Cystic Fibrosis Carrier States Are Associated With More Severe Cases of Bronchiectasis.

Background: People with cystic fibrosis (CF) are at increased risk for bronchiectasis, and several reports suggest that CF carriers may also be at higher risk for developing bronchiectasis. The purpose of this study was to determine if CF carriers are at risk for more severe courses or complications of bronchiectasis. Methods: Using MarketScan data (2001-2021), we built a cohort consisting of 105 CF carriers with bronchiectasis and 300 083 controls with bronchiectasis but without a CF carrier diagnosis. We evaluated if CF carriers were more likely to be hospitalized for bronchiectasis. In addition, we examined if CF carriers were more likely to be infected with Pseudomonas aeruginosa or nontuberculous mycobacteria (NTM) or to have filled more antibiotic prescriptions. We considered regression models for incident and rate outcomes that controlled for age, sex, smoking status, and comorbidities. Results: The odds of hospitalization were almost 2.4 times higher (95% CI, 1.116-5.255) for CF carriers with bronchiectasis when compared with non-CF carriers with bronchiectasis. The estimated odds of being diagnosed with a Pseudomonas infection for CF carriers vs noncarriers was about 4.2 times higher (95% CI, 2.417-7.551) and 5.4 times higher (95% CI, 3.398-8.804) for being diagnosed with NTM. The rate of distinct antibiotic fill dates was estimated to be 2 times higher for carriers as compared with controls (95% CI, 1.735-2.333), and the rate ratio for the total number of days of antibiotics supplied was estimated as 2.8 (95% CI, 2.290-3.442). Conclusions: CF carriers with bronchiectasis required more hospitalizations and more frequent administration of antibiotics as compared with noncarriers. Given that CF carriers were also more likely to be diagnosed with Pseudomonas and NTM infections, CF carriers with bronchiectasis may have a phenotype more resembling CF-related bronchiectasis than non-CF bronchiectasis.

Impact of elexacaftor/tezacaftor/ivacaftor on bacterial cultures from people with cystic fibrosis.

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown beneficial effects on both forced expiratory volume in 1 s (FEV1 ) and frequency of pulmonary exacerbations in people with cystic fibrosis (CF). These positive outcomes may be related to changes in bacterial colonization within the lungs. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the first triple therapy CFTR modulator approved for use in people with CF 6 years and older. This study aimed to determine the impact of ELX/TEZ/IVA on the isolation of Pseudomonas aeruginosa (Pa), methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA, respectively) in respiratory cultures. METHODS: A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVA for at least 12 months. The primary outcome was determined by assessing bacterial cultures pre- and postinitiation of ELX/TEZ/IVA. Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre- and posttriple combination therapy periods using an exact McNemar's test. RESULTS: One hundred and twenty-four subjects prescribed ELX/TEZ/IVA for at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre-ELX/TEZ/IVA period. Prevalence decreased to approximately 30%, 32%, and 24% (-24.2% [p < 0.0001], -0.7% [p = 1.00], and -6.5% [p = 0.0963], respectively) post-ELX/TEZ/IVA. The source of bacterial culture was predominantly sputum (70.2%) in the pre-ELX/TEZ/IVA group, whereas a throat source (66.1%) was more common post-ELX/TEZ/IVA. CONCLUSIONS: ELX/TEZ/IVA treatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single-center study to show the impact of triple therapy, ELX/TEZ/IVA, on bacterial isolation from airway secretions.

The Rapid Reduction of Infection-Related Visits and Antibiotic Use Among People With Cystic Fibrosis After Starting Elexacaftor-Tezacaftor-Ivacaftor.

BACKGROUND: People with cystic fibrosis (CF) routinely suffer from recurrent sinopulmonary infections. Such infections require frequent courses of antimicrobials and often involve multidrug-resistant organisms. The goal of this study was to identify real-world evidence for the effectiveness of elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) in decreasing infection-related visits and antimicrobial use in people with CF. METHODS: Using IBM MarketScan data, we identified 389 enrollees with CF who began taking ELX/TEZ/IVA before 1 December 2019 and were enrolled from 1 July 2019 to 14 March 2020. We also identified a comparison population who did not begin ELX/TEZ/IVA during the study period. We compared the following outcomes in the 15 weeks before and after medication initiation: total healthcare visits, inpatient visits, infection-related visits, and antimicrobial prescriptions. We analyzed outcomes using both a case-crossover analysis and a difference-in-differences analysis, to control for underlying trends. RESULTS: For the case-crossover analysis, ELX/TEZ/IVA initiation was associated with the following changes over a 15-week period: change in overall healthcare visit dates, -2.5 (95% confidence interval, -3.31 to -1.7); change in inpatient admissions, -0.16 (-.22 to -.10); change in infection-related visit dates, -0.62 (-.93 to -.31); and change in antibiotic prescriptions, -0.78 (-1.03 to -.54). Results from the difference-in-differences approach were similar. CONCLUSIONS: We show a rapid reduction in infection-related visits and antimicrobial use among people with CF after starting a therapy that was not explicitly designed to treat infections. Currently, there are >30 000 people living with CF in the United States alone. Given that this therapy is effective for approximately 90% of people with CF, the impact on respiratory infections and antimicrobial use may be substantial.

Early Lung Disease Exhibits Bacteria-Dependent and -Independent Abnormalities in Cystic Fibrosis Pigs.

Rationale: Although it is clear that cystic fibrosis (CF) airway disease begins at a very young age, the early and subsequent steps in disease pathogenesis and the relative contribution of infection, mucus, and inflammation are not well understood. Objectives: As one approach to assessing the early contribution of infection, we tested the hypothesis that early and continuous antibiotics would decrease the airway bacterial burden. We believed that, if they do, this might reveal aspects of the disease that are more or less sensitive to decreasing infection. Methods: Three groups of pigs were studied from birth until ∼3 weeks of age: 1) wild-type, 2) CF, and 3) CF pigs treated continuously with broad-spectrum antibiotics from birth until study completion. Disease was assessed with chest computed tomography, histopathology, microbiology, and BAL. Measurements and Main Results: Disease was present by 3 weeks of age in CF pigs. Continuous antibiotics from birth improved chest computed tomography imaging abnormalities and airway mucus accumulation but not airway inflammation in the CF pig model. However, reducing bacterial infection did not improve two disease features already present at birth in CF pigs: air trapping and submucosal gland duct plugging. In the CF sinuses, antibiotics did not prevent the development of infection or disease or the number of bacteria but did alter the bacterial species. Conclusions: These findings suggest that CF airway disease begins immediately after birth and that early and continuous antibiotics impact some, but not all, aspects of CF lung disease development.

Incidence, duration and risk factors associated with delayed and missed diagnostic opportunities related to tuberculosis: a population-based longitudinal study.

OBJECTIVES: Missed opportunities to diagnose tuberculosis are costly to patients and society. In this study, we (1) estimate the frequency and duration of diagnostic delays among patients with active pulmonary tuberculosis and (2) determine the risk factors for experiencing a diagnostic delay. DESIGN: A retrospective cohort study of patients with tuberculosis using longitudinal healthcare encounters prior to diagnosis. SETTING: Commercially insured enrollees from the Commercial Claims and Encounters or Medicare Supplemental IBM Marketscan Research Databases, 2001-2017. PARTICIPANTS: All patients diagnosed with, and receiving treatment for, pulmonary tuberculosis, enrolled at least 365 days prior to diagnosis. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the number of visits with tuberculosis-related symptoms prior to diagnosis that would be expected to occur in the absence of delays and compared this estimate to the observed pattern. We computed the number of visits representing a delay and used a simulation-based approach to estimate the number of patients experiencing a delay, number of missed opportunities per patient and duration of delays (ie, time between diagnosis and earliest missed opportunity). We also explored risk factors for missed opportunities. RESULTS: We identified 3371 patients diagnosed and treated for active tuberculosis that could be followed up for 1 year prior to diagnosis. We estimated 77.2% (95% CI 75.6% to 78.7%) of patients experienced at least one missed opportunity; of these patients, an average of 3.89 (95% CI 3.65 to 4.14) visits represented a missed opportunity, and the mean duration of delay was 31.66 days (95% CI 28.51 to 35.11). Risk factors for delays included outpatient or emergency department settings, weekend visits, patient age, influenza season presentation, history of chronic respiratory symptoms and prior fluoroquinolone use. CONCLUSIONS: Many patients with tuberculosis experience multiple missed diagnostic opportunities prior to diagnosis. Missed opportunities occur most commonly in outpatient settings and numerous patient-specific, environment-specific and setting-specific factors increase risk for delays.

Cystic fibrosis carriers are at increased risk for a wide range of cystic fibrosis-related conditions.

Autosomal recessive diseases, such as cystic fibrosis (CF), require inheritance of 2 mutated genes. However, some studies indicate that CF carriers are at increased risk for some conditions associated with CF. These investigations focused on single conditions and included small numbers of subjects. Our goal was to determine whether CF carriers are at increased risk for a range of CF-related conditions. Using the Truven Health MarketScan Commercial Claims database (2001-2017), we performed a population-based retrospective matched-cohort study. We identified 19,802 CF carriers and matched each carrier with 5 controls. The prevalence of 59 CF-related diagnostic conditions was evaluated in each cohort. Odds ratios for each condition were computed for CF carriers relative to controls. All 59 CF-related conditions were more prevalent among carriers compared with controls, with significantly increased risk (P < 0.05) for 57 conditions. Risk was increased for some conditions previously linked to CF carriers (e.g., pancreatitis, male infertility, bronchiectasis), as well as some conditions not previously reported (e.g., diabetes, constipation, cholelithiasis, short stature, failure to thrive). We compared our results with 23,557 subjects with CF, who were also matched with controls; as the relative odds of a given condition increased among subjects with CF, so did the corresponding relative odds for carriers (P < 0.001). Although individual-level risk remained low for most conditions, because there are more than 10 million carriers in the US, population-level morbidity attributable to the CF carrier state is likely substantial. Genetic testing may inform prevention, diagnosis, and treatment for a broad range of CF carrier-related conditions.

CFTR Heterozygotes Are at Increased Risk of Respiratory Infections: A Population-Based Study.

BACKGROUND: Patients heterozygous for mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene may be more susceptible to respiratory infections than the general population. METHODS: We conducted a retrospective case-control study using health insurance claims. We identified patients as either highly likely to be CFTR heterozygotes (CF carriers diagnosed during genetic counseling, parents of children with a diagnosis of CF, and children of mothers diagnosed with CF) or likely CFTR heterozygotes (children of CF carriers diagnosed during genetic counseling and parents of CF carriers diagnosed during genetic counseling). Next, we examined the rates of respiratory infections and antimicrobial prescriptions between both groups of CFTR patients and only the highly likely subcohort, compared with age/sex-matched controls. We examined the presence of any claim using McNemar's test and the number of claims using the sign test. RESULTS: CFTR heterozygotes (the pooled highly likely and likely heterozygotes) were more prone to have at least 1 claim for a respiratory infection (odds ratio [OR], 1.28; P = .020) and to have a greater number of claims for respiratory infections (53.5%; P = .043) than controls. Patients in the highly likely cohort were also more prone to have at least 1 claim for a respiratory infection (OR, 1.30; P = .028) and more claims (54.3%; P = .039) than controls. In addition, the highly likely CFTR heterozygotes were more prone to be prescribed an antibiotic used to treat respiratory infections (OR, 1.34; P = .018) and to have more of these prescriptions (54.3%; P = .035) than controls. CONCLUSIONS: Patients heterozygous for CFTR mutations are at higher risk for respiratory infections. Future work to describe clinical outcomes for CFTR heterozygotes is needed.

Gallium disrupts bacterial iron metabolism and has therapeutic effects in mice and humans with lung infections.

The lack of new antibiotics is among the most critical challenges facing medicine. The problem is particularly acute for Gram-negative bacteria. An unconventional antibiotic strategy is to target bacterial nutrition and metabolism. The metal gallium can disrupt bacterial iron metabolism because it substitutes for iron when taken up by bacteria. We investigated the antibiotic activity of gallium ex vivo, in a mouse model of airway infection, and in a phase 1 clinical trial in individuals with cystic fibrosis (CF) and chronic Pseudomonas aeruginosa airway infections. Our results show that micromolar concentrations of gallium inhibited P. aeruginosa growth in sputum samples from patients with CF. Ex vivo experiments indicated that gallium inhibited key iron-dependent bacterial enzymes and increased bacterial sensitivity to oxidants. Furthermore, gallium resistance developed slowly, its activity was synergistic with certain antibiotics, and gallium did not diminish the antibacterial activity of host macrophages. Systemic gallium treatment showed antibiotic activity in murine lung infections. In addition, systemic gallium treatment improved lung function in people with CF and chronic P. aeruginosa lung infection in a preliminary phase 1 clinical trial. These findings raise the possibility that human infections could be treated by targeting iron metabolism or other nutritional vulnerabilities of bacterial pathogens.

Weather-Dependent Risk for Legionnaires' Disease, United States.

Using the Nationwide Inpatient Sample and US weather data, we estimated the probability of community-acquired pneumonia (CAP) being diagnosed as Legionnaires' disease (LD). LD risk increases when weather is warm and humid. With warm weather, we found a dose-response relationship between relative humidity and the odds for LD. When the mean temperature was 60°-80°F with high humidity (>80.0%), the odds for CAP being diagnosed with LD were 3.1 times higher than with lower levels of humidity (<50.0%). Thus, in some regions (e.g., the Southwest), LD is rarely the cause of hospitalizations. In other regions and seasons (e.g., the mid-Atlantic in summer), LD is much more common. Thus, suspicion for LD should increase when weather is warm and humid. However, when weather is cold, dry, or extremely hot, empirically treating all CAP patients for LD might contribute to excessive antimicrobial drug use at a population level.

Diabetes as an increasingly common comorbidity among patient hospitalizations for tuberculosis in the USA.

OBJECTIVE: Diabetes is a risk factor for active tuberculosis (TB). The purpose of this paper was to estimate the risk of hospitalization for TB with and without a secondary diagnosis of diabetes in groups with different ethnic backgrounds. RESEARCH DESIGN AND METHODS: We used the Nationwide Inpatient Sample from 1998 to 2011, identifying all patients with a primary diagnosis of TB and/or a secondary diagnosis of diabetes (type 1 or type 2) or HIV. Next, we performed logistic regression to investigate the association of diabetes status, HIV status, and race (and the interaction of diabetes and race) with the risk of hospitalization with a primary diagnosis of TB. We also included a time covariate, to determine whether potential risk factors changed during the study period. RESULTS: Controlling for HIV status, diabetes did not increase the odds of TB in white and black patients. However, in Hispanic and Asian/Pacific Islander patients, diabetes increased the odds of TB by a factor of 1.7 (95% CI 1.51 to 1.83). Asian/Pacific Islanders who had diabetes but not HIV experienced 26.4 (95% CI 23.1 to 30.1) times the odds of TB relative to the white males without diabetes or HIV. In addition, the percent of TB cases that belong to these high-risk groups (Asian/Pacific Islander/Hispanic diabetics) has more than doubled from 4.6% in 1998 to 9.6% in 2011. CONCLUSIONS: In specific demographic groups, diabetes was a strong risk factor for hospital admissions for TB.

Missed Opportunities to Diagnose Tuberculosis Are Common Among Hospitalized Patients and Patients Seen in Emergency Departments.

Background. Delayed diagnosis of tuberculosis (TB) may lead to worse outcomes and additional TB exposures. Methods. To estimate the potential number of misdiagnosed TB cases, we linked all hospital and emergency department (ED) visits in California's Healthcare Cost and Utilization Project (HCUP) databases (2005-2011). We defined a potential misdiagnosis as a visit with a new, primary diagnosis of TB preceded by a recent respiratory-related hospitalization or ED visit. Next, we calculated the prevalence of potential missed TB diagnoses for different time windows. We also computed odds ratios (OR) comparing the likelihood of a previous respiratory diagnosis in patients with and without a TB diagnosis, controlling for patient and hospital characteristics. Finally, we determined the correlation between a hospital's TB volume and the prevalence of potential TB misdiagnoses. Results. Within 30 days before an initial TB diagnosis, 15.9% of patients (25.7% for 90 days) had a respiratory-related hospitalization or ED visit. Also, within 30 days, prior respiratory-related visits were more common in patients with TB than other patients (OR = 3.83; P < .01), controlling for patient and hospital characteristics. Respiratory diagnosis-related visits were increasingly common until approximately 90 days before the TB diagnosis. Finally, potential misdiagnoses were more common in hospitals with fewer TB cases (ρ = -0.845; P < .01). Conclusions. Missed opportunities to diagnose TB are common and correlate inversely with the number of TB cases diagnosed at a hospital. Thus, as TB becomes infrequent, delayed diagnoses may increase, initiating outbreaks in communities and hospitals.

Medical reversal of chronic sinusitis in a cystic fibrosis patient with ivacaftor.

BACKGROUND: Chronic sinusitis is universal in cystic fibrosis (CF) and our current treatments are ineffective in reversing sinus disease. The objective of this work was to determine if increasing CF transmembrane conductance regulator (CFTR) activity by ivacaftor could treat CF sinus disease and assess its effect on primary sinus epithelial cultures. METHODS: Case report of 1 patient with long-standing chronic sinus disease and a new diagnosis of CF with a mild mutation (P205S) and a severe mutation (G551D). We discuss clinical changes in symptoms, radiographic findings, nasal potential difference testing, and nasal pH values before and after treatment with ivacaftor. We then developed primary sinonasal epithelial cell cultures from a biopsy of the patient to determine changes in airway surface liquid (ASL) pH and ASL viscosity after ivacaftor treatment. RESULTS: Ivacaftor treatment reversed CT findings of CF sinus disease, increased nasal voltage and pH, and resolved sinus symptoms after 10 months of therapy. Ivacaftor significantly increased ASL pH and decreased ASL viscosity in primary airway cultures. CONCLUSION: This report documents the reversal of CF sinus disease. Based on our in vivo and in vitro results, we speculate that ivacaftor may reverse CF sinusitis by increasing ASL pH and decreasing ASL viscosity. These studies suggest that CFTR modulation may be effective in treating CF and perhaps non-CF sinusitis.

Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function.

Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.

Inhaled hypertonic saline in adults hospitalised for exacerbation of cystic fibrosis lung disease: a retrospective study.

BACKGROUND: Inhaled hypertonic saline (HTS) improves quality of life and reduces pulmonary exacerbations when given long term in patients with cystic fibrosis (CF). While increasingly being offered for acute pulmonary exacerbations, little is known about the efficacy in this setting. OBJECTIVES: The authors examined the tolerability and efficacy of HTS use among adult subjects hospitalised with a CF pulmonary exacerbation and hypothesised that use of HTS would improve pulmonary function during the admission. DESIGN: Pilot retrospective non-randomised study. SETTING: Single tertiary care centre. PARTICIPANTS: 45 subjects admitted to the inpatient service for acute CF pulmonary exacerbation in 2006-2007. A subset of 18 subjects who were also admitted in 2005 when HTS was not available was included in the comparative study. PRIMARY OUTCOME: Change in forced expiratory volume in one second from admission to discharge. SECONDARY OUTCOMES: Change in weight from admission to discharge and time to next exacerbation. RESULTS: Mean age was 32.5 years, and mean length of stay was 11.5 days. HTS was offered to 33 subjects and was well tolerated for a total use of 336 days out of 364 days of hospital stay. Baseline demographics, lung function and sputum culture results were comparable in first and second visits. Use of HTS was not associated with an improvement in forced expiratory volume in one second (p=0.1), weight gain (p=0.24) or in the time to next admission (p=0.08). CONCLUSIONS: These pilot data suggest that HTS is well tolerated during CF pulmonary exacerbation but offers no clear outcome benefits. It is possible that HTS may not have much advantage above and beyond intensive rehabilitation and intravenous antibiotics and may add to hospital costs and treatment burden.

Cystic fibrosis transmembrane conductance regulator intracellular processing, trafficking, and opportunities for mutation-specific treatment.

Recent advances in basic science have greatly expanded our understanding of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR), the chloride and bicarbonate channel that is encoded by the gene, which is mutated in patients with CF. We review the structure, function, biosynthetic processing, and intracellular trafficking of CFTR and discuss the five classes of mutations and their impact on the CF phenotype. The therapeutic discussion is focused on the significant progress toward CFTR mutation-specific therapies. We review the results of encouraging clinical trials examining orally administered therapeutics, including agents that promote read-through of class I mutations (premature termination codons); correctors, which overcome the CFTR misfolding that characterizes the common class II mutation F508del; and potentiators, which enhance the function of class III or IV mutated CFTR at the plasma membrane. Long-term outcomes from successful mutation-specific treatments could finally answer the question that has been lingering since and even before the CFTR gene discovery: Will therapies that specifically restore CFTR-mediated chloride secretion slow or arrest the deleterious cascade of events leading to chronic infection, bronchiectasis, and end-stage lung disease?

Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation.

BACKGROUND: A new approach in the treatment of cystic fibrosis involves improving the function of mutant cystic fibrosis transmembrane conductance regulator (CFTR). VX-770, a CFTR potentiator, has been shown to increase the activity of wild-type and defective cell-surface CFTR in vitro. METHODS: We randomly assigned 39 adults with cystic fibrosis and at least one G551D-CFTR allele to receive oral VX-770 every 12 hours at a dose of 25, 75, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 or 250 mg or placebo for 28 days (in part 2 of the study). RESULTS: At day 28, in the group of subjects who received 150 mg of VX-770, the median change in the nasal potential difference (in response to the administration of a chloride-free isoproterenol solution) from baseline was -3.5 mV (range, -8.3 to 0.5; P=0.02 for the within-subject comparison, P=0.13 vs. placebo), and the median change in the level of sweat chloride was -59.5 mmol per liter (range, -66.0 to -19.0; P=0.008 within-subject, P=0.02 vs. placebo). The median change from baseline in the percent of predicted forced expiratory volume in 1 second was 8.7% (range, 2.3 to 31.3; P=0.008 for the within-subject comparison, P=0.56 vs. placebo). None of the subjects withdrew from the study. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770. CONCLUSIONS: This study to evaluate the safety and adverse-event profile of VX-770 showed that VX-770 was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis. (Funded by Vertex Pharmaceuticals and others; ClinicalTrials.gov number, NCT00457821.).

An outbreak of severe Clostridium difficile-associated disease possibly related to inappropriate antimicrobial therapy for community-acquired pneumonia.

We report a severe outbreak of Clostridium difficile infection. According to a chart review, half of the patients who received treatment for bacterial pneumonia before they developed C. difficile infection may not have had pneumonia. Excessive use of the hospital's new pneumonia care plan during the influenza season may have contributed to the intensity of this outbreak.