Margaret Rosenfeld

Pulmonary exacerbations are associated with subsequent FEV1 decline in both adults and children with cystic fibrosis

Patients with cystic fibrosis (CF) frequently experience pulmonary exacerbations that may lead to a faster subsequent decline in pulmonary function; however, this relationship has not been clearly established. The purpose of this study was to determine the association between the frequency of pulmonary exacerbations and subsequent forced expiratory volume in 1 sec (FEV1) decline in adults and children with CF.

Accurate and privacy preserving cough sensing using a low-cost microphone

Audio-based cough detection has become more pervasive in recent years because of its utility in evaluating treatments and the potential to impact the quality of life for individuals with chronic cough. We critically examine the current state of the art in cough detection, concluding that existing approaches expose private audio recordings of users and bystanders. We present a novel algorithm for detecting coughs from the audio stream of a mobile phone. Our system allows cough sounds to be reconstructed from the feature set, but prevents speech from being reconstructed intelligibly. We evaluate our algorithm on data collected in the wild and report an average true positive rate of 92% and false positive rate of 0.5%. We also present the results of two psychoacoustic experiments which characterize the tradeoff between the fidelity of reconstructed cough sounds and the intelligibility of reconstructed speech.

SpiroSmart: using a microphone to measure lung function on a mobile phone

Home spirometry is gaining acceptance in the medical community because of its ability to detect pulmonary exacerbations and improve outcomes of chronic lung ailments. However, cost and usability are significant barriers to its widespread adoption. To this end, we present SpiroSmart, a low-cost mobile phone application that performs spirometry sensing using the built-in microphone. We evaluate SpiroSmart on 52 subjects, showing that the mean error when compared to a clinical spirometer is 5.1% for common measures of lung function. Finally, we show that pulmonologists can use SpiroSmart to diagnose varying degrees of obstructive lung ailments.

Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype

RATIONALE Primary ciliary dyskinesia (PCD) is a genetically heterogeneous recessive disorder of motile cilia, but the genetic cause is not defined for all patients with PCD. OBJECTIVES To identify disease-causing mutations in novel genes, we performed exome sequencing, follow-up characterization, mutation scanning, and genotype-phenotype studies in patients with PCD. METHODS Whole-exome sequencing was performed using NimbleGen capture and Illumina HiSeq sequencing. Sanger-based sequencing was used for mutation scanning, validation, and segregation analysis. MEASUREMENTS AND MAIN RESULTS We performed exome sequencing on an affected sib-pair with normal ultrastructure in more than 85% of cilia. A homozygous splice-site mutation was detected in RSPH1 in both siblings; parents were carriers. Screening RSPH1 in 413 unrelated probands, including 325 with PCD and 88 with idiopathic bronchiectasis, revealed biallelic loss-of-function mutations in nine additional probands. Five affected siblings of probands in RSPH1 families harbored the familial mutations. The 16 individuals with RSPH1 mutations had some features of PCD; however, nasal nitric oxide levels were higher than in patients with PCD with other gene mutations (98.3 vs. 20.7 nl/min; P < 0.0003). Additionally, individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043). Cilia from individuals with RSPH1 mutations had normal beat frequency (6.1 ± Hz at 25°C), but an abnormal, circular beat pattern. CONCLUSIONS The milder clinical disease and higher nasal nitric oxide in individuals with biallelic mutations in RSPH1 provides evidence of a unique genotype-phenotype relationship in PCD, and suggests that mutations in RSPH1 may be associated with residual ciliary function.

Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2–5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study

BACKGROUND Ivacaftor has been shown to be a safe, effective treatment for cystic fibrosis in patients aged 6 years or older with a CFTR gating mutation. We aimed to assess the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in children aged 2-5 years. METHODS In the two-part KIWI study, we enrolled children aged 2-5 years weighing 8 kg or more with a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele from 15 hospitals in the USA, UK, and Canada. Participants received oral ivacaftor 50 mg (if bodyweight <14 kg) or 75 mg (if bodyweight ≥14 kg) every 12 h for 4 days in part A (to establish the short-term safety of doses for subsequent assessment in part B), and then for 24 weeks in part B (to assess safety and longer-term pharmacodynamics). Children could participate in both or just one part of the study. Primary outcomes were pharmacokinetics and safety, analysed in all patients who received at least one dose of ivacaftor. Secondary outcomes were absolute change from baseline in sweat chloride concentrations and bodyweight, body-mass index (BMI), and height Z scores, and pharmacokinetic parameter estimation of ivacaftor. This study is registered with ClinicalTrials.gov, number NCT01705145. FINDINGS Between Jan 8, 2013, and March 1, 2013, nine patients were enrolled onto part A of the study, all of whom completed the 4 day treatment period, and eight of whom took part in part B. Between June 28, 2013, and Sept 26, 2013, 34 patients were enrolled in part B, 33 of whom completed the 24 week treatment period. All patients received at least one dose of ivacaftor. Results of ivacaftor pharmacokinetics suggested that exposure was similar to that reported in adults (median Cmin were 536 ng/mL for the 50 mg dose; 580 ng/mL for the 75 mg dose; median ivacaftor AUC values were 9840 ng × h/mL and 10 200 ng × h/mL, respectively). Common adverse events in part B included cough (in 19 [56%] of 34 patients) and vomiting (in ten [29%]). Five (15%) patients had liver function test (LFT) results that were more than eight times higher than the upper limit of normal, four of whom had study drug interrupted, and one of whom had study drug discontinued. Six (18%) of 34 patients had seven serious adverse events; a raised concentration of transaminases was the only serious adverse event regarded as related to ivacaftor and the only adverse event that resulted in study treatment discontinuation. At week 24, in patients for whom we had data, sweat chloride had changed from baseline by a mean of -46·9 mmol/L (SD 26·2, p<0·0001), weight Z score by 0·2 (0·3; p<0·0001), BMI Z score by 0·4 (0·4, p<0·0001), and height Z score by -0·01 (0·3; p=0·84). INTERPRETATION Ivacaftor at doses of 50 mg and 75 mg seems to be safe in children aged 2-5 years with cystic fibrosis with a gating mutation followed up for 24 weeks, although the frequency of elevated LFTs suggests that monitoring should be frequent in young children, particularly those with a history of elevated LFTs. Results of an ongoing extension study assessing durability of these effects and longer-term safety are warranted. FUNDING Vertex Pharmaceuticals Incorporated.

Risk factors for age at initial Pseudomonas acquisition in the cystic fibrosis epic observational cohort

BACKGROUND Risk factors for initial Pseudomonas aeruginosa (Pa) acquisition, particularly environmental exposures, are poorly understood. We aimed to identify such risk factors in order to inform prevention strategies and identify high-risk populations. METHODS The study cohort included all participants in the U.S. EPIC Observational Study who had no prior Pa-positive respiratory cultures (N=889). Cox proportional hazard models were used to test the effects of factors on age at first Pa-positive respiratory culture. RESULTS Cystic fibrosis (CF) genotype functional class had an important effect on age at initial Pa acquisition (hazard ratio (HR) comparing minimal to residual CFTR function 2.87 (95% CI 1.88, 4.39)). None of the modifiable risk factors evaluated, including cigarette smoke, hot tub use, breastfeeding, or daycare, was associated with age at Pa acquisition. Similarly, newborn screening was not associated with age at Pa acquisition (HR 0.85, 95% CI 0.66, 1.09). Key associations were validated in a CF Foundation National Patient Registry replication cohort. CONCLUSIONS Given the ubiquitous presence of Pa in the environment, it may be that many imposed lifestyle changes will have less impact on age at initial Pa acquisition than genetic determinants.

Early intervention studies in infants and preschool children with cystic fibrosis: are we ready?

Cystic fibrosis (CF) lung disease starts early in life and progresses even in the absence of clinical symptoms. Therefore, sensitive outcome measures to quantify and track these early abnormalities in infants and young children are needed; both for clinical care and interventional trials. Currently, the efficacy of most therapeutic interventions in CF has not been tested in children under the age of 6 years and drug development programmes have focused on assessing safety rather than efficacy in this age group. This article summarises the current status for outcome measures that can be utilised in clinical trials in infants and children with CF. Two methodologies are specifically highlighted in this review; chest computed tomography to assess structural damage of the lung and multiple breath washout as a technique to quantify ventilation inhomogeneity. While not all questions regarding the utility of these outcome measures in infants and young children have been resolved, significant advances have been made and it now appears feasible to design and conduct adequately powered efficacy studies in this age group. This could be a crucial step to further improve outcomes in CF patients as initiating effective treatment early is considered essential to prevent permanent lung damage.

Pseudomonas aeruginosa Phenotypes Associated with Eradication Failure in Children with Cystic Fibrosis

BACKGROUND Pseudomonas aeruginosa is a key respiratory pathogen in people with cystic fibrosis (CF). Due to its association with lung disease progression, initial detection of P. aeruginosa in CF respiratory cultures usually results in antibiotic treatment with the goal of eradication. Pseudomonas aeruginosa exhibits many different phenotypes in vitro that could serve as useful prognostic markers, but the relative relationships between these phenotypes and failure to eradicate P. aeruginosa have not been well characterized. METHODS We measured 22 easily assayed in vitro phenotypes among the baseline P. aeruginosa isolates collected from 194 participants in the 18-month EPIC clinical trial, which assessed outcomes after antibiotic eradication therapy for newly identified P. aeruginosa. We then evaluated the associations between these baseline isolate phenotypes and subsequent outcomes during the trial, including failure to eradicate after antipseudomonal therapy, emergence of mucoidy, and occurrence of an exacerbation. RESULTS Baseline P. aeruginosa isolates frequently exhibited phenotypes thought to represent chronic adaptation, including mucoidy. Wrinkly colony surface and irregular colony edges were both associated with increased risk of eradication failure (hazard ratios [95% confidence intervals], 1.99 [1.03-3.83] and 2.14 [1.32-3.47], respectively). Phenotypes reflecting defective quorum sensing were significantly associated with subsequent mucoidy, but no phenotype was significantly associated with subsequent exacerbations during the trial. CONCLUSIONS Pseudomonas aeruginosa phenotypes commonly considered to reflect chronic adaptation were observed frequently among isolates at early detection. We found that 2 easily assayed colony phenotypes were associated with failure to eradicate after antipseudomonal therapy, both of which have been previously associated with altered biofilm formation and defective quorum sensing.

Opportunities and pitfalls of registry data for clinical research

The use of disease registries for clinical epidemiological studies has become increasingly common and has led to advancements in the understanding of many disease processes. The availability of demographic and disease characteristic data on large patient populations, coupled with the minimal cost and relative speed of conducting retrospective investigations, provide an attractive alternative to original data collection. However, limitations inherent to the data collection process can result in the loss of generalizability and introduce bias, leading to erroneous or invalid results. Recognition and identification of these limitations will be unique to each investigation and to the registry being used. The purpose of this article is to highlight the opportunities that registries provide for researchers while presenting potential pitfalls in their use. We conclude with a discussion of a practical approach when considering registry data for clinical research.

WS01.5 An open-label study of the safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2 to 5 years with cystic fibrosis and a CFTR gating mutation: The KIWI study

Background Ivacaftor potentiates CFTR chloride transport and improves outcomes in patients ≥6 y with CF and a CFTR gating mutation. This 2-part study evaluated ivacaftor in patients aged 2–5 y with CF and a gating mutation. Methods In Part A, patients received ivacaftor (50 or 75 mg granules q12h for weight Results Part A enrolled 9 and Part B 34 patients (mean age 3.2 y). Ivacaftor exposure in Parts A and B was similar to that of adults in other studies. In Part A, the most common AE was pyrexia (44%); in Part B, cough (56%). Five patients (14.7%) experienced elevations in ALT or AST of >8×ULN, all of whom had liver function tests (LFTs) >2×ULN at study baseline and returned to baseline following interruption. At Week 24, significant mean (±SD) changes were seen in sweat chloride (–46.9±26.2 mmol/L; P Conclusion Ivacaftor 50 and 75 mg q12h regimens are appropriate for children aged 2–5 y. Improvements in sweat chloride, nutrition status, and pancreatic function were observed over 24 weeks. The majority of AEs seen were mild to moderate in severity. Elevations in ALT or AST were noted in some patients with abnormal baseline LFTs.