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6-Gingerol and 6-shogaol are the most abundant gingerols and shogaols in ginger root and have been shown to reduce the asthmatic phenotype in murine models of asthma. Several studies have described the pharmacokinetics of gingerols and shogaols in humans following the oral ingestion of ginger, while little was known about the metabolism of these components in humans, particularly in patients with asthma. In this study, a dietary supplement of 1.0 g of ginger root extract was administered to asthma patients twice daily for 56 days and serum samples were drawn at 0.5-8 h on days 0, 28, and 56. The metabolic profiles of gingerols and shogaols in human plasma and the kinetic changes of gingerols, shogaols, and their metabolites in asthma patients collected on the three different visits were analyzed using liquid chromatography-mass spectrometry (LC-MS). Ketone reduction was the major metabolic pathway of both gingerols and shogaols. Gingerdiols were identified as the major metabolites of 6-, 8-, and 10-gingerols. M11 and M9 were identified as the double-bond reduction and both the double-bond and ketone reduction metabolites of 6-shogaol, respectively. Cysteine conjugation was another major metabolic pathway of 6-shogaol in asthma patients, and two cysteine-conjugated 6-shogaol, M1 and M2, were identified as the major metabolites of 6-shogaol. Furthermore, gingerols, shogaols, and their metabolites were quantitated in the human serum collected at different time points during each of the three visits using a very sensitive high-resolution LC-MS method. The results showed that one-third of 6-gingerol was metabolized to produce its reduction metabolites, 6-gingerdiols, and more than 90% of 6-shogaol was metabolized to its phase I and cysteine-conjugated metabolites, suggesting the importance of considering the contribution of these metabolites to the bioavailability and health beneficial effects of gingerols and shogaols. All gingerols, shogaols, and their metabolites reached their peak concentrations in less than 2 h, and their half-lives (

RATIONALE: People with cystic fibrosis (CF) experience acute worsening of respiratory symptoms and lung function known as pulmonary exacerbations. Treatment with intravenous antimicrobials is common; however, there is scant evidence to support a standard treatment duration. OBJECTIVES: To test differing durations of intravenous antimicrobials for CF exacerbations. METHODS: STOP2 (Standardized Treatment of Pulmonary Exacerbations 2) was a multicenter, randomized, controlled clinical trial in exacerbations among adults with CF. After 7–10 days of treatment, participants exhibiting predefined lung function and symptom improvements were randomized to 10 or 14 days’ total antimicrobial duration; all others were randomized to 14 or 21 days’ duration. MEASUREMENTS AND MAIN RESULTS: The primary outcome was percent predicted FEV(1) (ppFEV(1)) change from treatment initiation to 2 weeks after cessation. Among early responders, noninferiority of 10 days to 14 days was tested; superiority of 21 days compared with 14 days was compared for the others. Symptoms, weight, and adverse events were secondary. Among 982 randomized people, 277 met improvement criteria and were randomized to 10 or 14 days of treatment; the remaining 705 received 21 or 14 days of treatment. Mean ppFEV(1) change was 12.8 and 13.4 for 10 and 14 days, respectively, a ‒0.65 difference (95% CI [‒3.3 to 2.0]), excluding the predefined noninferiority margin. The 21- and 14-day arms experienced 3.3 and 3.4 mean ppFEV(1) changes, a difference of ‒0.10 (‒1.3 to 1.1). Secondary endpoints and sensitivity analyses were supportive. CONCLUSIONS: Among adults with CF with early treatment improvement during exacerbation, ppFEV(1) after 10 days of intravenous antimicrobials is not inferior to 14 days. For those with less improvement after one week, 21 days is not superior to 14 days. Clinical trial registered with www.clinicaltrials.gov (NCT02781610).

Background Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator for cystic fibrosis (CF) patients homozygous or heterozygous for F508del. Effects of the drug on sinonasal symptoms have not been studied. Methods Adult participants were prospectively evaluated at baseline and after three months of treatment using validated questionnaires assessing sinonasal symptoms (SNOT-22) and CF-related quality of life (CFQ-R). Results Forty-three participants completed the study; 23 were taking other CF transmembrane conductance (CFTR) modulators at the time of study participation. There was a significant improvement in mean SNOT-22 from 34.8 (29.4–40, 95% confidence interval) to 24.4 (19.9–29.0) (p = 0.000003) and in the Respiratory domain of the CFQR from 60.6 (57.1–64.1) to 83.3 (79.4–87.2) (p = 0.0000002), both achieving a minimal clinically important difference. Patients previously taking CFTR modulators experienced a greater benefit in sinonasal and respiratory symptoms. Conclusions Elexacaftor-tezacaftor-ivacaftor is associated with significant improvement in sinonasal symptoms; previous use of CFTR modulators is associated with greater benefit.

Background Tezacaftor (TEZ)/ivacaftor (IVA) is an approved CFTR modulator shown to be efficacious and generally safe and well tolerated in people ≥12 years of age with cystic fibrosis (CF) homozygous for the F508del-CFTR mutation or heterozygous for the F508del-CFTR mutation and a residual function mutation. Although previous studies with IVA alone showed clinical benefits in people with CFTR gating mutations, TEZ/IVA has not yet been evaluated in a Phase 3 study of participants heterozygous for F508del-CFTR and a gating mutation (F/gating genotypes). Here, we present results from a randomized, double-blind, IVA-controlled, parallel-group, Phase 3 study assessing the efficacy, safety, and pharmacokinetics (PK) of TEZ/IVA in participants ≥12 years of age with F/gating genotypes. Methods Enrolled participants entered a 4-week IVA run-in period to create a stable IVA baseline. Participants were then randomized to receive IVA or TEZ/IVA for 8 weeks in an active comparator treatment period (ACTP). The primary endpoint was absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1). Key secondary endpoints were relative change in ppFEV1 and absolute change in CF Questionnaire–Revised respiratory domain score. Secondary endpoints included absolute change in sweat chloride (SwCl) concentration, PK parameters, and safety. All endpoints except PK parameters and safety were assessed from baseline through Week 8. Results Sixty-nine participants (92.0%) in the IVA group and 75 participants (98.7%) in the TEZ/IVA group completed treatment. No improvements were seen in efficacy endpoints from baseline at the end of the IVA run-in period through the end of the ACTP in the IVA group. No significant differences in ppFEV1 or any key secondary endpoint were observed between the IVA and TEZ/IVA groups. SwCl concentrations decreased more in the TEZ/IVA versus IVA group during the ACTP. The safety profile and PK parameters of TEZ/IVA were consistent with those of previous studies in participants ≥12 years of age with CF. Conclusions This Phase 3 study showed that the dual-combination regimen of TEZ/IVA demonstrated clinical efficacy but did not have significantly greater clinical efficacy than IVA alone in participants ≥12 years of age with F/gating genotypes. However, as reported in other studies, TEZ/IVA was generally safe and well tolerated (NCT02412111).

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

BACKGROUND: Biomarkers that can predict loss of asthma control among patients being considered for step-down therapy in well-controlled disease are lacking. OBJECTIVE: To evaluate whether baseline biomarkers of type 2 airway inflammation and/or serial measurement of fractional exhaled nitric oxide (Feno) predict loss of asthma control as therapy is stepped down. METHODS: In subanalyses of a multicenter randomized, double-blind, parallel 3-arm trial comparing strategies for step-down therapy in well-controlled asthma (Long-Acting Beta-Agonist Step-Down Study), we assessed whether baseline atopy as determined by serum aeroallergen allergy screening test (Phadiatop), baseline serum eosinophil peroxidase, or baseline or serial Feno measurements during follow-up predicted the time to loss of asthma control among participants. Loss of asthma control was defined in the study protocol. We analyzed these associations in adjusted models including all participants, after testing for interactions with assignment to each of the 3 treatment groups (continuation of stable dose of combination inhaled corticosteroid-long-acting beta-agonist, step-down of inhaled corticosteroid, or discontinuation of long-acting bronchodilator). RESULTS: Four hundred forty-seven of the 553 Long-Acting Beta-Agonist Step-Down Study participants who were randomized to 1 of 3 treatment arms and had at least 1 biomarker measurement were included in this analysis. At baseline, higher levels of Feno were significantly associated with greater levels of multiallergen IgE levels (P < .001), but not with serum eosinophil peroxidase (P = .742). Among all participants as a group, elevations in baseline biomarkers were not predictive of a higher risk of treatment failure. In addition, Feno levels measured serially at 6-week intervals demonstrated that compared with participants with low levels (50 parts per billion) levels did not have significantly increased likelihood of subsequent treatment failure (hazard ratios, 1.03 [95% CI, 0.59–1.78] and 1.29 [95% CI, 0.65–2.54], respectively). There were no significant interactions of treatment group and baseline biomarkers. CONCLUSIONS: In patients with well-controlled asthma, neither baseline levels of type 2 airway inflammatory biomarkers nor serial measures of Feno are strong predictors of treatment failure.

Background Elexacaftor/tezacaftor/ivacaftor is a highly effective modulator that improves function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting in improved pulmonary function in patients with cystic fibrosis (CF). We hypothesize that improvements in lung function are associated with improvements in health-related quality of life and sinonasal health. The aim of this study is to measure the effect of elexacaftor/tezacaftor/ivacaftor on patient-reported sinonasal and overall quality of life, and to determine the relationship between changes in these 2 outcome measures. Methods A prospective cohort study was conducted at an accredited adult CF care center. Participants completed the 22-item Sino-Nasal Outcome Test (SNOT-22) and the Cystic Fibrosis Questionnaire-Revised (CFQ-R), a validated patient-reported outcome metric for CF patients, at baseline and at 3 months after initiation of elexacaftor/tezacaftor/ivacaftor. Results Forty-three individuals completed the study. There was significant improvement in nearly all domains of the SNOT-22 and CFQ-R after 3 months of therapy. SNOT-22 improved from 34.8 to 24.4 (p = 0.000003). Mean baseline FEV-1 improved from 65% to 76% predicted (p = 0.0000005). The greatest effect was seen in those participants previously taking modulator therapy. Linear regression between the change in SNOT-22 individual domains and the CFQ-R respiratory domain revealed the strongest correlation between the extranasal domain score and the respiratory domain of the CFQ-R (R2 = 0.24). Conclusion CF patients taking elexacaftor/tezacaftor/ivacaftor experience a significant improvement in both sinonasal and health-related quality of life.

BACKGROUND Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent. METHODS We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV1. We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p

BACKGROUND: Cystic fibrosis (CF) chronic rhinosinusitis (CRS) has emerged as a distinct diagnostic entity, unique from other endotypes of CRS in its presentation, pathophysiology, diagnosis, treatment, and outcomes. As the sinonasal health of this patient population may have broad effects on pulmonary health and quality of life, a comprehensive understanding of the diagnostic and therapeutic approach to CF CRS is essential. Recognizing recent scientific advances and unique treatment modalities specific to this challenging patient population, this review systematically evaluates the scientific literature and provides an evidenced-based review with recommendations (EBRR) for fundamental management principles of CF CRS. METHODS: A systematic review of the literature was performed. Studies evaluating interventions for the management of CF CRS were included. An iterative review process was implemented in accordance with EBRR guidelines. A treatment recommendation was generated based on an assessment of the benefits, harms and the overall grade of evidence. RESULTS: This review evaluated the published literature on five unique topics. Each of the following therapeutic categories was investigated explicitly with regard to treatment outcomes in patients with CF CRS: 1) nasal saline; 2) intranasal corticosteroids (INCS); 3) topical antibiotics; 4) cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy; and 5) endoscopic sinus surgery (ESS). CONCLUSION: Based on the currently available evidence, nasal saline, ESS, and CFTR modulators are recommended in the management of CF CRS when appropriate. INCS and topical antibiotics are options. Clinical judgment and experience are essential in caring for patients with this uniquely challenging disorder.

Adults with cystic fibrosis (CF) have an increased risk of a variety of cancers, notably gastrointestinal cancers. In CF higher body mass index (BMI) is associated with improved long-term outcomes, yet in the general population high BMI is associated with increased cancer risk. We aimed to delineate associations between BMI and other factors with cancer risk in adults with CF.This was a retrospective cohort study using CF Foundation Patient Registry data from 1992 to 2015. Data were collected on age, sex, CFTR mutation class, pancreatic insufficiency, and annualized data on BMI and FEV1. The primary analysis was the association between BMI and cancer, with secondary analyses focused on BMI trajectory. Multivariable logistic regression was performed, with analyses stratified by history of transplant.Of 26,199 adults with CF, 446 (1.7%) had cancer diagnosed by histology at a mean age of 40.0 years (SD 12.2), with a higher proportion of transplanted patients developing cancer (137 (3.8%) v 309(1.4%), p 0.001). Among non-transplanted patients, there was no association between BMI and cancer (p for trend = 0.43). Pancreatic insufficiency (p 0.01) and higher FEV1 (p 0.01) were associated with increased cancer risk. In transplanted patients, higher BMI was associated with reduced risk of cancer (p for trend = 0.04). Older age was associated with increased risk in both groups (p 0.001). BMI trajectories were not associated with cancer risk in either group.Higher BMI is associated with a reduced risk of cancer in transplanted adults with CF. Pancreatic insufficiency is a risk factor for cancer in non-transplanted CF patients.

Objectives: Appropriate management of chronic rhinosinusitis (CRS) among patients with cystic fibrosis (CF) is important in improving quality of life. Otolaryngologists play a critical role in reducing CRS symptom burden. This study seeks to evaluate the role of patient-reported quality-of-life measures in guiding interventions for CF-related sinus disease. Methods: We performed a prospective, cross-sectional study of 105 patients presenting to a CF-accredited clinic between July and September 2018. Demographic data and sinus surgery history were collected, in addition to Sino-Nasal Outcome Test (SNOT-22) and Questionnaire of Olfactory Disorders (QOD-NS) scores. Statistical analysis was conducted using correlation and non-parametric Mann-Whitney U tests. Results: Baseline well-care visits accounted for 71.4% of all clinical evaluations. Prior otolaryngology intervention was noted in 69 (66%) patients, where the majority of these patients (63/69; 91%) underwent endoscopic sinus surgery (ESS). Patients with a history of otolaryngology intervention had an average SNOT-22 score of 33.2 (SD = 20.6) compared to 24.9 (SD = 18.5) for patients without prior intervention ( P = .048). The average QOD-NS score was 5.5 (SD = 6.4) among patients referred to otolaryngologists and 3.1 (SD = 5.7) for non-referred patients ( P = .012). SNOT-22 and QOD-NS scores were modestly correlated ( R of .43). Conclusion: CF patients with symptoms resulting in worse quality-of-life assessments were more likely to have established coordinated care with an otolaryngologist. Further validation of the utility of SNOT-22 and QOD-NS questionnaires as care coordination metrics is necessary in the CF population.

Background Evidence is conflicting regarding differential health outcomes in racial and ethnic minorities with cystic fibrosis (CF), a rare genetic disease affecting approximately 28,000 Americans. We performed a cross-sectional analysis of health outcomes in Black/Latinx patients compared with non-Hispanic Caucasian patients cared for in a CF center in New York City. Adult patients enrolled in the CF Foundation Patient Registry at the Columbia University Adult CF Program and seen at least once during 2019 were included. Health metrics were compared between Black/Latinx and non-Hispanic Caucasian patients. Results 262 patients were eligible. 39 patients (15%) identified as Black/Latinx or non-Hispanic Caucasian. Descriptive statistics are reported with mean (standard deviation). Current age was 35.9 (13.3) years for non-Hispanic Caucasian and 32.0 (9.3) years for Black/Latinx patients (p = 0.087). Age of diagnosis did not differ between groups; 9.56 (15.96) years versus 11.59 (15.8) years for non-Hispanic Caucasian versus Black/Latinx respectively (p = 0.464). Pulmonary function, measured as mean forced expiratory volume in one second (FEV1) was 70.6 (22.5) percent predicted in non-Hispanic Caucasian versus 59.50 (27.9) percent predicted in Black/Latinx patients (p = 0.010). Number of visits to the CF clinic were similar between groups. When controlled for age, gender, co-morbidities, median income, and insurance status, there was a continued association between minority status and lower FEV1. Conclusions Minorities with CF have significantly lower pulmonary function, the major marker of survival, than non-Hispanic Caucasians, even when controlled for a variety of demographic and socioeconomic factors that are known to affect health status in CF. Significant health disparities based on race and ethnicity exist at a single CF center in New York City, despite apparent similarities in access to guideline based care at an accredited CF Center. This data confirms the importance of design of culturally appropriate preventative and management strategies to better understand how to direct interventions to this vulnerable population with a rare disease.

People with cystic fibrosis (pwCF) may be at risk of complications from COVID-19 but the impact of COVID-19 on pwCF remains unknown.We conducted a multicenter retrospective cohort study to assess the impact of the COVID-19 pandemic first wave on pwCF in the New York metropolitan area (NY) from March 1, 2020 to August 31, 2020. Objectives were to determine (1) the prevalence of COVID-19 by PCR and IgG antibody testing, (2) the clinical characteristics of COVID-19, (3) delay in routine outpatient care, and (4) the effect on anxiety and depression in pwCF.There were 26 COVID-19 cases diagnosed by PCR or antibody testing among the study cohort of 810 pwCF. The prevalence of COVID-19 by PCR (1.6%) and IgG antibody (12.2%) testing was low. 58% of cases were asymptomatic and 82% were managed at home. 8% were hospitalized and 1 person died. 89% of pwCF experienced delay in care. The prevalence of anxiety increased from 43% baseline to 58% during the pandemic (P0.01). In post-hoc analysis, the proportion of patients with diabetes (38% versus 16%, P0.01) and pancreatic insufficiency (96% versus 66%, P0.01) were higher while CFTR modulator use was lower (46% versus 65%, P = 0.05) in pwCF who tested positive for COVID-19.The prevalence of COVID-19 among pwCF in NY during the pandemic first wave was low and most cases were managed at home. CFTR modulators may be protective. PwCF experienced delay in routine care and increased anxiety.

IntroductionThe current framework for investigating respiratory diseases is based on defining lung health as the absence of lung disease. In order to develop a comprehensive approach to prevent the development of lung disease, there is a need to evaluate the full spectrum of lung health spanning from ideal to impaired lung health. The American Lung Association (ALA) Lung Health Cohort is a new, population-based, cohort study focused primarily on characterising lung health in members of the millennial generation without diagnosed severe respiratory disease. Participants will be enrolled for the baseline study visit starting in 2021, and funding will be sought to support future study exams as part of a longitudinal cohort study. This study will be crucial for developing a novel paradigm of lung health throughout the adult life course.Methods and analysisThis study will leverage the existing infrastructure of the ALA Airways Clinical Research Centers network to enrol 4000 participants between ages 25 and 35 years old at 39 sites across the USA between April 2021 and December 2024. Study procedures will include physical assessment, spirometry, chest CT scan, accelerometry and collection of nasal epithelial lining fluid, nasal epithelial cells, blood and urine. Participants will complete questionnaires about their sociodemographic characteristics, home address histories and exposures, work history and exposure, medical histories, lung health and health behaviours and activity.Ethics and disseminationThe study was approved by the Johns Hopkins Medicine Institutional Review Board. Findings will be disseminated to the scientific community through peer-reviewed journals and at professional conferences. The lay public will receive scientific findings directly through the ALA infrastructure including the official public website. Deidentified datasets will be deposited to BioLINCC, and deidentified biospecimens may be made available to qualified investigators along with a limited-use datasets.

Despite therapeutic advances, people with cystic fibrosis (CF) develop progressive worsening and exacerbations of their lung disease, which can lead to acute respiratory failure. Historically, survival after mechanical ventilation (MV) has been poor. Outcomes related to use of extracorporeal membrane oxygenation (ECMO) have not been well described in CF.We conducted a retrospective analysis of adult patients with CF admitted to the ICU for acute respiratory failure and requiring invasive MV with or without ECMO between July 1, 2006 and June 30, 2016. Separate analysis for the subgroup of MV patients who were eligible for transplant was conducted.Mortality for all patients with respiratory failure requiring advanced support was 37%. Ten of 28 (36%) MV patients, 10 of 26 (38%) ECMO+MV patients and 7 of the 21 (33%) transplant eligible MV patients died. Intensive care unit (ICU) length of stay (LOS) was 24.5±16.6 days for ECMO+MV; 12.9±9.0 days for MV (p=0.001), and 12.3 ±10 days for transplant eligible MV patients (p=0.005 for ECMO+MV comparison). Seven transplant eligible MV patients (33%) and 16 ECMO+MV patients (62%) underwent lung transplantation (p0.001) during the hospital admission. One and 2-year survival for individuals who survived ICU admission was similar regardless of mode of support. Cox-proportional hazards model did not yield any variables that significantly influenced ICU mortality, 1-year or 2-year mortality.Survival for CF patients with acute respiratory failure requiring MV with or without ECMO has improved over time. ECMO may be an appropriate modality for respiratory support in patients with CF and acute respiratory failure who have greater risk of death from MV alone.

BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (

Background Cystic fibrosis (CF) patients have increased risks of gastrointestinal cancers, including esophageal adenocarcinoma. Gastroesophageal reflux disease (GERD) is highly prevalent in CF and manifests at early ages. CF patients may be at increased risk for long-term sequelae of chronic GERD, including Barrett's esophagus (BE). We aimed to assess whether patients with CF have an increased risk of BE or related neoplasia. Methods A matched cohort study was performed of adults with and without CF who had undergone upper endoscopy. Non-CF patients were matched in a 4:1 ratio by age, sex, year of exam, and endoscopist. Odds ratios were calculated for the association between CF and BE or related neoplasia, and multivariable logistic regression modeling was performed to adjust for matching variables and additional potential confounders. Results 122 CF patients underwent endoscopy, and 488 matched controls were identified. Seven (5.7%) CF patients had BE or related neoplasia, including one GE junction adenocarcinoma. Mean age of affected CF patients was 36.0, and 85.7% had a prior solid organ transplant. The odds of BE was significantly increased in CF patients (OR 2.91, 95% CI 1.08–7.81). The risk remained significantly increased in a multivariable model including matching variables (OR 3.32, 95% CI 1.19–9.22) and in a parsimonious model (OR 2.99, 95% CI 1.06–8.42). Conclusions Adults with CF have a 3-fold increased risk of BE or related neoplasia and appears to develop at younger ages. Consideration should be given to screening for BE in select CF patients, especially those who have undergone solid organ transplantation.

Few treatment options are available for oseltamivir-resistant influenza. It has been proposed that baloxavir can be effective in this setting due to its distinct mechanism of action but clinical experience is lacking for immunocompromised patients. We report two such cases treated with baloxavir after failure of oseltamivir and detection of oseltamivir resistance mutations. Baloxavir/zanamivir combination therapy was effective in one patient, but persistent viral shedding was noted with baloxavir monotherapy in the other patient.

Severe asthma accounts for almost half the cost associated with asthma. Severe asthma is driven by heterogeneous molecular mechanisms. Conventional clinical trial design often lacks the power and efficiency to target subgroups with specific pathobiological mechanisms. Furthermore, the validation and approval of new asthma therapies is a lengthy process. Alarge proportion of that time is taken by clinical trials to validate asthma interventions. The National Institutes of Health Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program was established with the goal of designing and executing a trial that uses adaptive design techniques to rapidly evaluate novel interventions in biomarker-defined subgroups of severe asthma, while seeking to refine these biomarker subgroups, and to identify early markers of response to therapy. The novel trial design is an adaptive platform trial conducted under a single master protocol that incorporates precision medicine components. Furthermore, it includes innovative applications of futility analysis, cross-over design with use of shared placebo groups, and early futility analysis to permit more rapid identification of effective interventions. The development and rationale behind the study design are described. The interventions chosen for the initial investigation and the criteria used to identify these interventions are enumerated. The biomarker-based adaptive design and analytic scheme are detailed as well as special considerations involved in the final trial design.

The Precision Interventions for Severe and/or Exacerbation-prone Asthma (PrecISE) study is an adaptive platform trial designed to investigate novel interventions to severe asthma. The study is conducted under a master protocol and utilizes a crossover design with each participant receiving up to five interventions and at least one placebo. Treatment assignments are based on the patients’ biomarker profiles and precision health methods are incorporated into the interim and final analyses. We describe key elements of the PrecISE study including the multistage adaptive enrichment strategy, early stopping of an intervention for futility, power calculations, and the primary analysis strategy.

Background Several underlying conditions have been associated with severe acute respiratory syndrome coronavirus 2 illness, but it remains unclear whether underlying asthma is associated with worse coronavirus disease 2019 (COVID-19) outcomes. Objective Given the high prevalence of asthma in the New York City area, our objective was to determine whether underlying asthma was associated with poor outcomes among hospitalized patients with severe COVID-19 compared with patients without asthma. Methods Electronic heath records were reviewed for 1298 sequential patients 65 years or younger without chronic obstructive pulmonary disease who were admitted to our hospital system with a confirmed positive severe acute respiratory syndrome coronavirus 2 test result. Results The overall prevalence of asthma among all hospitalized patients with COVID-19 was 12.6%, yet a higher prevalence (23.6%) was observed in the subset of 55 patients younger than 21 years. There was no significant difference in hospital length of stay, need for intubation, length of intubation, tracheostomy tube placement, hospital readmission, or mortality between patients with and without asthma. Observations between patients with and without asthma were similar when stratified by obesity, other comorbid conditions (ie, hypertension, hyperlipidemia, and diabetes), use of controller asthma medication, and absolute eosinophil count. Conclusions Among hospitalized patients 65 years or younger with severe COVID-19, asthma diagnosis was not associated with worse outcomes, regardless of age, obesity, or other high-risk comorbidities. Future population-based studies are needed to investigate the risk of developing COVID-19 among patients with asthma once universal testing becomes readily available., Graphical abstract

Background Ataluren was developed for potential treatment of nonsense-mutation cystic fibrosis (CF). A previous phase 3 ataluren study failed to meet its primary efficacy endpoint, but post-hoc analyses suggested that aminoglycosides may have interfered with ataluren's action. Thus, this subsequent trial (NCT02139306) was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation CF not receiving aminoglycosides. Methods Eligible subjects with nonsense-mutation CF (aged ≥6 years; percent predicted (pp) FEV1 ≥40 and ≤90) from 75 sites in 16 countries were randomly assigned in double-blinded fashion to receive oral ataluren or matching placebo thrice daily for 48 weeks. The primary endpoint was absolute change in average ppFEV1 from baseline to the average of Weeks 40 and 48. Findings 279 subjects were enrolled; 138 subjects in the ataluren arm and 136 in the placebo arm were evaluable for efficacy. Absolute ppFEV1 change from baseline did not differ significantly between the ataluren and placebo groups at Week 40 (–0.8 vs –1.8) or Week 48 (–1.7 vs –2.4). Average ppFEV1 treatment difference from baseline to Weeks 40 and 48 was 0.6 (95% CI –1.3, 2.5; p = 0.54). Pulmonary exacerbation rate per 48 weeks was not significantly different (ataluren 0.95 vs placebo 1.13; rate ratio p = 0.40). Safety was similar between groups. No life-threatening adverse events or deaths were reported. Interpretation Neither ppFEV1 change nor pulmonary exacerbation rate over 48 weeks were statistically different between ataluren and placebo groups. Development of a nonsense-mutation CF therapy remains elusive.

Postmenopausal (PM) women using inhaled glucocorticoids (IGCs) had substantial abnormalities in volumetric BMD (vBMD), microarchitecture, and stiffness using high resolution peripheral computed tomography (HRpQCT) compared to age- and race-matched controls. Abnormalities were most severe at the radius. These preliminary results suggest that there may be major, heretofore unrecognized, skeletal deficits in PM women using IGCs. While oral glucocorticoids are well recognized to have destructive skeletal effects, less is known about the effects of IGCs. The detrimental skeletal effects of IGCs may be greatest in PM women, in whom they compound negative effects of estrogen loss and aging. The goal of this study was to evaluate microarchitecture and stiffness in PM women using chronic IGCs. This case-control study compared PM women using IGCs for ≥ 6 months (n = 20) and controls matched for age and race/ethnicity (n = 60). Skeletal parameters assessed included areal BMD (aBMD) by DXA, trabecular and cortical vBMD and microarchitecture by HRpQCT of the radius and tibia, and whole bone stiffness by finite element analysis. By DXA, mean values in both groups were in the osteopenic range; hip aBMD was lower in IGC users (P

BackgroundThe use of inflammatory biomarkers to delineate the type of lung inflammation present in asthmatic subjects is increasingly common. However, the effect of obesity on these markers is unknown.ObjectivesWe aimed to determine the effect of obesity on conventional markers of inflammation in asthmatic subjects.MethodsWe performed secondary analysis of data from 652 subjects previously enrolled in 2 Asthma Clinical Research Network trials. We performed linear correlations between biomarkers and logistic regression analysis to determine the predictive value of IgE levels, blood eosinophil counts, and fraction of exhaled nitric oxide values in relationship to sputum eosinophil counts (>2%), as well as to determine whether cut points existed that would maximize the sensitivity and specificity for predicting sputum eosinophilia in the 3 weight groups.ResultsOverall, statistically significant but relatively weak correlations were observed among all 4 markers of inflammation. Within obese subjects, the only significant correlation found was between IgE levels and blood eosinophil counts (r=0.33, P&nbsp

Individuals with cystic fibrosis (CF) have lower bone mineral density (BMD) by DXA and are at higher risk of fracture than healthy controls. However, the 2-dimensional measurement of areal BMD (aBMD) provided by DXA is influenced by bone size and the true extent of the bone deficit is unclear. Our objective was to use high-resolution peripheral quantitative computed tomography (HR-pQCT) and individual trabecula segmentation (ITS) analysis to compare volumetric BMD (vBMD), microarchitecture and estimated strength at the distal radius and tibia in 26 young adults with CF and 26 controls matched for age, gender, and race. To assess the effect of limb length and minimize the confounding effects of size on HR-pQCT outcomes, we scanned participants at both the standard fixed HR-pQCT measurement sites and at a subject-specific relative site that varied according to limb length. CF participants did not differ significantly in age, height, weight, or BMI from controls. Ulnar and tibial lengths were 9mm shorter in CF patients, though differences were not significant. CF patients had significantly lower BMI-adjusted aBMD by DXA at the lumbar spine (8.9%, p0.01), total hip (11.5%, p0.01) and femoral neck (14.5%, p0.01), but not at the forearm. At the fixed radius site, thickness of trabecular plates and torsional stiffness were significantly lower in CF participants than controls. At the relative radius site, only torsional stiffness was significantly lower in CF participants. At the tibia, total, trabecular and cortical vBMD were significantly lower at both fixed and relative sites in CF participants, with fewer, more widely-spaced trabecular plates, lower trabecular connectivity, and lower axial and torsional stiffness. Our results confirm that aBMD is lower at the spine and hip in young adults with CF, independent of BMI and body size. We also conclude that vBMD and stiffness are lower at the weight-bearing tibia. The pathogenesis of these differences in bone density and strength at the tibia appear to be related to trabecular drop-out and reduced trabecular connectivity and to be independent of differences in limb length, as assessed by scanning participants at both standard and relative sites. We concluded that significant deficits in bone structure and strength persist in young adults with CF, despite advances in care that permit them to attain relatively normal height and weight.

Patient: Male, 23-year-old (7 months at the diagnosis) Final Diagnosis: Cystic fibrosis Symptoms: Cough Medication:— Clinical Procedure: Transplantation Specialty: Pulmonology Objective: Unusual clinical course Background: Individuals with cystic fibrosis (CF) constituted approximately 10% of organ transplants in 2019, with the majority of transplants consisting of bilateral lung transplant. Multiorgan transplantation in individuals with cystic fibrosis (CF) is rare, and usually involves the liver and lung combined. Since kidney disease is not a common sequela of CF, the need for renal transplant in individuals who have not previously undergone lung transplant is uncommon. Case Report: We report a case of successful liver-lung-kidney transplant in a 23-year-old man with CF-related liver and lung disease, who developed renal failure due to IgA nephropathy. He required renal replacement therapy during the months before transplantation. After discussions among the liver, lung, and renal transplant teams, the patient was listed for multiorgan transplantation. An appropriate single donor for all organs was identified, and the patient underwent transplantation. The patient required extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) perioperatively, with total operative time of 23 h and 1 min. Postoperative course was notable for hemothorax and medication-induced acute tubular necrosis, which resolved without the need for renal replacement therapy. Liver and lung graft function was normal at 6 months, and renal function was minimally reduced. Conclusions: Triple organ transplantation in CF is a viable option for individuals with multiorgan failure who may otherwise not qualify for single/dual organ transplantation. Use of ECMO and CRRT can be necessary during the long operative procedure. Optimal immunosuppression protocols for this group of patients has not yet been established, and ethical concerns regarding multiorgan transplantation exist.

Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. We conducted a proof-of-principle trial to evaluate the effect of imatinib, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.We conducted a randomized, double-blind, placebo-controlled, 24-week trial of imatinib in patients with poorly controlled severe asthma who had airway hyperresponsiveness despite receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PCAmong the 62 patients who underwent randomization, imatinib treatment reduced airway hyperresponsiveness to a greater extent than did placebo. At 6 months, the methacholine PCIn patients with severe asthma, imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT-dependent processes and mast cells contribute to the pathobiologic basis of severe asthma. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01097694 .).

There is limited data on disease progression and survival in adult diagnosis cystic fibrosis (CF). This study evaluates change of lung function over time and rates of death/lung transplant in adult diagnosis CF.The CF Foundation Patient Registry was reviewed for patients diagnosed 1993-2003. Rate of FEV1 decline was calculated up to 2010 for age groups 6-11, 12-17, and 18 and above. Kaplan Meier method was used for 10 and 15year survival rate calculations for patients diagnosed as adults. Cox Proportional hazards models using predictors affecting disease progression and survival without transplant were run.Between 1993 and 2003, 11,884 patients were diagnosed with CF, of which 2848 were ages 6 and older. Annual rate of change of FEV1% predicted over 5years differed by diagnosis age group: -1.42% per year for ages 6-11, -2.04% for ages 12-17 and -1.13% for ages 18-65 (p0.0001). Pseudomonas aeruginosa infection was associated with faster rates of lung function decline in all age groups. Survival without transplant for CF patients diagnosed at ≥18years were 76% and 65% by 10 and 15years, respectively. Of adults with FEV1 of70% predicted at diagnosis, 95% were alive without transplant at 10years, whereas of those with FEV140% predicted at diagnosis, 31% were alive without transplant at 10years.Lung function declines at a slower rate in adult diagnosis CF. However, particularly in those with low lung function at diagnosis, rates of death or transplant in adult diagnosis CF after 10 and 15years is not negligible.

Background Advanced cystic fibrosis lung disease (ACFLD) is common, is associated with reduced quality of life, and remains the most frequent cause of death in individuals with cystic fibrosis (CF). These consensus guidelines provide recommendations to the CF community on management of both common and unique issues that arise when individuals reach a state of ACFLD. Methods The CF Foundation assembled a multidisciplinary expert panel consisting of three workgroups: Pulmonary management; Management of comorbid conditions; Symptom management and psychosocial issues. Topics were excluded if the management considerations did not differ in ACFLD from in the overall CF population or if already addressed in other published guidelines. Recommendations were based on a systematic literature review combined with expert opinion when appropriate. Results The committee formulated twenty-three recommendation statements specific to ACFLD that address the definition of ACFLD, pulmonary and intensive care unit management, management of selected comorbidities, symptom control, and psychosocial issues. Conclusions These recommendations are intended to be paired with previously published management guidelines for the overall CF population, with the objective of reducing practice variability and improving overall care, quality of life, and survival in those with ACFLD.

BACKGROUND In cystic fibrosis (CF), the relationship between chronic rhinosinusitis (CRS) and pulmonary disease is poorly understood. The purpose of this study was to evaluate the relationship between scores on the 22-item Sino-Nasal Outcome Test (SNOT-22) and CF Questionnaire-revised for adolescents and adults over 14 (CFQ-R 14+), and pulmonary function tests in 2 cohorts of CF patients: those at their baseline health and those with a pulmonary exacerbation. METHODS Patients >18 years old seen in a Cystic Fibrosis Foundation-accredited clinic completed the SNOT-22 and CFQ-R 14+ instruments. Patients presenting for routine care represented the baseline cohort. Patients diagnosed with a pulmonary exacerbation represented the exacerbation cohort. Average SNOT-22 and CFQ-R 14+ scores for both groups were compared using a 2-sample t test, and correlation coefficient was calculated. RESULTS One hundred three patients were enrolled over 3 months (30 exacerbations and 73 baseline). Patients' mean age was 32 years (56% female and 44% male). Average SNOT-22 and CFQ-R 14+ scores were significantly worse for exacerbation patients (p = 0.001 and p = 0.0003, respectively). Percent predicted forced expiratory volume in 1 second and forced vital capacity were both higher for baseline patients (p = 0.002 and p = 0.001, respectively). Average SNOT-22 score for all patients was worse than the average score for non-CF, non-CRS patients. CONCLUSION CF patients with pulmonary exacerbations have worse SNOT-22 and CFQ-R 14+ scores than CF patients at their baseline health. This finding suggests a temporal relationship between sinonasal and pulmonary quality of life, and that worsening of both is associated with reduced pulmonary function.

Long-acting beta agonists (LABAs) are effective for controlling asthma, however questions about their safety have led to concerns over use. Genetic polymorphisms at the 16 amino acid position of the beta-2 adrenergic receptor gene (B2AR) may be associated with increased risk.A randomized, double blind study was conducted in patients with moderate to severe asthma being treated with combined inhaled corticosteroids/LABA (ICS/LABA), comparing the effect of LABA continuation versus withdrawal on asthma outcomes among patients stratified by B2AR genotype (Arg/Arg vs. Gly/Gly at the 16th amino acid position).67 participants (31 Arg/Arg, 36 Gly/Gly) were randomized to receive fluticasone alone (F) or continue combined fluticasone/salmeterol (F/S) after a run-in period on F/S. Among Gly/Gly subjects, those in the F/S treatment group showed improvement in AM PEFR (+ 8.4 L/s) whereas those receiving F alone experienced a reduction in AM PEFR over the study period (-14.4 L/s), (p = 0.06). There was no significant difference in morning peak expiratory flow rate (AM PEFR) in Arg/Arg participants randomized to receive F/S (-15.7L) vs F alone (-5.6 L/s) (p = 0.61). There was no significant difference in exacerbations in the Arg/Arg subjects treated with F/S compared with those treated with F (p = 0.65).Withdrawal of LABA therapy in asthmatics with the Arg/Arg genotype at the 16th amino acid position of B2AR did not lead to significant improvement in AM PEFR. LABA withdrawal in the Gly/Gly genotype however led to a borderline significant decline in AM PEFR.

The bacterium Pseudomonas aeruginosa is especially pathogenic, often being associated with intractable pneumonia and high mortality. How P. aeruginosa avoids immune clearance and persists in the inflamed human airway remains poorly understood. In this study, we show that P. aeruginosa can exploit the host immune response to maintain infection. Notably, unlike other opportunistic bacteria, we found that P. aeruginosa alters its metabolic and immunostimulatory properties in response to itaconate, an abundant host-derived immunometabolite in the infected lung. Itaconate induces bacterial membrane stress, resulting in downregulation of lipopolysaccharides (LPS) and upregulation of extracellular polysaccharides (EPS). These itaconate-adapted P. aeruginosa accumulate lptD mutations, which favor itaconate assimilation and biofilm formation. EPS, in turn, induces itaconate production by myeloid cells, both in the airway and systemically, skewing the host immune response to one permissive of chronic infection. Thus, the metabolic versatility of P. aeruginosa needs to be taken into account when designing therapies.

The tumor suppressor PTEN controls cell proliferation by regulating phosphatidylinositol-3-kinase (PI3K) activity, but the participation of PTEN in host defense against bacterial infection is less well understood. Anti-inflammatory PI3K-Akt signaling is suppressed in patients with cystic fibrosis (CF), a disease characterized by hyper-inflammatory responses to airway infection. We found that Ptenl-/- mice, which lack the NH2-amino terminal splice variant of PTEN, were unable to eradicate Pseudomonas aeruginosa from the airways and could not generate sufficient anti-inflammatory PI3K activity, similar to what is observed in CF. PTEN and the CF transmembrane conductance regulator (CFTR) interacted directly and this interaction was necessary to position PTEN at the membrane. CF patients under corrector-potentiator therapy, which enhances CFTR transport to the membrane, have increased PTEN amounts. These findings suggest that improved CFTR trafficking could enhance P. aeruginosa clearance from the CF airway by activating PTEN-mediated anti-bacterial responses and might represent a therapeutic strategy.

Gastroesophageal reflux (GER) is common in patients with cystic fibrosis (CF) and is often regarded as playing a role in the pathogenesis of CF lung disease. Individuals with CF have many predisposing factors to the development of GER, with a reported prevalence ranging from 35 to 81%. Several studies have suggested that patients with CF who have coexisting GER have more severe lung disease with lower pulmonary function and increased numbers of respiratory exacerbations. Furthermore, GER may alter the respiratory microbiology in CF. Both the acid and nonacid components of GER may have an effect on lung disease. More than 50% of U.S. patients with CF were being treated with proton pump inhibitors in 2012; however, data regarding safety and efficacy of these agents in CF are lacking. Pharmacologic and surgical treatment of GER may improve respiratory morbidity, although prospective controlled studies have not been performed. Given the lack of evidence-based guidelines for evaluation, diagnosis, and treatment of GER in CF, initiation of treatment for symptomatic GER should be based on standard guidelines for the general population. Because there is no clear evidence that GER leads to worse respiratory outcomes in CF or that treatment of GER improves pulmonary outcomes, invasive testing for GER in patients without reflux symptoms is not warranted. Further studies to determine the role of GER in CF lung disease and the risks and benefits of surgical and pharmacologic therapy for GER are warranted.

Intervention for cystic fibrosis lung disease early in its course has the potential to delay or prevent progressive changes that lead to irreversible airflow obstruction. Denufosol is a novel ion channel regulator designed to correct the ion transport defect and increase the overall mucociliary clearance in cystic fibrosis lung disease by increasing chloride secretion, inhibiting sodium absorption, and increasing ciliary beat frequency in the airway epithelium independently of cystic fibrosis transmembrane conductance regulator genotype.To evaluate the efficacy and safety of denufosol in patients with cystic fibrosis who had normal to mildly impaired lung function characteristic of early cystic fibrosis.A total of 352 patients greater than or equal to 5 years old with cystic fibrosis who had FEV(1) greater than or equal to 75% of predicted normal were randomized to receive inhaled denufosol, 60 mg, or placebo three times daily in a Phase 3, randomized, double-blind, placebo-controlled, 24-week trial.Main outcome measures included change in FEV(1) from baseline to Week 24 endpoint and adverse events. Mean change from baseline to Week 24 endpoint in FEV(1) (primary efficacy endpoint) was 0.048 L for denufosol (n = 178) and 0.003 L for placebo (n = 174; P = 0.047). No significant differences between groups were observed for secondary endpoints including exacerbation rate and other measures of lung function. Denufosol was well tolerated with adverse event and growth profiles similar to placebo.Denufosol improved lung function relative to placebo in cystic fibrosis patients with normal to mildly impaired lung function. Clinical trial registered with www.clinicaltrials.gov (NCT00357279).

Background Stepping down therapy when asthma is well controlled on combination inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) is recommended, but it is not known whether lowering the ICS dose or stopping LABA is superior. Objective To evaluate whether step-down therapy with LABA is superior to one without; and, secondarily, to evaluate whether reducing the ICS dose while maintaining LABA is noninferior to remaining on stable-ICS/LABA. Methods The study was a randomized, double-masked 3-arm parallel group trial in participants aged 12 years or older. Following an 8-week run-in, 459 participants were randomly assigned to continue medium-dose ICS/LABA, reduced-dose ICS/LABA, or ICS alone (LABA-step-off) and followed for 48 weeks. The primary outcome was time to treatment failure, a composite of health care utilization, systemic corticosteroid use, increase in rescue therapy, decline in lung function, or participant or physician decision. Results Time to treatment failure did not differ significantly between reduced- ICS/LABA and LABA-step-off (hazard ratio, 1.07; 95.3% CI, 0.69-1.65, P = .76). Nor was there a difference between stable-ICS/LABA and reduced-ICS/LABA (hazard ratio, 1.11; 95% CI, 0.70-1.76; P = .67), but the 10% noninferiority margin was exceeded. Lung function declines and hospitalization rates were significantly greater in the LABA-step-off group. Conclusions The 2 step-down regimens did not differ in terms of treatment failure, although stopping LABA was associated with a decline in lung function and more hospitalizations. There was no evidence to support the noninferiority of reduced-ICS/LABA as compared with stable-ICS/LABA.

Silent gastroesophageal reflux (GER) is common in patients with asthma, but it is unclear whether GER is associated with worse asthma symptoms or reduced lung function.To determine in patients with poorly controlled asthma, whether proximal or distal esophageal reflux is associated with asthma severity, symptoms, physiology, or functional status.Baseline asthma characteristics were measured in patients with asthma enrolled in a multicenter trial assessing the effectiveness of esomeprazole on asthma control. All participants underwent 24-hour esophageal pH probe monitoring. Lung function, methacholine responsiveness, asthma symptoms, and quality-of-life scores were compared in subjects with and without GER.Of 304 participants with probe recordings, 53% had reflux. Of 242 participants with recordings of proximal pH, 38% had proximal reflux. There was no difference in need for short-acting bronchodilators, nocturnal awakenings, dose of inhaled corticosteroid, use of long-acting beta-agonists, lung function, or methacholine reactivity between individuals with and without proximal or distal GER. Participants with GER reported more use of oral corticosteroids and had worse asthma quality of life and subjects with proximal GER had significantly worse asthma quality of life and health-related quality of life compared with participants without GER.Asymptomatic GER is not associated with distinguishing asthma symptoms or lower lung function in individuals with suboptimal asthma control who are using inhaled corticosteroids. Patients with proximal reflux report significantly worse asthma and health-related quality of life despite lack of physiologic impairment or increase in asthma symptoms. Clinical trial registered with www.clinicaltrials.gov (NCT00069823).

Long-acting beta-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA.

Asthma exacerbations are associated with decreased quality of life and increased health care usage. Identification of characteristics that predict increased risk of future exacerbations in patients with suboptimal control of asthma could guide treatment decisions.To examine patient characteristics associated with risk of asthma exacerbations in patients with uncontrolled persistent asthma.A retrospective analysis of adults and children with inadequately controlled asthma despite asthma controller therapy and enrolled in 2 randomized trials was conducted. Baseline characteristics of subjects who experienced an asthma exacerbation during the treatment period were compared with those of subjects who did not experience an exacerbation.Of 718 subjects (402 adults and 295 children), 108 adults (27%) and 110 children (37%) experienced an asthma exacerbation during the study period. Unscheduled health care visits for asthma or use of oral corticosteroids in the previous year were significantly associated with asthma exacerbation during the study period (P.01). Adult subjects who experienced an exacerbation had significantly lower forced expiratory volume in 1 second compared with those who did not (2.3 vs 2.5 L, respectively, P = .02). Children who experienced an exacerbation had lower baseline pre- and post-bronchodilator ratios of forced expiratory volume in 1 second to forced vital capacity (77% vs 81%, P.01; 82% vs 86%, P.001, respectively). Symptom scores on validated questionnaires were significantly worse in adults but not in children who developed an exacerbation.Spirometric measurements can help identify adults and children at increased risk for asthma exacerbation. Symptom scores could be helpful in identifying adults who are at high risk for exacerbations but could be less helpful in children.

Background Environmental exposures to indoor allergens are major contributors to asthma symptoms, particularly in inner cities. The effectiveness of household allergen reduction as an adjunct to National Asthma Education Prevention Program guideline–based pharmacologic therapy in asthma has not been prospectively studied. Objective To study the effect of individualized allergen reduction on ability to reduce asthma pharmacologic therapy over 40 weeks. Methods We performed a randomized controlled trial to determine the effect of multifaceted indoor allergen avoidance measures on the ability to reduce asthma controller therapy in adults and children residing in New York City who were both sensitized and exposed to at least 1 indoor allergen. Asthma treatment and control were optimized in all subjects before randomization. Results A total of 125 subjects were randomized to receive individualized household allergen reduction and 122 received a sham intervention. Subjects in the intervention group significantly reduced all measured allergen levels (cat, dog, dust mite allergens in the bedroom, cockroach and mouse allergens in the kitchen and bedroom); those in the control group reduced only dust mite and mouse allergens in the bedroom and cockroach allergen in the kitchen. Participants in the intervention arm reduced National Asthma Education Prevention Program–based therapy from step 4.4 at randomization to 3.50 postintervention (range, 0-6); participants in the control arm reduced medication from step 4.4 to 3.4 ( P = .76). There were no differences in other measured asthma outcomes. Conclusions Targeted allergen avoidance measures do not allow for reduction in asthma pharmacologic therapy compared with usual care in patients already receiving optimal controller therapy.

Importance Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. Objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Interventions Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. Main Outcomes and Measures The primary outcome measure was change in forced expiratory volume in the first second (FEV 1 ) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Results Mean changes in prebronchodilator FEV 1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different ( P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL ( P Conclusions and Relevance Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. Trial Registration clinicaltrials.gov Identifier:NCT01052116

Objective To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV 1 %pred) variability as potential predictors of future FEV 1 %pred decline in patients with cystic fibrosis. Study design We included 13 827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV 1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV 1 %pred to best follow-up FEV 1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV 1 %pred. Results All 5 measures of FEV 1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV 1 %pred in the baseline period. The contribution to explanatory power (R 2 ) was substantial and exceeded the total contribution of all other factors excluding the FEV 1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Conclusions Median deviation from the best FEV 1 %pred is a simple metric that markedly improves prediction of FEV 1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV 1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.

A central bronchus that is readily visible end-on in approximately 50% of normal frontal chest radiographs is the bronchus to the anterior segment of either upper lobe. Bronchial wall thickening, or "cuffing," is considered to be a radiographic sign of an asthmatic exacerbation and is cited as a useful sign in a number of leading textbooks; however, to the authors' knowledge, no prior chest radiographic study has quantitatively assessed this specific sign in a population of asthmatics suffering an acute exacerbation. Posterior chest radiographs were reviewed retrospectively for 51 nonasthmatic, nonsmoking control subjects and for 45 adult asthmatic subjects during an acute exacerbation of moderate to severe asthma. Readers were blinded as to whether the radiograph was from an asthmatic or control subject. If visible end-on, the bronchus to the anterior segment of either upper lobe was assessed by measuring the diameter of the lumen and the thickness of the bronchial wall. At least one clearly defined bronchus to the anterior segment of an upper lobe was visible end-on in 22 patients (43%) in the control group and in 21 patients (47%) in the asthma group (p = NS). Mean wall thickness was 0.7 +/- 0.1 mm in the control group and 0.8 +/- 0.1 mm in the asthma group (p = 0.04). Lumen/wall thickness was 3.1 +/- 0.2 (SEM) in the control group and 2.5 +/- 0.2 in the asthma group (p = 0.055). The presence of bronchial wall thickness does not reliably distinguish radiographs of acutely asthmatic from normal individuals.

PMN-dominated airway inflammation is a major component of cystic fibrosis (CF) lung disease. Epithelial cells respond to organisms such as Pseudomonas aeruginosa, the major pathogen in CF, by expressing the leukocyte chemokine IL-8. Experiments were performed using several different types of respiratory epithelial cells that demonstrate that ligation of ceramide-associated receptors on epithelial surfaces by P. aeruginosa pili is a major stimulus for the translocation of transcription factor nuclear factor (NF)-kappaB and initiation of IL-8 expression by epithelial cells. Using electrophoretic mobility shift assays and Western hybridizations, nuclear NF-kappaB was found shortly after epithelial cells were stimulated by either whole organisms, isolated pili, or antibody to the pilin receptor asialoGM1. IB3 cells, which express mutations in cystic fibrosis transmembrane conductance regulator (CFTR) (DeltaF508/W1282X), were noted to have significantly greater amounts of endogenous nuclear NF-kappaB, but not the transcription factor C/EBP, than CF cells corrected by episomal copies of normal CFTR (C-38) or IB3 cells grown at a permissive temperature (25 degreesC). Activation of NF-kappaB and subsequent IL-8 expression in epithelial cells can result from activation of at least two pathways: an exogenous signaling cascade that is activated by ligation of ceramide-associated adhesins such as P. aeruginosa pilin, or endogenous stimulation, suggested to be a consequence of cell stress caused by the accumulation of mutant CFTR in the endoplasmic reticulum.

Background Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described. Objective We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response. Methods Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV 1 , morning peak expiratory flow (PEF), and asthma control days (ACDs). Results Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV 1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV 1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P P = 0.021), as did a decreased FEV 1 /forced vital capacity ratio (FEV 1 response increased 0.39% of baseline for every 1% decrease in FEV 1 /forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not. Conclusion Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.

Respiratory epithelial cells play a crucial role in the inflammatory response during Pseudomonas aeruginosa infection in the lungs of patients with cystic fibrosis. In this study, we determined whether the binding of specific Pseudomonas gene products (pilin, flagellin) to their receptors on respiratory epithelial cells would result in production of the neutrophil chemoattractant IL-8. Piliated wild-type organisms, purified pili, or antibody to the pilin receptor (asialoGM1) evoked significant production of IL-8 by immortalized airway epithelial cells, whereas nonpiliated organisms were less able to bind to respiratory epithelial cells and stimulated much less IL-8 secretion (P < 0.01). A piliated, nonflagellated strain was also associated with decreased binding and a diminished level of IL-8 production when compared to wild-type organisms. Isogenic, nonadherent rpoN mutants, lacking pilin and flagellin, did not bind or elicit an IL-8 response. In addition, the IL-8 response was four-fold higher in a cystic fibrosis cell line compared with its corrected cell line. The Pseudomonas autoinducer, an exoproduct secreted during chronic infection, was found to stimulate IL-8 in a dose-dependent manner. P. aeruginosa adhesins, which are necessary for initial infection, directly stimulate IL-8 production by respiratory epithelial cells and therefore play a major role in the pathogenesis of Pseudomonas infection in patients with cystic fibrosis. The inflammatory response is subsequently perpetuated by Pseudomonas autoinducer which is secreted during chronic infection.

Background The American Lung Association Asthma Clinical Research Centers (ALA-ACRC) reported that the inactivated influenza vaccine is safe for patients with asthma and recommended its use to reduce the morbidity associated with infection. Objective Because the ALA-ACRC's recommendation would include vaccination of all patients with asthma, including those with severe asthma and first-time vaccinees, we conducted a parallel study to address whether patients with asthma who report bronchospasm after vaccination might be demonstrating a hypersensitivity response to the vaccine. Methods Thirty-two adult patients with asthma from the ALA-ACRC cohort were recruited. Subjects were randomly assigned to receive influenza vaccine or placebo and then recorded asthma symptoms and peak expiratory flow rates for 14 days. On day 14, influenza vaccine and egg antigen–induced mononuclear cell proliferation and IFN-γ, IL-5, and IL-4 production were measured and compared with symptoms. Results Increased influenza but not egg antigen–induced mononuclear cell proliferation was present among vaccinated subjects. These responses were unrelated to asthma exacerbations after vaccine. There were no differences in cytokine production in response to either influenza or egg antigen in association with asthma exacerbations. Conclusions Episodes of bronchospasm after influenza vaccination do not seem related to hypersensitivity to the vaccine.

Context No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms. Objective To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma. Design, Setting, and Participants A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment–based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010. Interventions For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use. Main Outcome Measure The primary outcome was time to treatment failure. Results There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3). Conclusion Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure. Trial Registration clinicaltrials.gov Identifier: NCT00495157

Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies.To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures.We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993-2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race.A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV(1) (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2-2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3-3.6; P = 0.004), even when used with other controller therapies.Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.