routine care were cultured for standard pathogens. P. aeruginosa isolates recovered from samples were analysed for in vitro growth characteristics, antibiotic susceptibility, clonality, and membrane phospholipid and lipid A composition. Genetic mutations were identified by whole genome sequencing. RESULTS: P. aeruginosa isolates collected over 5 years from respiratory samples of a CF patient frequently harboured a mutation in phosphatidylserine decarboxylase (psd), encoding an enzyme responsible for phospholipid synthesis. This mutant could only grow at 37°C when in the presence of supplemented magnesium, glycerol, or, surprisingly, the antibiotic sulfamethoxazole, which the source patient had repeatedly received. Of concern, this mutant was not detectable on standard selective medium at 37°C. This growth defect correlated with alterations in membrane phospholipid and lipid A content. CONCLUSIONS: A P. aeruginosa mutant chronically infecting a CF patient exhibited dependence on sulphonamides and would likely evade detection using standard clinical laboratory methods. The diagnostic and therapeutic challenges presented by this mutant highlight the complex interplay between bacterial adaptation, antibiotics, and laboratory practices, during chronic bacterial infections.

Implementation strategies for depression and anxiety screening in a pediatric cystic fibrosis center: A quality improvement project.

BACKGROUND: Guidelines to integrate mental health screening (MHS) into Cystic fibrosis (CF) care has increased adoption across the United States and European CF Centers, however, there has been limited discussion on specific strategies for implementation. OBJECTIVE: Share key strategies that led to successful MHS implementation in one pediatric CF center and report implementation and screening outcomes. METHODS: Parent partners, mental health experts from the Department of Psychiatry, and the CF clinic team codesigned interventions to support three major stakeholders: (a) patients and families (b) clinic team, and (c) hospital system. The mental health coordinator approached patients (12 and older) to introduce MHS and administered screening and reviewed results using an electronic tablet and digital measurement-feedback system. We used strategies that promoted visibility of screening progress and sharing of data with hospital administration. Descriptive statistics were used to assess prevalence of clinically significant symptoms of anxiety and depression and symptom severity within our sample. RESULTS: Over the first 2 years of the project, we exceeded our goal of screening 80% of eligible patients per year (80%-95% screened) and are on a similar trajectory within the first 7 months of year 3. We identified high prevalence of clinically significant symptoms of depression (16%) and anxiety (14%) similar to those found in other chronic illness populations. These data helped us advocate hospital leadership to support the development of new mental health services to address identified needs at our center. CONCLUSION: Leveraging coproduction to address stakeholder needs led to successful implementation of a sustainable MHS process.

Maintenance tobramycin primarily affects untargeted bacteria in the CF sputum microbiome.

RATIONALE: The most common antibiotic used to treat people with cystic fibrosis (PWCF) is inhaled tobramycin, administered as maintenance therapy for chronic Pseudomonas aeruginosa lung infections. While the effects of inhaled tobramycin on P. aeruginosa abundance and lung function diminish with continued therapy, this maintenance treatment is known to improve long-term outcomes, underscoring how little is known about why antibiotics work in CF infections, what their effects are on complex CF sputum microbiomes and how to improve these treatments. OBJECTIVES: To rigorously define the effect of maintenance tobramycin on CF sputum microbiome characteristics. METHODS AND MEASUREMENTS: We collected sputum from 30 PWCF at standardised times before, during and after a single month-long course of maintenance inhaled tobramycin. We used traditional culture, quantitative PCR and metagenomic sequencing to define the dynamic effects of this treatment on sputum microbiomes, including abundance changes in both clinically targeted and untargeted bacteria, as well as functional gene categories. MAIN RESULTS: CF sputum microbiota changed most markedly by 1 week of antibiotic therapy and plateaued thereafter, and this shift was largely driven by changes in non-dominant taxa. The genetically conferred functional capacities (ie, metagenomes) of subjects' sputum communities changed little with antibiotic perturbation, despite taxonomic shifts, suggesting functional redundancy within the CF sputum microbiome. CONCLUSIONS: Maintenance treatment with inhaled tobramycin, an antibiotic with demonstrated long-term mortality benefit, primarily impacted clinically untargeted bacteria in CF sputum, highlighting the importance of monitoring the non-canonical effects of antibiotics and other treatments to accurately define and improve their clinical impact.

Comparison of Multiple Breath Washout and Spirometry in Children with Primary Ciliary Dyskinesia and Cystic Fibrosis and Healthy Controls.

Rationale: In cystic fibrosis (CF), the lung clearance index (LCI), derived from multiple breath washout (MBW), is more sensitive in detecting early lung disease than FEV1; MBW has been less thoroughly evaluated in young patients with primary ciliary dyskinesia (PCD).Objectives: Our objectives were 1) to evaluate the sensitivity of MBW and spirometry for the detection of mild lung disease in young children with PCD and CF compared with healthy control (HC) subjects and 2) to compare patterns of airway obstruction between disease populations.Methods: We used a multicenter, single-visit, observational study in children with PCD and CF with a forced expiratory volume in 1 second (FEV1) greater than 60% predicted and HC subjects, ages 3-12 years. Nitrogen MBW and spirometry were performed and overread for acceptability. χ2 and Kruskall-Wallis tests compared demographics and lung function measures between groups, linear regression evaluated the effect of disease state, and Spearman's rank correlation coefficient compared the LCI and spirometric measurements.Results: Twenty-five children with PCD, 49 children with CF, and 80 HC children were enrolled, among whom 17 children with PCD (68%), 36 children with CF (73%), and 53 (66%) HC children performed both acceptable spirometry and MBW; these children made up the analytic cohort. The median age was 9.0 years (interquartile range [IQR], 6.8-11.1). The LCI was abnormal (more than 7.8) in 10 of 17 (59%) patients with PCD and 21 of 36 (58%) patients with CF, whereas FEV1 was abnormal in three of 17 (18%) patients with PCD and six of 36 (17%) patients with CF. The LCI was significantly elevated in patients with PCD and CF compared with HC subjects (ratio of geometric mean vs. HC: PCD 1.27; 95% confidence interval [CI], 1.15-1.39; and CF 1.24; 95% CI, 1.15-1.33]). Children with PCD had lower midexpiratory-phase forced expiratory flow % predicted compared with children with CF (62% [IQR, 50-78%] vs. 85% [IQR, 68-99%]; P = 0.05). LCI did not correlate with FEV1.Conclusions: The LCI is more sensitive than FEV1 in detecting lung disease in young patients with PCD, similar to CF. LCI holds promise as a sensitive endpoint for the assessment of early PCD lung disease.

Elevated exopolysaccharide levels in Pseudomonas aeruginosa flagellar mutants have implications for biofilm growth and chronic infections.

Pseudomonas aeruginosa colonizes the airways of cystic fibrosis (CF) patients, causing infections that can last for decades. During the course of these infections, P. aeruginosa undergoes a number of genetic adaptations. One such adaptation is the loss of swimming motility functions. Another involves the formation of the rugose small colony variant (RSCV) phenotype, which is characterized by overproduction of the exopolysaccharides Pel and Psl. Here, we provide evidence that the two adaptations are linked. Using random transposon mutagenesis, we discovered that flagellar mutations are linked to the RSCV phenotype. We found that flagellar mutants overexpressed Pel and Psl in a surface-contact dependent manner. Genetic analyses revealed that flagellar mutants were selected for at high frequencies in biofilms, and that Pel and Psl expression provided the primary fitness benefit in this environment. Suppressor mutagenesis of flagellar RSCVs indicated that Psl overexpression required the mot genes, suggesting that the flagellum stator proteins function in a surface-dependent regulatory pathway for exopolysaccharide biosynthesis. Finally, we identified flagellar mutant RSCVs among CF isolates. The CF environment has long been known to select for flagellar mutants, with the classic interpretation being that the fitness benefit gained relates to an impairment of the host immune system to target a bacterium lacking a flagellum. Our new findings lead us to propose that exopolysaccharide production is a key gain-of-function phenotype that offers a new way to interpret the fitness benefits of these mutations.

Resilience in adolescents and young adults with cystic fibrosis: A pilot feasibility study of the promoting resilience in stress management intervention.

BACKGROUND: Disease burden in cystic fibrosis (CF) impacts quality of life, distress, and treatment adherence. The promoting resilience in stress management (PRISM), is a brief patient-focused intervention to promote resilience in adolescents and young adults (AYAs), which may mitigate the negative outcomes, and is proven to be feasible and acceptable in other diseases. OBJECTIVE: Our aim was to test the feasibility and acceptability of PRISM among AYAs with CF in addition to collecting pilot data regarding patient-reported resilience, distress, and quality of life. METHODS: Eligible English speaking, 12 to 21 year patients admitted to the hospital were enrolled. We defined feasibility as 80% completion of all sessions. Acceptability was defined qualitatively based on feedback about timing, content and delivery of intervention. As an exploratory aim, questionnaires measuring resilience (Connor-Davidson resilience scale), distress (Kessler-6 scale), and disease-specific health-related quality of life (CF questionnaire-revised [CFQ-R]) were given at baseline and postintervention. RESULTS: 10 out of 17 (59%) patients consented to participate. Eight were Caucasian, eight female with age range 13 to 20 years (median: 18). Nine completed all PRISM sessions with universally positive feedback. Health perception and respiratory domain scores of the CFQ-R improved (47.2-65.1; 95% confidence interval [CI], 2.6-35.6; 50.9-61.9; 95% CI, 1.7-19.9, respectively), however in the setting of inpatient exacerbation treatment it would be hard to attribute these changes to PRISM. CONCLUSION: PRISM was feasible and highly acceptable among AYAs with CF. Future research is needed to test the efficacy of PRISM among a larger group of patients with CF in a multicenter trial.

Prevalence and clinical associations of Staphylococcus aureus small-colony variant respiratory infection in children with cystic fibrosis (SCVSA): a multicentre, observational study.

BACKGROUND: Staphylococcus aureus is the bacterium cultured most often from respiratory secretions of people with cystic fibrosis. Both meticillin-susceptible S aureus and meticillin-resistant S aureus (MRSA) can adapt to form slow-growing, antibiotic-resistant isolates known as small-colony variants that are not routinely identified by clinical laboratories. We aimed to determine the prevalence and clinical significance of S aureus small-colony variants and their subtypes among children with cystic fibrosis. METHODS: The Small Colony Variant Staphylococcus aureus (SCVSA) study was a 2-year longitudinal study of children aged 6-16 years at five US cystic fibrosis centres, using culture methods sensitive for small-colony variants. Children were eligible if they had a documented diagnosis of cystic fibrosis and a minimum of two cystic fibrosis clinic visits and two respiratory cultures in the previous 12 months at enrolment. Participants attended clinic visits quarterly, at which respiratory tract samples were taken and measures of lung function (percentage of predicted forced expiratory volume in 1 s [FEV1] and frequency of respiratory exacerbations) were recorded. We determined the prevalence of small-colony variants and their subtypes, and assessed their independent associations with lung function and respiratory exacerbations using linear mixed-effects and generalised estimating equation logistic regression models. Analyses included both univariate models (unadjusted) and multivariate models that adjusted for potential confounders, including age, sex, race, baseline microbiology, treatment with CFTR modulator, and CTFR genotype. FINDINGS: Between July 1, 2014, and May 26, 2015, we enrolled 230 children. Participants were followed-up for 2 years, with a mean of 6·4 visits (SD 1·14) per participant (range 2-9 visits) and a mean interval between visits of 3·94 months (SD 1·77). Across the 2-year period, S aureus small-colony variants were detected in 64 (28%) participants. Most (103 [56%] of 185) of the small-colony variants detected in these participants were thymidine dependent. Children with small-colony variants had significantly lower mean percentage of predicted FEV1 at baseline than did children without small-colony variants (85·5 [SD 19] vs 92·4 [SD 18·6]; p=0·0145). Small-colony variants were associated with significantly lower percentage of predicted FEV1 throughout the study in regression models, both in univariate analyses (regression coefficient -7·07, 95% CI -12·20 to -1·95; p=0·0068) and in multivariate analyses adjusting for potential confounders (-5·50, -10·51 to -0·48; p=0·0316). Small colony variants of the thymidine-dependent subtype had the strongest association with lung function in multivariate regression models (regression coefficient -10·49, -17·25 to -3·73; p=0·0024). Compared with children without small-colony variants, those with small-colony variants had significantly increased odds of respiratory exacerbations in univariate analyses (odds ratio 1·73, 95% CI 1·19 to 2·52; p=0·0045). Children with thymidine-dependent small-colony variants had significantly increased odds of respiratory exacerbations (2·81, 1·69-4·67; p=0·0001), even after adjusting for age, sex, race, genotype, CFTR modulator, P aeruginosa culture status, and baseline percentage of predicted FEV1 (2·17, 1·33-3·57; p=0·0021), whereas those with non-thymidine-dependent small-colony variants did not. In multivariate models including small-colony variants and MRSA status, P aeruginosa was not independently associated with lung function (regression coefficient -4·77, 95% CI -10·36 to 0·83; p=0·10) and was associated with reduced odds of exacerbations (0·54, 0·36 to 0·81; p=0·0028). Only the small-colony variant form of MRSA was associated with reduced lung function (-8·44, -16·15 to -0·72; p=0·0318) and increased odds of exacerbations (2·15, 1·24 to 3·71; p=0·0061). INTERPRETATION: Infection with small-colony variants, and particularly thymidine-dependent small-colony variants, was common in a multicentre paediatric population with cystic fibrosis and associated with reduced lung function and increased risk of respiratory exacerbations. The adoption of small-colony variant identification and subtyping methods by clinical laboratories, and the inclusion of small-colony variant prevalence data in cystic fibrosis registries, should be considered for ongoing surveillance and study. FUNDING: The Cystic Fibrosis Foundation and the National Institutes of Health.

Age-related heterogeneity in dental caries and associated risk factors in individuals with cystic fibrosis ages 6-20 years: A pilot study.

BACKGROUND: The literature conflicts regarding dental caries risk in cystic fibrosis (CF) relative to controls. METHODS: Prospective, observational study of age-related heterogeneity in caries rates and potential risk factors in individuals with CF ages 6-20 at a single clinic in Washington state (N=85). Caries rates for enrolled CF participants and historical controls from NHANES were compared using cubic spline regression models. Generalized linear regression models identified correlates of age and caries in CF. RESULTS: Children ages 6-9 with CF had significantly lower caries than controls (Holm's P<0.05). There was no difference for ages 10-20 by CF status (Holm's P>0.05). Various biological/intraoral, medical, and behavioral factors were associated with caries and age in CF. CONCLUSIONS: Younger children with CF may be protected from caries, but there is apparent loss of protection in early adolescence associated with multiple risk factors. Additional studies are needed to confirm these findings.

Islet Interleukin-1ß Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to ß-Cell Failure.

OBJECTIVE: Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), increasing patient morbidity and mortality. Poor understanding of CFRD pathogenesis limits the development of targeted therapies to treat and/or prevent the disease. The aim of this study was to evaluate islet pathology, specifically, inflammation, amyloid deposition, and endocrine cell composition in subjects with CF with diabetes and with CF without diabetes. RESEARCH DESIGN AND METHODS: A retrospective analysis of archived pancreas tissue collected at autopsy was conducted using pancreas tissue from subjects with CF and diabetes (CFRD) (n = 18) and CF without diabetes (CF-no DM) (n = 17). Two cohorts of control non-CF subjects were identified, each matched to CFRD and CF-no DM subjects for age, sex, and BMI (non-CF older, n = 20, and non-CF younger, n = 20), respectively. Immunohistochemistry was performed to assess interleukin-1ß (IL-1ß) and islet hormone (insulin, glucagon, somatostatin, and pancreatic polypeptide) immunoreactivity; histochemistry was performed to quantify amyloid deposition. RESULTS: Islet IL-1ß immunoreactivity was substantially increased in both CFRD and CF-no DM subjects compared with non-CF subjects and was common in young subjects with CF (≤10 years of age). In contrast, islet amyloid deposition was increased only in CFRD subjects. We also observe abnormal islet hormone immunoreactivity, characterized by increased glucagon immunoreactivity, in CF-no DM and CFRD subjects compared with non-CF subjects. CONCLUSIONS: These findings reveal novel molecular pathways and therapeutic targets underlying islet pathology in CF subjects and may be important in developing new approaches to treat CFRD.

Multimodal Pain Management for Enhanced Recovery: Reinforcing the Shift From Traditional Pathways Through Nurse-Led Interventions.

Despite recent advances in perioperative patient care, postsurgical pain continues to be undermanaged. There is increasing acceptance of the concept that effective postsurgical pain management is best achieved through combined use of more than one analgesic agent or technique, and overreliance on opioids produces unwanted side effects limiting their utility. Accordingly, a balanced, multimodal approach to pain management within the larger framework of an Enhanced Recovery After Surgery (ERAS) pathway has become standard at many institutions for perioperative care, to control postsurgical pain, reduce opioid-related adverse events, hasten postsurgical recovery, and shorten length of hospital stay. The success of ERAS is dependent on nurses and the multidisciplinary team to execute its standardized processes across the care continuum, including patient education, perioperative care, and postsurgical evaluation. Here, we review current concepts related to multimodal analgesia and ERAS regarding care of adult surgical patients and discuss the perioperative nurse's role within this paradigm.

Sinonasal Quality of Life in Children With Cystic Fibrosis.

IMPORTANCE: Sinusitis is the most common otolaryngologic complaint in children with cystic fibrosis (CF). However, basic knowledge about the effect of sinusitis on these children is lacking. OBJECTIVE: To evaluate the incidence and quality-of-life impact of chronic rhinosinusitis (CRS) in an unbiased cohort of children with CF. DESIGN, SETTING, AND PARTICIPANTS: Survey study of consecutive pediatric patients with CF presenting for routine quarterly evaluation at a tertiary CF clinic at an academic pediatric hospital. Surveys were completed during the period from December 2012 to January 2013. MAIN OUTCOMES AND MEASURES: Surveys designed to assess major criteria for diagnosis of CRS and a validated pediatric sinonasal quality-of-life instrument, the Sinonasal-5 (SN-5). Statistical analysis was performed to evaluate association between demographic features and survey responses. RESULTS: Of the 102 consecutive eligible patients, 47 children (46%) aged 2 to 20 years (mean [SD] age, 12.9 [5.6] years; 24 [51%] female) completed the surveys. Depending on the exact diagnostic criteria used, 5 (11%) to 18 (38%) of children with CF had CRS. Mean domain (2.16; 95% CI, 2.02-2.30) and overall visual-analog scale (8.26; 95% CI, 8.01-8.51) scores on the SN-5 were consistent with minimal effect on quality of life and comparable to historical posttreatment scores. Mean scores on nasal obstruction (3.07; 95% CI, 2.80-3.34) and sinusitis (2.68;; 95% CI, 2.42-2.94) were the most affected domains, whereas allergy (1.83; 95% CI, 1.65-2.01), emotional disturbance (1.76; 95% CI, 1.56-1.96), and activity restriction (1.43; 95% CI, 1.31-1.57) were minimally affected. Children with a diagnosis of CRS had higher mean SN-5 scores (2.60; 95% CI, 2.31-2.89 vs 2.05; 95% CI, 1.90-2.20; difference of 0.55; 95% CI, 0.29-0.80). Twenty-five patients (53%) had undergone some treatment for sinusitis. There was no association between SN-5 score and CRS treatment history. CONCLUSIONS AND RELEVANCE: In this study, the incidence of symptomatic CRS was high, but quality-of-life impact was relatively low among children with CF. Use of standardized assessment scales, including consensus diagnostic criteria and validated quality-of-life surveys, may be helpful to guide referral and management decisions.