State of the Art in Exocrine Pancreatic Insufficiency.

Medicina (Kaunas). 2020 Oct 07;56(10):

Authors: Diéguez-Castillo C, Jiménez-Luna C, Prados J, Martín-Ruiz JL, Caba O

Abstract
Exocrine pancreatic insufficiency (EPI) is defined as the maldigestion of foods due to inadequate pancreatic secretion, which can be caused by alterations in its stimulation, production, transport, or interaction with nutrients at duodenal level. The most frequent causes are chronic pancreatitis in adults and cystic fibrosis in children. The prevalence of EPI is high, varying according to its etiology, but it is considered to be underdiagnosed and undertreated. Its importance lies in the quality of life impairment that results from the malabsorption and malnutrition and in the increased morbidity and mortality, being associated with osteoporosis and cardiovascular events. The diagnosis is based on a set of symptoms, indicators of malnutrition, and an indirect non-invasive test in at-risk patients. The treatment of choice combines non-restrictive dietary measures with pancreatic enzyme replacement therapy to correct the associated symptoms and improve the nutritional status of patients. Non-responders require the adjustment of pancreatic enzyme therapy, the association of proton pump inhibitors, and/or the evaluation of alternative diagnoses such as bacterial overgrowth. This review offers an in-depth overview of EPI in order to support the proper management of this entity based on updated and integrated knowledge of its etiopathogenesis, prevalence, diagnosis, and treatment.

PMID: 33036352 [PubMed - as supplied by publisher]

Detargeting Lentiviral-Mediated CFTR Expression in Airway Basal Cells Using miR-106b.

Genes (Basel). 2020 Oct 06;11(10):

Authors: Choi SH, Reeves RE, Romano Ibarra GS, Lynch TJ, Shahin WS, Feng Z, Gasser GN, Winter MC, Evans TIA, Liu X, Luo M, Zhang Y, Stoltz DA, Devor EJ, Yan Z, Engelhardt JF

Abstract
Lentiviral-mediated integration of a CFTR transgene cassette into airway basal cells is a strategy being considered for cystic fibrosis (CF) cell-based therapies. However, CFTR expression is highly regulated in differentiated airway cell types and a subset of intermediate basal cells destined to differentiate. Since basal stem cells typically do not express CFTR, suppressing the CFTR expression from the lentiviral vector in airway basal cells may be beneficial for maintaining their proliferative capacity and multipotency. We identified miR-106b as highly expressed in proliferating airway basal cells and extinguished in differentiated columnar cells. Herein, we developed lentiviral vectors with the miR-106b-target sequence (miRT) to both study miR-106b regulation during basal cell differentiation and detarget CFTR expression in basal cells. Given that miR-106b is expressed in the 293T cells used for viral production, obstacles of viral genome integrity and titers were overcome by creating a 293T-B2 cell line that inducibly expresses the RNAi suppressor B2 protein from flock house virus. While miR-106b vectors effectively detargeted reporter gene expression in proliferating basal cells and following differentiation in the air-liquid interface and organoid cultures, the CFTR-miRT vector produced significantly less CFTR-mediated current than the non-miR-targeted CFTR vector following transduction and differentiation of CF basal cells. These findings suggest that miR-106b is expressed in certain airway cell types that contribute to the majority of CFTR anion transport in airway epithelium.

PMID: 33036232 [PubMed - as supplied by publisher]

Protocol for Project Fizzyo, an analytic longitudinal observational cohort study of physiotherapy for children and young people with cystic fibrosis, with interrupted time-series design.

BMJ Open. 2020 Oct 07;10(10):e039587

Authors: Raywood E, Douglas H, Kapoor K, Filipow N, Murray N, O'Connor R, Stott L, Saul G, Kuzhagaliyev T, Davies G, Liakhovich O, Van Schaik T, Furtuna B, Booth J, Shannon H, Bryon M, Main E

Abstract
INTRODUCTION: Daily physiotherapy is believed to mitigate the progression of cystic fibrosis (CF) lung disease. However, physiotherapy airway clearance techniques (ACTs) are burdensome and the evidence guiding practice remains weak. This paper describes the protocol for Project Fizzyo, which uses innovative technology and analysis methods to remotely capture longitudinal daily data from physiotherapy treatments to measure adherence and prospectively evaluate associations with clinical outcomes.
METHODS AND ANALYSIS: A cohort of 145 children and young people with CF aged 6-16 years were recruited. Each participant will record their usual physiotherapy sessions daily for 16 months, using remote monitoring sensors: (1) a bespoke ACT sensor, inserted into their usual ACT device and (2) a Fitbit Alta HR activity tracker. Real-time breath pressure during ACTs, and heart rate and daily step counts (Fitbit) are synced using specific software applications. An interrupted time-series design will facilitate evaluation of ACT interventions (feedback and ACT-driven gaming). Baseline, mid and endpoint assessments of spirometry, exercise capacity and quality of life and longitudinal clinical record data will also be collected.This large dataset will be analysed in R using big data analytics approaches. Distinct ACT and physical activity adherence profiles will be identified, using cluster analysis to define groups of individuals based on measured characteristics and any relationships to clinical profiles assessed. Changes in adherence to physiotherapy over time or in relation to ACT interventions will be quantified and evaluated in relation to clinical outcomes.
ETHICS AND DISSEMINATION: Ethical approval for this study (IRAS: 228625) was granted by the London-Brighton and Sussex NREC (18/LO/1038). Findings will be disseminated via peer-reviewed publications, at conferences and via CF clinical networks. The statistical code will be published in the Fizzyo GitHub repository and the dataset stored in the Great Ormond Street Hospital Digital Research Environment.
TRIAL REGISTRATION NUMBER: ISRCTN51624752; Pre-results.

PMID: 33033031 [PubMed - in process]

Cost-Effectiveness of Ivacaftor Therapy for Treatment of Cystic Fibrosis Patients With the G551D Gating Mutation.

Value Health. 2020 Oct;23(10):1332-1339

Authors: Wherry K, Williamson I, Chapman RH, Kuntz KM

Abstract
OBJECTIVES: Cystic fibrosis (CF) is a rare genetic disease with no cure. Until recently, treatment has targeted symptoms of the disease and not the disease-causing genetic defect. Ivacaftor is included in a new class of breakthrough drugs targeting the genetic defects of CF. We sought to estimate the long-term cost-effectiveness of ivacaftor from a US payer perspective.
METHODS: We developed an individual-level microsimulation model that followed a cohort of heterogeneous US CF patients over a lifetime. The primary outcome of interest was quality-adjusted life years (QALYs). We also compared unadjusted life years, count of acute pulmonary exacerbations, and count of lung transplants over a lifetime between patients treated with ivacaftor plus best supportive care and patients treated with best supportive care alone. We conducted one-way and probabilistic sensitivity analyses to test the impact of various model inputs and uncertainties.
RESULTS: We found a substantial increase in QALYs, life years, and treatment costs over a lifetime for patients treated with ivacaftor plus best supportive care versus best supportive care alone. Discounted results for ivacaftor were 22.92 QALYs and $8 797 840 in total lifetime costs compared to 16.12 QALYs and $2 336 366 lifetime costs for best supportive care alone. The incremental cost-effectiveness ratios (ICERs) were $950 217 per QALY. Results from the probabilistic sensitivity analysis indicated a 0% chance that ivacaftor was cost-effective at a willingness-to-pay (WTP) threshold of $500 000 per QALY.
CONCLUSIONS: Treatment with ivacaftor plus best supportive care versus best supportive care alone is not cost-effective at or near commonly accepted WTP thresholds.

PMID: 33032777 [PubMed - in process]

Serum levels of hyaluronic acid are associated with COPD severity and predict survival.

Eur Respir J. 2019 03;53(3):

Authors: Papakonstantinou E, Bonovolias I, Roth M, Tamm M, Schumann D, Baty F, Louis R, Milenkovic B, Boersma W, Stieltjes B, Kostikas K, Blasi F, Aerts JG, Rohde GGU, Lacoma A, Torres A, Welte T, Stolz D

Abstract
Hyaluronic acid (HA) and its degradation products play an important role in lung pathophysiology and airway remodelling in chronic obstructive pulmonary disease (COPD).We investigated if HA and its degrading enzyme hyaluronidase (HYAL)-1 are associated with COPD severity and outcome.Serum HA was assessed in a discovery cohort of 80 COPD patients at stable state and exacerbations. HA, HYAL-1 and HYAL-1 enzymatic activity were evaluated at stable state, exacerbations and 4 weeks after exacerbations in 638 COPD patients from the PROMISE validation cohort.In the discovery cohort, serum HA was higher at exacerbations compared with the stable state (p=0.015). In the validation cohort, HA was higher at moderate and severe exacerbations than at baseline (p<0.001), and remained higher after 4 weeks (p<0.001). HA was strongly predictive for overall survival since it was associated with time to death (p<0.001) independently of adjusted Charlson score, annual exacerbation rate and BODE (body mass, airflow obstruction, dyspnoea, exercise capacity) index. Serum HYAL-1 was increased at moderate (p=0.004) and severe (p=0.003) exacerbations, but decreased after 4 weeks (p<0.001). HYAL-1 enzymatic activity at stable state was inversely correlated with FEV1 % pred (p=0.034) and survival time (p=0.017).Serum HA is associated with COPD severity and predicts overall survival. Degradation of HA is associated with airflow limitation and impairment of lung function.

PMID: 30705130 [PubMed - indexed for MEDLINE]

FREQMAX provides an alternative approach for determining high-resolution allele frequency thresholds in carrier screening.

Hum Mutat. 2020 Oct 08;:

Authors: Subaran RL, Stewart WCL

Abstract
As whole-genome data become available for increasing numbers of individuals across diverse populations, the list of genomic variants of unknown significance (VOUS) continues to grow. One powerful tool in VOUS interpretation is determining whether an allele is too common to be considered pathogenic. Since genetic and epidemiological parameters vary across disease models, so too does the pathogenic allele frequency threshold for each disease gene. One threshold-setting approach is the maximum credible allele frequency (MCAF) method. However, estimating some of the input values MCAF requires, especially those involving heterogeneity, can present non-trivial statistical challenges. Here, we introduce FREQMAX, our alternative approach for determining allele frequency thresholds in carrier screening. FREQMAX makes efficient use of the data available for well-studied traits and exhibits flexibility for traits where information may be less complete. For cystic fibrosis, more alleles are excluded as benign by FREQMAX than by MCAF. For less comprehensively characterized traits like ciliary dyskinesia and Smith-Lemli-Opitz syndrome, FREQMAX is able to set the allele frequency threshold without requiring a priori estimates of maximum genetic and allelic contributions. Furthermore, while we describe FREQMAX in the context of carrier screening, its classical population genetics framework also provides context for adaptation to other trait models. This article is protected by copyright. All rights reserved.

PMID: 33032373 [PubMed - as supplied by publisher]

The Enemy of my Enemy: Bacterial Competition in the Cystic Fibrosis Lung.

Cell Host Microbe. 2020 Oct 07;28(4):502-504

Authors: Kazmierczak BI

Abstract
Bacterial competition within host-associated polymicrobial communities shapes their composition, often with far-reaching consequences for human health. In this issue of Cell Host & Microbe, Perault et al. reveal how competition between two opportunistic pathogens could account for the epidemiology of chronic lung infections in people with cystic fibrosis.

PMID: 33031766 [PubMed - as supplied by publisher]

Toll like Receptor signalling by Prevotella histicola activates alternative NF-κB signalling in Cystic Fibrosis bronchial epithelial cells compared to P. aeruginosa.

PLoS One. 2020;15(10):e0235803

Authors: Bertelsen A, Elborn SJ, Schock BC

Abstract
Cystic Fibrosis (CF), caused by mutations affecting the CFTR gene, is characterised by viscid secretions in multiple organ systems. CF airways contain thick mucus, creating a gradient of hypoxia, which promotes the establishment of polymicrobial infection. Such inflammation predisposes to further infection, a self-perpetuating cycle in mediated by NF-κB. Anaerobic Gram-negative Prevotella spp. are found in sputum from healthy volunteers and CF patients and in CF lungs correlate with reduced levels of inflammation. Prevotella histicola (P. histicola) can suppress murine lung inflammation, however, no studies have examined the role of P. histicola in modulating infection and inflammation in the CF airways. We investigated innate immune signalling and NF-kB activation in CF epithelial cells CFBE41o- in response to clinical stains of P. histicola and Pseudomonas aeruginosa (P. aeruginosa). Toll-Like Receptor (TLR) expressing HEK-293 cells and siRNA assays for TLRs and IKKα were used to confirm signalling pathways. We show that P. histicola infection activated the alternative NF-kB signalling pathway in CF bronchial epithelial cells inducing HIF-1α protein. TLR5 signalling was responsible for the induction of the alternative NF-kB pathway through phosphorylation of IKKα. The induction of transcription factor HIF-1α was inversely associated with the induction of the alternative NF-kB pathway and knockdown of IKKα partially restored canonical NF-kB activation in response to P. histicola. This study demonstrates that different bacterial species in the respiratory microbiome can contribute differently to inflammation, either by activating inflammatory cascades (P. aeruginosa) or by muting the inflammatory response by modulating similar or related pathways (P. histicola). Further work is required to assess the complex interactions of the lung microbiome in response to mixed bacterial infections and their effects in people with CF.

PMID: 33031374 [PubMed - as supplied by publisher]

Lung Clearance Index to Track Acute Respiratory Events in School-age Children with Cystic Fibrosis.

Am J Respir Crit Care Med. 2020 Oct 08;:

Authors: Perrem L, Stanojevic S, Shaw M, Jensen R, McDonald N, Isaac SM, Davis M, Clem C, Guido J, Jara S, France L, Solomon M, Grasemann H, Waters V, Sweezey N, Sanders DB, Davis SD, Ratjen F

Abstract
OBJECTIVE: The lung clearance index (LCI) is responsive to acute respiratory events in preschool children with cystic fibrosis (CF) but its' utility to identify and manage these events in school-age children with CF is not well defined.
METHODS: In a multisite prospective observational study, LCI and forced expiratory volume in 1 second (FEV1) were measured quarterly and during acute respiratory events. Linear regression was used to compare relative changes in LCI and FEV1 % predicted at acute respiratory events. Logistic regression was used to compare the odds of a significant worsening in LCI and FEV1 % predicted at acute respiratory events. Generalized estimating equation models were used to account for repeated events in the same subject.
RESULTS: A total of 98 children with CF were followed for two years. There were 265 acute respiratory events. Relative to a stable baseline measure, LCI (+8.9%; 95% CI 6.5 to 11.3) and FEV1% predicted (-6.6%; 95% CI -8.3 to -5.0) worsened with acute respiratory events. A greater proportion of events had a worsening in LCI compared to a decline in FEV1% predicted (41.7% vs 30.0%; p=0.012); 53.9% events were associated with worsening in LCI or FEV1. Neither LCI nor FEV1 recovered to baseline values at the next follow-up visit.
CONCLUSIONS: In school-age children with CF, LCI is a sensitive measure to assess lung function worsening with acute respiratory events and incomplete recovery at follow-up. LCI and FEV1 in combination capture a higher proportion of events with functional impairment.

PMID: 33030967 [PubMed - as supplied by publisher]

The Association of Grip Strength, Body Mass Index, and Lung Function in Youth with Cystic Fibrosis.

Nutr Clin Pract. 2020 Oct 07;:

Authors: Bouma SF, Iwanicki C, McCaffery H, Nasr SZ

Abstract
Compared with body mass index (BMI), lean body mass and fat-free mass are strongly associated with lung function in children and adolescents with cystic fibrosis (CF). Methods of measuring body composition in youth with CF are often unreliable, expensive, or not clinically feasible. Grip strength (GS), a measure of muscle function, is used as a surrogate for muscle mass and is an indicator of nutrition status. This quality improvement project explored the feasibility of measuring GS in medically stable youth with CF, aged 6-21 years. A total 361 GS measurements were performed by using a digital hand dynamometer in youth from a single CF center. Using reference tables that were created for this project by merging data from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Surveys, youth with CF were found to be weaker than age- and gender-matched peers, even when controlled for differences in size. A positive association (P < .001) was found between GS percentile and lung function, as measured by forced expiratory volume in 1 second percent predicted (FEV1pp). Statistical analysis revealed that both BMI percentile and absolute GS (AGS) percentile were positively associated with FEV1pp and with each other, primarily at the lower levels of BMI percentile (<50%) and AGS percentile (<50%). GS may provide a reliable, less expensive, and clinically feasible alternative to body composition measurements in monitoring nutrition status in youth with CF, especially in youth whose BMI is in the <50th percentile.

PMID: 33029840 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa Volatilome Characteristics and Adaptations in Chronic Cystic Fibrosis Lung Infections.

mSphere. 2020 Oct 07;5(5):

Authors: Davis TJ, Karanjia AV, Bhebhe CN, West SB, Richardson M, Bean HD

Abstract
Pseudomonas aeruginosa chronic lung infections in individuals with cystic fibrosis (CF) significantly reduce quality of life and increase morbidity and mortality. Tracking these infections is critical for monitoring patient health and informing treatments. We are working toward the development of novel breath-based biomarkers to track chronic P. aeruginosa lung infections in situ Using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC×GC-TOF-MS), we characterized the in vitro volatile metabolomes ("volatilomes") of 81 P. aeruginosa isolates collected from 17 CF patients over at least a 5-year period of their chronic lung infections. We detected 539 volatiles produced by the P. aeruginosa isolates, 69 of which were core volatiles that were highly conserved. We found that each early infection isolate has a unique volatilome, and as infection progresses, the volatilomes of isolates from the same patient become increasingly dissimilar, to the point that these intrapatient isolates are no more similar to one another than to isolates from other patients. We observed that the size and chemical diversity of P. aeruginosa volatilomes do not change over the course of chronic infections; however, the relative abundances of core hydrocarbons, alcohols, and aldehydes do change and are correlated with changes in phenotypes associated with chronic infections. This study indicates that it may be feasible to track P. aeruginosa chronic lung infections by measuring changes to the infection volatilome and lays the groundwork for exploring the translatability of this approach to direct measurement using patient breath.IMPORTANCE Pseudomonas aeruginosa is a leading cause of chronic lung infections in cystic fibrosis (CF), which are correlated with lung function decline. Significant clinical efforts are therefore aimed at detecting infections and tracking them for phenotypic changes, such as mucoidy and antibiotic resistance. Both the detection and tracking of lung infections rely on sputum cultures, but due to improvements in CF therapies, sputum production is declining, although risks for lung infections persist. Therefore, we are working toward the development of breath-based diagnostics for CF lung infections. In this study, we characterized of the volatile metabolomes of 81 P. aeruginosa clinical isolates collected from 17 CF patients over a duration of at least 5 years of a chronic lung infection. We found that the volatilome of P. aeruginosa adapts over time and is correlated with infection phenotype changes, suggesting that it may be possible to track chronic CF lung infections with a breath test.

PMID: 33028687 [PubMed - in process]

Focusing on the penultimate step: increasing early lung transplant discussion in cystic fibrosis clinic to prepare patients for referral.

BMJ Open Qual. 2020 Oct;9(4):

Authors: Bartley BL, St John A, Neuringer IP, Cummings BM, Yonker LM

PMID: 33028657 [PubMed - in process]

Prospective longitudinal association between repeated multiple breath washout measurements and computed tomography scores in children with cystic fibrosis.

J Cyst Fibros. 2020 Oct 04;:2121

Authors: Sandvik RM, Kongstad T, Green K, Voldby C, Buchvald F, Skov M, Pressler T, Nielsen KG

Abstract
BACKGROUND: Progression of structural lung disease (SLD) is a major risk factor for morbidity in patients with cystic fibrosis (CF). We studied changes in SLD and correlations with spirometry and nitrogen multiple breath washout (N2MBW) outcomes to explore associations in contemporary evolution between structural and functional abnormalities in CF lung disease.
METHODS: Spirometry-controlled chest-CTs using PRAGMA-CF for scoring extent of SLD, spirometry, and N2MBW were performed at two-year intervals in school-age children with CF.
RESULTS: Fifty-seven children aged 6-18 years were included. No significant progression in mean PRAGMA-CF scores was observed. Half of the children showed improvement in the proportion of bronchiectasis (%Bx). Lung Clearance Index (LCI) and the second moment ratio (M2) increased significantly and baseline values correlated significantly with SLD at follow-up (p ≤ 0.0002). The correlation between the change in M2 (∆M2) and the change in total SLD was R = 0.27 (p = 0.048). We found high negative predictive values (100%) for ∆M2<10% to exclude progression in SLD. For stable or improving values of LCI and M2, the predicted probability for progression in SLD was 16% and 14%, respectively (upper 95% confidence limit: 33%). Evolution in N2MBW and CT outcomes was discordant in half of the children.
CONCLUSIONS: We found no progression in SLD over 2 years in school-age children with CF, in contrast to both LCI and M2, which along with discordant outcomes in half of the children underlines that N2MBW and CT assess different aspects of CF lung disease. However, stable outcomes from N2MBW were associated with stable structural lung disease.

PMID: 33028501 [PubMed - as supplied by publisher]

The Antibacterial and Anti-biofilm Activity of Metal Complexes Incorporating 3,6,9-Trioxaundecanedioate and 1,10-Phenanthroline Ligands in Clinical Isolates of Pseudomonas Aeruginosa from Irish Cystic Fibrosis Patients.

Antibiotics (Basel). 2020 Oct 05;9(10):

Authors: O'Shaughnessy M, McCarron P, Viganor L, McCann M, Devereux M, Howe O

Abstract
Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria's capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4].EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid; phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components; exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined.

PMID: 33027987 [PubMed]

TMEM16A Mediated Mucus Production in Human Airway Epithelial Cells.

Am J Respir Cell Mol Biol. 2020 Oct 07;:

Authors: Cabrita I, Benedetto R, Wanitchakool P, Lerias J, Centeio R, Ousingsawat J, Schreiber R, Kunzelmann K

Abstract
TMEM16A is a Ca2+ activated chloride channel that was shown to enhance production and secretion of mucus in inflamed airways. It is, however, not clear whether TMEM16A is truly responsible for mucus production, or whether mucin and TMEM16A are upregulated independently during inflammatory airway diseases such as asthma and cystic fibrosis (CF). We examined this question using BCi-NS1 cells, a human airway basal cell line that maintains multipotent differentiation capacity, and the two human airway epithelial cell lines, Calu-3 and CFBE. The data demonstrate that exposure of airway epithelial cells to IL-8 and IL-13, two cytokines known to be enhanced in CF and asthma, respectively, leads to increase in mucus production. Expression of MUC5AC was fully dependent on expression of TMEM16A, as shown by siRNA-knockdown of TMEM16A. In addition, different inhibitors of TMEM16A attenuated IL-13 induced mucus production. Interestingly, in CFBE cells expressing F508delCFTR, IL-13 was unable to upregulate membrane expression of TMEM16A or Ca2+-activated whole cell currents. The regulator of TMEM16A, CLCA1, strongly augmented both Ca2+- and cAMP-activated Cl- currents in cells expressing wtCFTR, but failed to augment membrane expression of TMEM16A in F508delCFTR-expressing CFBE cells. The data confirm the functional relationship between CFTR and TMEM16A and suggest an impaired upregulation of TMEM16A by IL-13 or CLCA1 in cells expressing the most frequent CF-causing mutation F508delCFTR.

PMID: 33026825 [PubMed - as supplied by publisher]

Lack of airway submucosal glands impairs respiratory host defenses.

Elife. 2020 Oct 07;9:

Authors: Ostedgaard LS, Price MP, Whitworth KM, Abou Alaiwa MH, Fischer AJ, Warrier A, Samuel M, Spate LD, Allen PD, Hilkin BM, Romano Ibarra GS, Ortiz Bezara ME, Goodell BJ, Mather SE, Powers LS, Stroik MR, Gansemer ND, Hippee CE, Zarei K, Goeken JA, Businga TR, Hoffman EA, Meyerholz DK, Prather RS, Stoltz DA, Welsh MJ

Abstract
Submucosal glands (SMGs) are a prominent structure that lines human cartilaginous airways. Although it has been assumed that SMGs contribute to respiratory defense, that hypothesis has gone without a direct test. Therefore, we studied pigs, which have lungs like humans, and disrupted the gene for ectodysplasin (EDA-KO), which initiates SMG development. EDA-KO pigs lacked SMGs throughout the airways. Their airway surface liquid had a reduced ability to kill bacteria, consistent with SMG production of antimicrobials. In wild-type pigs, SMGs secrete mucus that emerges onto the airway surface as strands. Lack of SMGs and mucus strands disrupted mucociliary transport in EDA-KO pigs. Consequently, EDA-KO pigs failed to eradicate a bacterial challenge in lung regions normally populated by SMGs. These in vivo and ex vivo results indicate that SMGs are required for normal antimicrobial activity and mucociliary transport, two key host defenses that protect the lung.

PMID: 33026343 [PubMed - as supplied by publisher]

Laparoscopic surgery in patients with cystic fibrosis: A systematic review.

Asian J Endosc Surg. 2020 Oct 06;:

Authors: El Boghdady M, Ewalds-Kvist BM

Abstract
INTRODUCTION: Laparoscopic surgery may be advantageous for cystic fibrosis (CF) patients because it leads to fewer complications than open surgery. However, it could still lead to pulmonary and cardiovascular complications in CF patients. We aimed to systematically review the use of laparoscopic surgery in CF patients.
METHODS: A systematic review was performed in compliance with PRISMA guidelines. A literature search was performed using PubMed/MEDLINE, ScienceDirect, EMBASE, and Google Scholar, with "cystic fibrosis and laparoscopic surgery" and "cystic fibrosis and minimally invasive surgery" used as the search terms. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria were applied. The protocol was registered with the PROSPERO register.
RESULTS: Six studies met the predetermined inclusion criteria; accordingly, two studies provided high-quality evidence and four provided moderate-quality evidence. The interrater correlation was convincing (rs = .95, P = .02, two-tailed). Therefore, three quantitative studies and three qualitative studies were assessed and evidence-graded in accordance with the GRADE protocol.
CONCLUSION: The benefits of laparoscopic surgical interventions for patients with CF were supported with good evidential value and recognized as a safe and suitable surgical option.

PMID: 33025750 [PubMed - as supplied by publisher]

A Cohort Study of Sleep Quality in Adult Patients with Acute Pulmonary Exacerbations of Cystic Fibrosis.

Intern Med J. 2020 Oct 06;:

Authors: Henderson D, Moore V, MacMorran K, Castellini J, Hay K, Keegan V, Reid D, Curtin D, Tay G

Abstract
INTRODUCTION: The impact of an acute pulmonary exacerbation of CF on sleep quality has not been established. Patients have greater burden of symptoms, higher intensity of therapy, and are often admitted to hospital outside of their usual sleeping environment.
METHODS: This prospective, observational study determined the prevalence of impaired sleep quality and associated factors in adult patients admitted to a single CF unit with an acute pulmonary exacerbation of CF. Sleep quality was defined by the Pittsburgh Sleep Quality Index (PSQI), with >5 indicating poor sleep quality. Data was obtained through patient questionnaires, chart review, and examination.
RESULTS: Sixty-six percent of patients had impaired sleep quality. Patients with poor sleep had more sleep disruption due to pain (median response "mild sleep disruption" vs "no sleep disruption" p=0.003) and insomnia (mean insomnia severity index (ISI) 13 vs 5, p<0.001). In patients with symptoms of restless legs, poor sleepers had worse symptoms (mean IRLSS 15 vs 5, p=0.029). Univariate modelling showed relationships between PSQI and symptoms of depression and anxiety as well as with sleep disruption due to pain, general noise, and nursing observations. In a multivariable model, ISI was the only variable that remained significantly associated with PSQI. Mean PSQI score increased 0.58 units for each 1 unit increase in ISI (95% CI 0.42-0.73, p<0.001).
CONCLUSIONS: Poor sleep quality is common among patients admitted with an acute exacerbation of CF and is strongly associated with insomnia symptoms in this cohort. This article is protected by copyright. All rights reserved.

PMID: 33025684 [PubMed - as supplied by publisher]

Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity.

World J Biol Chem. 2020 Sep 27;11(2):30-51

Authors: Gopallawa I, Lee RJ

Abstract
The airway innate immune system maintains the first line of defense against respiratory infections. The airway epithelium and associated immune cells protect the respiratory system from inhaled foreign organisms. These cells sense pathogens via activation of receptors like toll-like receptors and taste family 2 receptors (T2Rs) and respond by producing antimicrobials, inflammatory cytokines, and chemokines. Coordinated regulation of fluid secretion and ciliary beating facilitates clearance of pathogens via mucociliary transport. Airway cells also secrete antimicrobial peptides and radicals to directly kill microorganisms and inactivate viruses. The phosphoinositide-3-kinase/protein kinase B (Akt) kinase pathway regulates multiple cellular targets that modulate cell survival and proliferation. Akt also regulates proteins involved in innate immune pathways. Akt phosphorylates endothelial nitric oxide synthase (eNOS) enzymes expressed in airway epithelial cells. Activation of eNOS can have anti-inflammatory, anti-bacterial, and anti-viral roles. Moreover, Akt can increase the activity of the transcription factor nuclear factor erythroid 2 related factor-2 that protects cells from oxidative stress and may limit inflammation. In this review, we summarize the recent findings of non-cancerous functions of Akt signaling in airway innate host defense mechanisms, including an overview of several known downstream targets of Akt involved in innate immunity.

PMID: 33024516 [PubMed]

Tobacco smoke exposure limits the therapeutic benefit of tezacaftor/ivacaftor in pediatric patients with cystic fibrosis.

J Cyst Fibros. 2020 Oct 03;:

Authors: Baker E, Harris WT, Rowe SM, Rutland SB, Oates GR

Abstract
OBJECTIVES: Tobacco smoke exposure reduces CFTR functional expression in vitro and contributes to acquired CFTR dysfunction. We investigated whether it also inhibits the clinical benefit of CFTR modulators, focusing on tezacaftor/ivacaftor, approved in February 2018 for individuals with CF age ≥12 years.
METHODS: A retrospective longitudinal analysis of encounter-based data from the CF Foundation Patient Registry (2016-2018) compared the slope of change in lung function (GLI FEV1% predicted) before and after tezacaftor/ivacaftor initiation in smoke-exposed vs unexposed age-eligible pediatric patients. Tobacco smoke exposure (Ever/Never) was determined from caregiver self-report. Statistical analyses used hierarchical linear mixed modeling and fixed effects regression modeling.
RESULTS: The sample included 6,653 individuals with a total of 105,539 person-period observations. Tezacaftor/ivacaftor was prescribed to 19% (1,251) of individuals, mean age 17 years, mean baseline ppFEV1 83%, 28% smoke-exposed. Tezacaftor/ivacaftor users who were smoke-exposed had a lower baseline ppFEV1 and experienced a greater lung function decline. Over two years, the difference in ppFEV1 by smoke exposure among tezacaftor/ivacaftor users increased by 1.2% (7.6% to 8.8%, p<0.001). In both mixed effects and fixed effects regression models, tezacaftor/ivacaftor use was associated with improved ppFEV1 among unexposed individuals (1.2% and 1.7%, respectively; p<0.001 for both) but provided no benefit among smoke-exposed counterparts (0.3%, p = 0.5 and 0.6%, p = 0.07, respectively).
CONCLUSION: Tobacco smoke exposure nullifies the therapeutic benefit of tezacaftor/ivacaftor among individuals with CF aged 12-20 years old. To maximize the therapeutic opportunity of CFTR modulators, every effort must be taken to eliminate smoke exposure in CF.

PMID: 33023836 [PubMed - as supplied by publisher]