The gain-of-function MUC5B promoter variant rs35705950 is the dominant risk factor for developing idiopathic pulmonary fibrosis (IPF). Here we show in humans that MUC5B, a mucin thought to be ...restricted to conducting airways, is co-expressed with surfactant protein C (SFTPC) in type 2 alveolar epithelia and in epithelial cells lining honeycomb cysts, indicating that cell types involved in lung fibrosis in distal airspace express MUC5B. In mice, we demonstrate that Muc5b concentration in bronchoalveolar epithelia is related to impaired mucociliary clearance (MCC) and to the extent and persistence of bleomycin-induced lung fibrosis. We also establish the ability of the mucolytic agent P-2119 to restore MCC and to suppress bleomycin-induced lung fibrosis in the setting of Muc5b overexpression. Our findings suggest that mucociliary dysfunction might play a causative role in bleomycin-induced pulmonary fibrosis in mice overexpressing Muc5b, and that MUC5B in distal airspaces is a potential therapeutic target in humans with IPF.
The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs ...in at least 85% of people with CF.
PROMISE is a postapproval study to understand the broad effects of ETI through 30 months' clinical use in a more diverse U.S. patient population with planned analyses after 6 months.
Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV
(ppFEV
), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms.
Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV
improved 9.76 percentage points (95% confidence interval CI, 8.76 to 10.76) from baseline, cystic fibrosis questionnaire-revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased -41.7 mmol/L (95% CI, -43.8 to -39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline.
ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV
in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).
Spirometry plays a crucial role in the diagnosis of asthma. The hallmark spirometry finding of expiratory airflow variability can be demonstrated in several ways including peak airflow and ...bronchodilator and bronchoprovocation testing. Challenges of overdiagnosis and underdiagnosis underscore the need to consider clinical context while interpreting these tests. A meticulous and multifaceted approach prioritizing objective testing is imperative while diagnosing asthma.
•Common airway diseases including COPD, asthma and non-CF bronchiectasis (NCFBE) share the common pathophysiologic feature of mucus obstruction.•Acquired CFTR dysfunction is a potential overlapping ...mechanism to explain abnormal mucus clearance in these diseases.•CFTR modulators have shown promise in CF and thus should be tested in diseases with acquired CFTR dysfunction.•Early studies indicate safety and promise efficacy for the CFTR potentiator ivacaftor in COPD with chronic bronchitis.
Airways diseases, especially chronic obstructive pulmonary disease (COPD) and asthma, are common causes of morbidity and mortality worldwide. There is an ongoing unmet need for novel and effective therapies. There is an established pathophysiological link and phenotypic similarity between the chronic bronchitis phenotype of COPD and cystic fibrosis (CF). New evidence suggests that CFTR dysfunction may play a role in other common airways diseases such as COPD, non-atopic asthma and non-CF bronchiectasis. Newly approved and investigational drugs that target both mutant and wild-type CFTR channels have provided a new treatment opportunity addressing the mucus defect in pulmonary diseases that share the same pathophysiology with CF.
The use of airway clearance strategies as supplementary treatment in respiratory disease has been best investigated in patients with cystic fibrosis (CF) and non-cystic fibrosis bronchiectasis ...(NCFBE), conditions which are traditionally characterized by excessive mucus stasis and mucociliary dysfunction. A variety of airway clearance therapies both pharmacological and non-pharmacological have been shown to ameliorate disease progression in this population and have hence been assimilated into routine respiratory care. This self-propagating cycle of mucus retention and airway damage leading to chronic inflammation and infections can also be applied to patients with respiratory failure requiring mechanical ventilation. Furthermore, excessive trachea-bronchial secretions have been associated with extubation failure presenting an opportunity for intervention. Evidence for the use of adjunctive mucoactive agents and other therapies to facilitate secretion clearance in these patients are not well defined, and this subgroup still remains largely underrepresented in clinical trials. In this review, we discuss the role of mucus clearance techniques with a proven benefit in patients with CF and NCFBE, and their potential role in patients requiring mechanical ventilation while highlighting the need for standardization and adoption of mucus clearance strategies in these patient populations.
Cystic fibrosis (CF) is a genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Although impairment of mucociliary clearance contributes to severe morbidity ...and mortality in people with CF, a clear understanding of the pathophysiology is lacking. This is, in part, due to the absence of clinical imaging techniques capable of capturing CFTR-dependent functional metrics at the cellular level. Here, we report the clinical translation of a 1-μm resolution micro-optical coherence tomography (μOCT) technology to quantitatively characterize the functional microanatomy of human upper airways. Using a minimally invasive intranasal imaging approach, we performed a clinical study on age- and sex-matched CF and control groups. We observed delayed mucociliary transport rate at the cellular level, depletion of periciliary liquid layer, and prevalent loss of ciliation in subjects with CF. Distinctive morphological differences in mucus and various forms of epithelial injury were also revealed by μOCT imaging and had prominent effects on the mucociliary transport apparatus. Elevated mucus reflectance intensity in CF, a proxy for viscosity in situ, had a dominant effect. These results demonstrate the utility of μOCT to determine epithelial function and monitor disease status of CF airways on a per-patient basis, with applicability for other diseases of mucus clearance.
Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion transporter that regulates mucus hydration, viscosity and acidity of the airway epithelial surface. Genetic defects in
impair ...regulation of mucus homeostasis, causing severe defects of mucociliary clearance as seen in cystic fibrosis. Recent work has established that CFTR dysfunction can be acquired in chronic obstructive pulmonary disease (COPD) and may also contribute to other diseases that share clinical features of cystic fibrosis, such as asthma, allergic bronchopulmonary aspergillosis and bronchiectasis. Protean causes of CFTR dysfunction have been identified including cigarette smoke exposure, toxic metals and downstream effects of neutrophil activation pathways. Recently, CFTR modulators, small molecule agents that potentiate CFTR or restore diminished protein levels at the cell surface, have been successfully developed for various
gene defects, prompting interest in their use to treat diseases of acquired dysfunction. The spectrum of CFTR dysfunction, strategies for CFTR modulation, and candidate diseases for CFTR modulation beyond cystic fibrosis will be reviewed in this manuscript.
The increasing prevalence and recognition of bronchiectasis in clinical practice necessitates a better understanding of the economic disease burden to improve the management and achieve better ...clinical and economic outcomes. This study aimed to assess the economic burden of bronchiectasis based on a review of published literature.
A systematic literature review was conducted using MEDLINE, Embase, EconLit and Cochrane databases to identify publications (1 January 2001 to 31 December 2016) on the economic burden of bronchiectasis in adults.
A total of 26 publications were identified that reported resource use and costs associated with management of bronchiectasis. Two US studies reported annual incremental costs of bronchiectasis versus matched controls of US$5681 and US$2319 per patient. Twenty-four studies reported on hospitalization rates or duration of hospitalization for patients with bronchiectasis. Mean annual hospitalization rates per patient, reported in six studies, ranged from 0.3-1.3, while mean annual age-adjusted hospitalization rates, reported in four studies, ranged from 1.8-25.7 per 100,000 population. The average duration of hospitalization, reported in 12 studies, ranged from 2 to 17 days. Eight publications reported management costs of bronchiectasis. Total annual management costs of €3515 and €4672 per patient were reported in two Spanish studies. Two US studies reported total costs of approximately US$26,000 in patients without exacerbations, increasing to US$36,00-37,000 in patients with exacerbations. Similarly, a Spanish study reported higher total annual costs for patients with > 2 exacerbations per year (€7520) compared with those without exacerbations (€3892). P. aeruginosa infection increased management costs by US$31,551 to US$56,499, as reported in two US studies, with hospitalization being the main cost driver.
The current literature suggests that the economic burden of bronchiectasis in society is significant. Hospitalization costs are the major driver behind these costs, especially in patients with frequent exacerbations. However, the true economic burden of bronchiectasis is likely to be underestimated because most studies were retrospective, used ICD-9-CM coding to identify patients, and often ignored outpatient burden and cost. We present a conceptual framework to facilitate a more comprehensive assessment of the true burden of bronchiectasis for individuals, healthcare systems and society.
•This manuscript describes a 2-center case series of pregnancy in FwCF taking Elexacaftor/tezacaftor/Ivacaftor (ETI).•Our findings suggest increased fertility in this patient population.•Clinical ...care guidelines should be revised to include counseling on family planning as data emerges regarding alteration in female fertility when taking CFTR modulators.
Infertility and subfertility are commonly faced by females with cystic fibrosis (FwCF) and resulting in decreased contraceptive use and increased utilization of reproductive technologies. Elexacaftor-tezacaftor-ivacaftor (ETI) is a CFTR modulator that affects common causes of subfertility.
Two CF centers conducted a retrospective chart review on females with CF who were receiving ETI and became pregnant. We analyzed obstetrical-gynecological history, genotype, and clinical response to ETI therapy. Fourteen FwCF on ETI became pregnant. Half (7) of the FwCFs were previously attempting to conceive, but only three were using contraceptives. Four FwCF had a history of infertility; two were reconsidering use of reproductive technologies (IUI). Patients achieved conception at mean 8 weeks after initiating ETI. ETI may lessen CF-associated factors that affect fertility; however, its exact mechanism is unknown. This warrants counseling on contraceptive use and family planning prior to initiation of therapy and at routine intervals while utilizing ETI.
The respiratory tract is lined with multiciliated epithelial cells that function to move mucus and trapped particles via the mucociliary transport apparatus. Genetic and acquired ciliopathies result ...in diminished mucociliary clearance, contributing to disease pathogenesis. Recent innovations in imaging technology have advanced our understanding of ciliary motion in health and disease states. Application of imaging modalities including transmission electron microscopy, high-speed video microscopy, and micron-optical coherence tomography could improve diagnostics and be applied for precision medicine. In this review, we provide an overview of ciliary motion, imaging modalities, and ciliopathic diseases of the respiratory system including primary ciliary dyskinesia, cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis.
PDF
