Sonya L. Heltshe

Clinical Mechanism of the Cystic Fibrosis Transmembrane Conductance Regulator Potentiator Ivacaftor in G551D-mediated Cystic Fibrosis

RATIONALE Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator recently approved for patients with CF age 6 and older with the G551D mutation. OBJECTIVES To evaluate ivacaftor in a postapproval setting and determine mechanism of action and response of clinically relevant markers. METHODS We conducted a longitudinal cohort study in 2012-2013 in G551D CF patients age 6 and older with no prior exposure to ivacaftor. Study assessments were performed at baseline, 1, 3, and 6 months after ivacaftor initiation. Substudies evaluated mucociliary clearance, β-adrenergic sweat secretion rate, gastrointestinal pH, and sputum inflammation and microbiology Measurements and Main Results: A total of 151 of 153 subjects were prescribed ivacaftor and 88% completed the study through 6 months. FEV1 % predicted improved from baseline to 6 months (mean absolute change, 6.7%; P < 0.001). Similarly, body mass index improved from baseline to 6 months (mean change, 0.8 kg/m(2); P < 0.001). Sweat chloride decreased from baseline to 6 months (mean change, -53.8 mmol/L; 95% confidence interval, -57.7 to -49.9; P < 0.001), reflecting augmented CFTR function. There was significant improvement in hospitalization rate (P < 0.001) and Pseudomonas aeruginosa burden (P < 0.01). Significant improvements in mucociliary clearance (P < 0.001), gastrointestinal pH (P = 0.001), and microbiome were also observed, providing clinical mechanisms underlying the therapeutic benefit of ivacaftor. CONCLUSIONS Significant clinical and physiologic improvements were observed on initiation of ivacaftor in a broad patient population, including reduced infection with P. aeruginosa. Biomarker studies substantially improve the understanding of the mechanistic consequences of CFTR modulation on pulmonary and gastrointestinal physiology.

Risk of Total and Aggressive Prostate Cancer and Pesticide Use in the Agricultural Health Study

Because pesticides may operate through different mechanisms, the authors studied the risk of prostate cancer associated with specific pesticides in the Agricultural Health Study (1993-2007). With 1,962 incident cases, including 919 aggressive prostate cancers among 54,412 applicators, this is the largest study to date. Rate ratios and 95% confidence intervals were calculated by using Poisson regression to evaluate lifetime use of 48 pesticides and prostate cancer incidence. Three organophosphate insecticides were significantly associated with aggressive prostate cancer: fonofos (rate ratio (RR) for the highest quartile of exposure (Q4) vs. nonexposed = 1.63, 95% confidence interval (CI): 1.22, 2.17; P(trend) < 0.001); malathion (RR for Q4 vs. nonexposed = 1.43, 95% CI: 1.08, 1.88; P(trend) = 0.04); and terbufos (RR for Q4 vs. nonexposed = 1.29, 95% CI: 1.02, 1.64; P(trend) = 0.03). The organochlorine insecticide aldrin was also associated with increased risk of aggressive prostate cancer (RR for Q4 vs. nonexposed = 1.49, 95% CI: 1.03, 2.18; P(trend) = 0.02). This analysis has overcome several limitations of previous studies with the inclusion of a large number of cases with relevant exposure and detailed information on use of specific pesticides at 2 points in time. Furthermore, this is the first time specific pesticides are implicated as risk factors for aggressive prostate cancer.

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.

A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis.

BACKGROUND Airway inflammation, mediated in part by LTB4, contributes to lung destruction in patients with cystic fibrosis (CF). LTB(4)-receptor inhibition may reduce airway inflammation. We report the results of a randomized, double-blind, placebo-controlled study of the efficacy and safety of the leukotriene B(4) (LTB(4))-receptor antagonist BIIL 284 BS in CF patients. METHODS CF patients aged ≥6 years with mild to moderate lung disease were randomized to oral BIIL 284 BS or placebo once daily for 24 weeks. Co-primary endpoints were change in FEV(1) and incidence of pulmonary exacerbation. RESULTS After 420 (155 children, 265 adults) of the planned 600 patients were randomized, the trial was terminated after a planned interim analysis revealed a significant increase in pulmonary related serious adverse events (SAEs) in adults receiving BIIL 284 BS. Final analysis revealed SAEs in 36.1% of adults receiving BIIL 284 BS vs. 21.2% receiving placebo (p = 0.007), and in 29.6% of children receiving BIIL 284 BS vs. 22.9% receiving placebo (p = 0.348). In adults, the incidence of protocol-defined pulmonary exacerbation was greater in those receiving BIIL 284 BS than in those receiving placebo (33.1% vs. 18.2% respectively; p = 0.005). In children, the incidence of protocol-defined pulmonary exacerbation was 19.8% in the BIIL 284 BS arm, and 25.7% in the placebo arm (p = 0.38). CONCLUSIONS While the cause of increased SAEs and exacerbations due to BIIL 284 BS is unknown, the outcome of this trial provides a cautionary tale for the administration of potent anti-inflammatory compounds to individuals with chronic infections, as the potential to significantly suppress the inflammatory response may increase the risk of infection-related adverse events.

Pseudomonas aeruginosa in Cystic Fibrosis Patients With G551D-CFTR Treated With Ivacaftor

BACKGROUND Ivacaftor improves outcomes in cystic fibrosis (CF) patients with the G551D mutation; however, effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. METHODS The G551D Observational Study enrolled a longitudinal observational cohort of US patients with CF aged 6 years and older with at least 1 copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US Cystic Fibrosis Foundations National Patient Registry. Pseudomonas aeruginosa infection category in the year before and year after ivacaftor was compared and correlated with clinical findings. RESULTS Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared with the year prior were reduced by 35% (odds ratio [OR], 0.65; P < .001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR, 0.77; P = .013) and Aspergillus (OR, 0.47; P = .039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher forced expiratory volume in 1 second (FEV1) were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, body mass index, or hospitalizations. CONCLUSIONS Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.

Multiple-Breath Washout as a Lung Function Test in Cystic Fibrosis. A Cystic Fibrosis Foundation Workshop Report

The lung clearance index (LCI) is a lung function parameter derived from the multiple-breath washout (MBW) test. Although first developed 60 years ago, the technique was not widely used for many years. Recent technological advances in equipment design have produced gains in popularity for this test among cystic fibrosis (CF) researchers and clinicians, particularly for testing preschool-aged children. LCI has been shown to be feasible and sensitive to early CF lung disease in patients of all ages from infancy to adulthood. A workshop was convened in January 2014 by the North American Cystic Fibrosis Foundation to determine the readiness of the LCI for use in multicenter clinical trials as well as clinical care. The workshop concluded that the MBW text is a valuable potential outcome measure for CF clinical trials in preschool-aged patients and in older patients with FEV1 in the normal range. However, gaps in knowledge about the choice of device, gas, and standardization across systems are key issues precluding its use as a clinical trial end point in infants. Based on the current evidence, there are insufficient data to support the use of LCI or MBW parameters in the routine clinical management of patients with CF.

Short-term and long-term response to pulmonary exacerbation treatment in cystic fibrosis

Background Treatment of pulmonary exacerbations (PEx) in cystic fibrosis (CF) varies widely with no consensus on management practices or best indicators of therapeutic success. To design trials evaluating PEx treatment factors, we characterise the heterogeneity of PEx care in adults and paediatrics, and correlate it with measures of clinical response including short-term and long-term lung function changes, change in symptom severity score and time to next intravenous antibiotic therapy. Methods Data were used from a prospective observational study of patients with CF ≥10 years of age enrolled at six sites between 2007 and 2010. All were started on intravenous antibiotics for a clinically diagnosed PEx. Analysis of variance, logistic and Cox regression were used to examine the association of treatment factors with short-term and long-term clinical response. Results Of 123 patients with CF (60% women, aged 23.1±10.2 years), 33% experienced <10% relative improvement in FEV1 during treatment, which was associated with failing to recover baseline lung function 3 months after treatment (OR=7.8, 95% CI 1.9 to 31.6, p=0.004) and a longer time to next intravenous antibiotic (HR=0.48, 95% CI 0.27 to 0.85, p=0.011). Symptom improvement was observed but was not associated with subsequent lung function or time to next antibiotic therapy, which had a median recurrence time of 143 days. Conclusions Immediate symptomatic or respiratory response to PEx treatment did not have a clear relationship with subsequent outcomes such as lung function or intravenous antibiotic-free interval. These results can inform future research of treatment regimens for PEx in terms of interventions and outcome measures. Trial registration NCT00788359 (www.clinicaltrials.gov).

Escherichia coli dysbiosis correlates with gastrointestinal dysfunction in children with cystic fibrosis

Cystic fibrosis gastrointestinal disease includes nutrient malabsorption and intestinal inflammation. We show that the abundances of Escherichia coli in fecal microbiota were significantly higher in young children with cystic fibrosis than in controls and correlated with fecal measures of nutrient malabsorption and inflammation, suggesting that E. coli could contribute to cystic fibrosis gastrointestinal dysfunction.

Automated ct scan scores of bronchiectasis and air trapping in cystic fibrosis

BACKGROUND Computer analysis of high-resolution CT (HRCT) scans may improve the assessment of structural lung injury in children with cystic fibrosis (CF). The goal of this cross-sectional pilot study was to validate automated, observer-independent image analysis software to establish objective, simple criteria for bronchiectasis and air trapping. METHODS HRCT scans of the chest were performed in 35 children with CF and compared with scans from 12 disease control subjects. Automated image analysis software was developed to count visible airways on inspiratory images and to measure a low attenuation density (LAD) index on expiratory images. Among the children with CF, relationships among automated measures, Brody HRCT scanning scores, lung function, and sputum markers of inflammation were assessed. RESULTS The number of total, central, and peripheral airways on inspiratory images and LAD (%) on expiratory images were significantly higher in children with CF compared with control subjects. Among subjects with CF, peripheral airway counts correlated strongly with Brody bronchiectasis scores by two raters (r=0.86, P<.0001; r=0.91, P<.0001), correlated negatively with lung function, and were positively associated with sputum free neutrophil elastase activity. LAD (%) correlated with Brody air trapping scores (r=0.83, P<.0001; r=0.69, P<.0001) but did not correlate with lung function or sputum inflammatory markers. CONCLUSIONS Quantitative airway counts and LAD (%) on HRCT scans appear to be useful surrogates for bronchiectasis and air trapping in children with CF. Our automated methodology provides objective quantitative measures of bronchiectasis and air trapping that may serve as end points in CF clinical trials.

Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis

Objective Diazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. Methods Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993–1997) and follow-up (1998–2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with ≥10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). Results We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; Ptrend=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; Ptrend=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RRLT days=1.77; 95% CI 0.90 to 3.51; Ptrend=0.09; RRIW days 1.37; 95% CI 0.64 to 2.92; Ptrend=0.50), as were risks for aggressive prostate cancer (N=656). Conclusions Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation.