Clinical Effectiveness of Elexacaftor/Tezacaftor/Ivacaftor in People with Cystic Fibrosis: A Clinical Trial.

Rationale: The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives: PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods: Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results: Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions: ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Oral Glutathione and Growth in Cystic Fibrosis: A Multicenter, Randomized, Placebo-controlled, Double-blind Trial.

OBJECTIVES: The nutritional status of children with cystic fibrosis (CF) is associated with mortality and morbidity. Intestinal inflammation may contribute to impaired digestion, absorption, and nutrient utilization in patients with CF and oral glutathione may reduce inflammation, promoting improved nutritional status in patients with CF. METHODS: The GROW study was a prospective, multicenter, randomized, placebo-controlled, double-blind, phase II clinical trial in pancreatic insufficient patients with CF between the ages of 2 and 10 years. Patients received reduced glutathione or placebo orally daily for 24 weeks. The primary endpoint was the difference in change in weight-for-age z-scores from baseline through week 24 between treatment groups. Secondary endpoints included other anthropometrics, serum, and fecal inflammatory markers in addition to other clinical outcomes. RESULTS: Fifty-eight participants completed the study. No significant differences were seen between glutathione (n = 30) and placebo (n = 28) groups in the 6-month change in weight-for-age z-score (-0.08; 95% CI: -0.22 to 0.06; P = 0.25); absolute change in weight (kg) (-0.18; 95% CI: -0.55 to 0.20; P = 0.35); or absolute change in BMI kg/m (-0.06; 95% CI: -0.37 to 0.25; P = 0.69). There were no significant differences in other secondary endpoints. Overall, glutathione was safe and well tolerated. CONCLUSIONS: Oral glutathione supplementation did not impact growth or change serum or fecal inflammatory markers in pancreatic insufficient children with CF when compared with placebo.

Azithromycin for Early Pseudomonas Infection in Cystic Fibrosis. The OPTIMIZE Randomized Trial.

RATIONALE: New isolation of Pseudomonas aeruginosa (Pa) is generally treated with inhaled antipseudomonal antibiotics such as tobramycin inhalation solution (TIS). A therapeutic approach that complements traditional antimicrobial therapy by reducing the risk of pulmonary exacerbation and inflammation may ultimately prolong the time to Pa recurrence. OBJECTIVES: To test the hypothesis that the addition of azithromycin to TIS in children with cystic fibrosis and early Pa decreases the risk of pulmonary exacerbation and prolongs the time to Pa recurrence. METHODS: The OPTIMIZE (Optimizing Treatment for Early Pseudomonas aeruginosa Infection in Cystic Fibrosis) trial was a multicenter, double-blind, randomized, placebo-controlled, 18-month trial in children with CF, 6 months to 18 years of age, with early Pa. Azithromycin or placebo was given 3× weekly with standardized TIS. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the time to pulmonary exacerbation requiring antibiotics and the secondary endpoint was the time to Pa recurrence, in addition to other clinical and safety outcomes. A total of 221 participants (111 placebo, 110 azithromycin) out of a planned 274 were enrolled. Enrollment was stopped early by the NHLBI because the trial had reached the prespecified interim boundary for efficacy. The risk of pulmonary exacerbation was reduced by 44% in the azithromycin group as compared with the placebo group (hazard ratio, 0.56; 95% confidence interval, 0.37-0.83; P = 0.004). Weight increased by 1.27 kg in the azithromycin group compared with the placebo group (95% confidence interval, 0.01-2.52; P = 0.046). No significant differences were seen in microbiological or other clinical or safety endpoints. CONCLUSIONS: Azithromycin was associated with a significant reduction in the risk of pulmonary exacerbation and a sustained improvement in weight, but had no impact on microbiological outcomes in children with early Pa. Clinical trial registered with clinicaltrials.gov (NCT02054156).

Pancreatic Enzyme Replacement Therapy Use in Infants With Cystic Fibrosis Diagnosed by Newborn Screening.

OBJECTIVES: The aim of the study is to describe pancreatic enzyme practices during the first year of life in infants with cystic fibrosis (CF) and evaluate associations between dosing and outcomes, including growth and gastrointestinal (GI) symptoms. METHODS: We analyzed data from a subset of infants who were in a prospective cohort study conducted at 28 US CF centers. Anthropometric measurements and medications were recorded at each visit. Diaries with infant diet, pancreatic enzyme replacement therapy (PERT) dosing, stool frequency and consistency, and pain were completed by a parent/guardian for 3 days before each visit. RESULTS: Two hundred and thirty-one infants were enrolled in the main study; 205 of these met criteria for pancreatic insufficiency (PI). PERT dose between birth and 6 months was on average 1882 LU/kg per meal (range: 492-3727) and was similar between 6 and 12 months (mean: 1842 LU/kg per mean, range: 313-3612). PERT dose had a weak, negative association with weight z score at 3 and 6 months (r = -0.16, 95% confidence interval [CI] -0.29 to -0.02 and r = -0.18, 95% CI -0.31 to -0.04, respectively) but not at 12 months. There was not a clear relationship between PERT dosing and number of stools per day, stool consistency or pain. One hundred and forty-four infants (70%) were placed on acid suppression medication. Weight z score mean was 0.37 higher in infants using proton pump inhibitors (PPIs) exclusively versus those using histamine-2 blockers exclusively (95% CI -0.02 to 0.76, P = 0.06). CONCLUSIONS: We did not observe that centers with a higher PERT dosing strategy yielded greater clinical benefit than dosing at the lower end of the recommended range.

Impact of Sustained Eradication of New Pseudomonas aeruginosa Infection on Long-term Outcomes in Cystic Fibrosis.

BACKGROUND: Pseudomonas aeruginosa (Pa) is the most important pathogen infecting the airways in individuals with cystic fibrosis. A key question is whether children with newly acquired Pa infection who are able to achieve sustained eradication after early antipseudomonal therapy demonstrate improved long-term health outcomes compared with those who are unable to achieve a sustained microbiologic response. METHODS: This cohort study utilized observational follow-up data on children participating in the Early Pseudomonas Infection Control trial who received standardized therapy for newly acquired Pa. Sustained eradicators were defined as those who maintained Pa-negative cultures for 12 months after initial antipseudomonal therapy. Associations between eradication status and outcomes were assessed. RESULTS: Of the 249 trial participants included in the study, 172 (69%) achieved sustained eradication of Pa during the trial (sustained eradicators). Over the median 5-year follow-up, sustained eradicators had a 74% reduced risk of developing chronic Pa (hazard ratio [HR], 0.26; 95% confidence interval [CI], .17-.40) and a 57% reduced risk of mucoidy (HR, 0.43; 95% CI, .25-.73) compared with nonsustained eradicators. Sustained eradicators had significantly less anti-Pa antibiotic usage during follow-up compared with nonsustained eradicators. There was no association between eradication status and clinical outcomes including rate of exacerbation and lung function decline. CONCLUSIONS: This is the first study to quantify the long-term durability of microbiological response associated with early antipseudomonal therapy, demonstrating the critical importance of optimizing antipseudomonal therapies during early Pa infection. The clinical impact of failure to achieve sustained Pa eradication remains unclear, however, and may be confounded by anti-Pa antibiotic usage. CLINICAL TRIALS REGISTRATION: NCT00097773.

The cost of simplifying treatments for cystic fibrosis: Implications of the SIMPLIFY trial.

BACKGROUND: Dornase alfa and hypertonic saline are mucoactive therapies that can improve respiratory symptoms in people with cystic fibrosis (CF). A recent randomized control trial showed that participants with well-preserved pulmonary function taking elexacaftor + tezacaftor + ivacaftor (ETI) who discontinued dornase alfa or hypertonic saline for 6 weeks had no clinically meaningful decline in lung function. This may prompt discussions with care providers regarding ongoing use of these medications. OBJECTIVE: To compare the costs of outpatient medications between people taking ETI who continued or discontinued (1) dornase alfa or (2) hypertonic saline from 2 clinical trials and project cost differences in the US CF population if these 2 medications were used only intermittently for symptom relief instead of chronically. METHODS: The SIMPLIFY study was 2 parallel multicenter trials that randomized participants 1:1 to either continue or discontinue therapy. To estimate costs, we used data from the Merative MarketScan Databases to identify people with CF from 2020 to 2021. Our primary outcomes were differences in costs of outpatient prescription drugs among those who continued vs discontinued dornase alfa and, separately, hypertonic saline. We obtained adjusted differences in median costs. To estimate the annual cost savings if the population of people with CF taking ETI used these medications only intermittently, we multiplied the proportion of people in MarketScan with CF diagnoses who were taking each of these medications by the median cost savings per year and subtracted the cost of "rescue" use. RESULTS: A total of 392 participants from the dornase alfa trial and 273 from the hypertonic saline trial were included in analyses. The adjusted difference in median medication costs was not significant for the hypertonic saline trial, but we observed a significantly decreased 6-week cost of medications in the dornase alfa trial (adjusted median difference in costs between discontinue and continue of $5,860 (95% CI = $4,870-$6,850); P < 0.0001). We estimated that two-thirds of people with CF use ETI and dornase alfa in the United States; if they discontinued dornase alfa except for intermittent use, the resulting annual savings would be $1.21 billion. CONCLUSIONS: Although the costs of dornase alfa and hypertonic saline are smaller compared with ETI, reduction in use would lead to substantial prescription drug cost savings and reduce the treatment burden. However, individual benefits of these therapies should be considered, and decisions regarding changes in therapy remain an important discussion between people with CF and their providers. Study registration number: NCT04378153.

Lung function from infancy to preschool in a cohort of children with cystic fibrosis.

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability. 45 children had 252 acceptable measurements (137 IPFTs and 115 preschool spirometries) at ages 0.3-6.5 yrs. The median number of measurements per participant was 6 (range 3-9). Recent Pseudomonas aeruginosa infection was associated with 5.1% (95% CI 0.01-9.9%) lower forced expiratory volume in 0.5 s (FEV(0.5)) and 16.4% (95% CI 7.0-24.9%) lower forced expiratory flow at 25-25% of forced vital capacity (FEF(25-75%)), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1-10.1%) lower FEV(0.5) and 10.1% (95% CI 0.6-18.7%) lower FEF(25-75%). Even after accounting for infection status, cough, sex, length, test type and centre, there was significant inter-individual variability in lung function (p<0.01 for each of FEV(0.5), FEF(25-75%) and forced vital capacity). Recent P. aeruginosa infection and cough are associated with lower lung function in children with CF. Significant inter-individual variability in lung function remains to be explained.

Association of lung function, chest radiographs and clinical features in infants with cystic fibrosis.

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.

Multicenter evaluation of infant lung function tests as cystic fibrosis clinical trial endpoints.

RATIONALE: The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES: To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS: Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS: A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF75) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS: In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Long-term azithromycin use is not associated with QT prolongation in children with cystic fibrosis.

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.

Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial.

CONTEXT: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF. OBJECTIVE: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center. INTERVENTION: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule. MAIN OUTCOME MEASURES: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored. RESULTS: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants. CONCLUSION: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00431964.

Pulmonary findings in infants with cystic fibrosis during the first year of life: Results from the Baby Observational and Nutrition Study (BONUS) cohort study.

IMPORTANCE: Treatment recommendations for infants with CF standardize care, but most surveillance or treatment guidance of pulmonary manifestations are consensus-based due to sparse evidence. OBJECTIVE: To report observations about pulmonary correlates of growth and other clinical features in infants with CF. METHODS: We analyzed data from the prospective Baby Observational and Nutrition Study conducted in 28 centers across the US, including clinical features, medications, guardian diaries of respiratory symptoms, oropharyngeal swab cultures and chest radiographs (CXR) collected over the first year of life. RESULTS: Cough was reported in 84% of infants in the first year. Up to 30% had clinically important cough but only 6.3% had crackles; 16.5% had wheeze. Wisconsin CXR score was above 5 in 23% (normal = 0; maximum score = 100). Pseudomonas was recovered from at least one respiratory culture in 24% of infants and was associated with crackles/wheezes and use of proton pump inhibitors (PPI) (OR = 5.47; 95%CI = 1.36, 21.92; P = 0.02) or PPI plus histamine-2 (H2) blocker (OR = 8.2; 95%CI = 2.41, 27.93; P = 0.001), but not H2 blocker alone. Hospitalization for respiratory indications occurred in 18% of infants and was associated with crackles/wheeze and abnormal CXR but not low weight, Pseudomonas or use of acid blockade. CONCLUSIONS: Cough is common in infants with CF, but few present with crackles/wheeze or CXR changes. Pseudomonas is associated with use of PPI or PPI plus H2 blocker, but not with respiratory hospitalization. These observations cannot prove cause and effect but add to our understanding of pulmonary manifestations of CF in infants. TRIAL REGISTRATION: United States ClinicalTrials.Gov registry NCT01424696 (clinicaltrials.gov).

Predicting the complex structure and functional motions of the outer membrane transporter and signal transducer FecA.

Escherichia coli requires an efficient transport and signaling system to successfully sequester iron from its environment. FecA, a TonB-dependent protein, serves a critical role in this process: first, it binds and transports iron in the form of ferric citrate, and second, it initiates a signaling cascade that results in the transcription of several iron transporter genes in interaction with inner membrane proteins. The structure of the plug and barrel domains and the periplasmic N-terminal domain (NTD) are separately available. However, the linker connecting the plug and barrel and the NTD domains is highly mobile, which may prevent the determination of the FecA structure as a whole assembly. Here, we reduce the conformation space of this linker into most probable structural models using the modeling tool CABS, then apply normal-mode analysis to investigate the motions of the whole structure of FecA by using elastic network models. We relate the FecA domain motions to the outer-inner membrane communication, which initiates transcription. We observe that the global motions of FecA assign flexibility to the TonB box and the NTD, and control the exposure of the TonB box for binding to the TonB inner membrane protein, suggesting how these motions relate to FecA function. Our simulations suggest the presence of a communication between the loops on both ends of the protein, a signaling mechanism by which a signal could be transmitted by conformational transitions in response to the binding of ferric citrate.

Effects of Diagnosis by Newborn Screening for Cystic Fibrosis on Weight and Length in the First Year of Life.

Importance: Since the implementation of universal newborn screening (NBS) for cystic fibrosis (CF), the timing and magnitude of growth deficiency or its association with correlates of disease among infants with CF who underwent NBS has not been well described. Objective: To examine incremental weight gain, linear growth, and clinical features in the first year of life among infants with CF who underwent NBS. Design, Setting, and Participants: The Baby Observational and Nutrition Study (BONUS), a multicenter, longitudinal, observational cohort study, was conducted during regular CF clinic visits in the first 12 months of life at 28 US Cystic Fibrosis Foundation-accredited Care Centers from January 7, 2012, through May 31, 2015. Participants included 231 infants younger than 3.5 months who underwent NBS and had confirmed CF, with a gestational age of at least 35 weeks, birth weight of at least 2.5 kg, and toleration of full oral feeds. Of these, 222 infants (96.1%) had follow-up beyond 6 months of age and 215 (93.1%) completed 12 months of follow-up. Exposure: Cystic fibrosis. Main Outcome and Measures: Attained weight and length for age and World Health Organization normative z scores at ages 1 to 6 and 8, 10, and 12 months (defined a priori). Results: Of the 231 infants enrolled, 110 infants (47.6%) were female and 121 (52.4%) were male, with a mean (SD) age of 2.58 (0.69) months. BONUS infants had lower than mean birth weights (mean z score, -0.15; 95% CI, -0.27 to -0.04) and higher birth lengths (mean z score, 0.44; 95% CI, 0.26 to 0.62). They achieved normal weight by 12 months, a significant improvement over a prescreening cohort of newborns with CF from 20 years before the contemporary cohort (mean z score increase, 0.57; 95% CI, 0.37-0.77). However, length was lower than the mean at 12 months (mean z score, -0.56; 95% CI, -0.70 to -0.42). Only 30 infants (13.6%) were at less than the 10th percentile of weight for age, whereas 53 (23.9%) were at less than the 10th percentile of length for age at more than half their visits. Male sex, pancreatic insufficiency, meconium ileus, histamine blocker use, and respiratory Pseudomonas aeruginosa infection were associated with lower weight or length during the first year. Insulinlike growth factor 1 levels were significantly lower among low-length infants. Persistently low-weight infants consumed significantly more calories, and weight and length z scores were negatively correlated with caloric intake. Conclusions and Relevance: Since initiation of universal NBS for CF, significant improvement has occurred in nutritional status, with normalization of weight in the first year of life. However, length stunting remains common.

Multicenter Observational Study on Factors and Outcomes Associated with Various Methicillin-Resistant Staphylococcus aureus Types in Children with Cystic Fibrosis.

RATIONALE: Methicillin-resistant Staphylococcus aureus (MRSA) prevalence continues to increase in patients with cystic fibrosis (CF) in the United States, reaching 26.5% in 2012. Approximately 30% of strains are SCCmec (staphylococcal cassette chromosome mec) IV type, frequently USA300, which in the general population have different genotypic and phenotypic features than SCCmec II type. OBJECTIVES: We hypothesized that risk factors for acquisition and outcomes in patients with CF differed for "health care-associated" (SCCmec II) versus "community-associated" (SCCmec IV) MRSA strains. METHODS: To determine the role of SCCmec type and Panton-Valentine leukocidin (PVL), MRSA isolates from patients not more than 18 years old at seven CF centers were typed and the association of potential risk factors and subsequent clinical course was assessed, using data provided by the CF Patient Registry. MEASUREMENTS AND MAIN RESULTS: Participants with chronic MRSA (295) had typeable isolates and clinical data; 205 (69.5%) had SCCmec II PVL(-), 39 (13.2%) had SCCmec IV PVL(-), and 51 (17.3%) had SCCmec IV PVL(+) strains. SCCmec IV, compared with SCCmec II, increased during the study period, 1996-2010 (P = 0.03). SCCmec II was associated with Pseudomonas aeruginosa-positive cultures and three or more clinic visits in the 6 months preceding the first positive MRSA culture (adjusted odds ratio, 2.05; 95% confidence interval, 1.13-3.74; P = 0.019). Lung function and anthropometrics remained unchanged in the 6 months after initial MRSA detection compared with the 6 months prior. Although CF care increased for participants in both groups in the 6 months after MRSA detection, inhaled antibiotics were prescribed more frequently in those with SCCmec II strains and increased hospitalizations occurred in those with SCCmec IV PVL(-) strains compared with those with PVL(+) strains (adjusted difference, 34.10%; 95% confidence interval, 7.58-60.61; P = 0.012). Participants in both groups had an increase in CF care in the 2 years after MRSA detection compared with the 2 years prior. CONCLUSIONS: Increased exposure to CF clinics and P. aeruginosa may constitute risk factors for acquisition of SCCmec II MRSA strains. Clinical interventions increased 6 months and 2 years after initial MRSA detection regardless of SCCmec type.

Outcomes and Treatment of Chronic Methicillin-Resistant Staphylococcus aureus Differs by Staphylococcal Cassette Chromosome mec (SCCmec) Type in Children With Cystic Fibrosis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infects ∼25% of patients with cystic fibrosis (CF) in the United States. We hypothesized that health-related outcomes differed between healthcare-associated (staphylococcal cassette chromosome mec [SCCmec] II) vs community-associated (SCCmec IV) MRSA strains in patients chronically infected with CF. METHODS: At 7 CF centers, MRSA isolates were prospectively obtained from patients ≤18 years old with 2 or more positive MRSA cultures within 1 year. Isolates were classified by SCCmec type and Panton-Valentine-leukocidin (PVL) status at a core laboratory, and sites remained blinded to SCCmec type and PVL results. Prospective clinical data including antibiotic use, respiratory symptoms, and pulmonary exacerbations were obtained. RESULTS: Among the 295 cohort participants with typeable MRSA isolates, 69.5% had SCCmec II PVL(-), 13.2% had SCCmec IV PVL(-), and 17.3% had SCCmec IV PVL(+) strains. During follow-up of 287 patients with prospective data after enrollment, the risk for pulmonary exacerbations was significantly higher among participants with SCCmec II than SCCmec IV strains (risk ratio [RR] = 1.13; P = .03) and higher in those with SCCmec IV PVL(-) than SCCmec IV PVL(+) strains (RR = 1.62; P < .0001). Neither decline in lung function nor changes in nutritional outcomes differed by SCCmec type or PVL status during the study period. CONCLUSIONS: Participants harboring chronic SCCmec II MRSA received more antibiotics and may have more lung disease than those with SCCmec IV; PVL(+) isolates were not associated with more advanced disease.

Pulmonary exacerbations in CF patients with early lung disease.

BACKGROUND: Current definitions of pulmonary exacerbation (PE) in cystic fibrosis are based on studies in participants with significant lung disease and may not reflect the spectrum of findings observed in younger patients with early lung disease. METHODS: We used data from a recent trial assessing the efficacy of azithromycin in children to study signs and symptoms associated with PEs and related changes in lung function and weight. RESULTS: While increased cough was present in all PEs, acute weight loss and reduction in oxygen saturation were not observed. Changes in lung function did not differ between subjects who did experience a PE and those who were exacerbation-free. CONCLUSIONS: Cough was the predominant symptom in CF patients with early lung disease experiencing a PE. There was no significant difference in mean 6-month change in lung function or weight among subjects with one or more exacerbations and those without an exacerbation.

Incidence and clinical significance of elevated liver function tests in cystic fibrosis clinical trials.

RATIONALE: Emergence of elevated liver function tests (LFTs) during a clinical trial may be due to underlying disease factors of the participants, thus cofounding safety assessments of therapies. Limited data exist addressing the frequency of elevated LFTs in the chronic disease setting of cystic fibrosis (CF). The objectives of this study were to characterize emergence rates of elevated LFTs in CF trials and their association with clinical outcomes. METHODS: The cohort was comprised of participants of three completed multicenter CF trials. LFTs were collected as safety endpoints, and hospitalization rates and changes in pulmonary function and weight were used to assess the association between elevated LFTs and clinical outcome. RESULTS: 93/376 (25%) participants had ≥1 emergent elevated LFT exceeding the normal reference range over an average 8.3 month follow-up, and only 12/93 (13%) had a value determined by the physician as clinically significant. The emergence of an elevated LFT was not significantly associated with a greater rate of decline in pulmonary function or weight as compared to participants with normal LFTs. The emergence of an elevated LFT value was however associated with a higher hospitalization risk (relative risk:1.67, 95% confidence interval:1.11, 2.53). CONCLUSIONS: Elevated LFTs are common among CF trials, although in most cases they are not deemed clinically significant. These elevated LFTs are associated with more frequent hospitalizations, but additional studies are needed to determine the causality of this association. Therapeutic trials in CF must define a priori criteria for clinical significance of elevated LFTs to enable unbiased safety assessments.

Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.

BACKGROUND: In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. METHODS: A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. RESULTS: 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]). CONCLUSION: PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies.