Treatment of pulmonary exacerbations in cystic fibrosis.

Curr Opin Pulm Med. 2020 Sep 02;:

Authors: Ng C, Nadig T, Smyth AR, Flume P

Abstract
PURPOSE OF REVIEW: This review will discuss the challenges of defining a pulmonary exacerbations in cystic fibrosis and the key pathogens, which contribute. It will discuss the treatment options currently available and the importance of preventing pulmonary exacerbations.
RECENT FINDINGS: The basis for treatment of pulmonary exacerbations remains unchanged over the past 15 years and whilst there have been trials exploring alternative antibiotics, there has been little change. However, there are ongoing studies that are expected to establish a platform for identifying best practices. Chronic cystic fibrosis therapies have been shown to reduce pulmonary exacerbations. In the era of new CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapies, the number of pulmonary exacerbations are expected to be even fewer. However, it is unclear whether the other chronic therapies can be discontinued without losing their benefits in reducing exacerbations.
SUMMARY: Although there is no universal definition of a pulmonary exacerbation in cystic fibrosis, proposed definitions have many similarities. We have outlined the current recommendations for treatment of pulmonary exacerbations, including the duration and location of treatments. We have also summarized the key therapies used for prevention of pulmonary exacerbations in cystic fibrosis.

PMID: 32890021 [PubMed - as supplied by publisher]

Aerosolized lancovutide in adolescents (≥12 years) and adults with cystic fibrosis - a randomized trial.

J Cyst Fibros. 2020 Sep 01;:

Authors: Eber E, Trawinska-Bartnicka M, Sands D, Bellon G, Mellies U, Bolbás K, Quattrucci S, Mazurek H, Widmann R, Schoergenhofer C, Jilma B, Ratjen F

Abstract
BACKGROUND: Lancovutide activates a chloride channel (TMEM-16A) other than the cystic fibrosis (CF) transmembrane conductance regulator protein and could benefit CF patients.
METHODS: In this randomized, multi-center, double-blind, placebo-controlled, parallel-group trial 161 patients ≥12 years with a confirmed diagnosis of CF were randomized to either placebo (saline) or active drug in 3 different dosing schemes of 2.5mg inhaled lancovutide (once daily, every other day or twice a week) for eight weeks. The primary endpoint was the change in the forced expiratory volume in 1 second (FEV1) percent predicted. Secondary endpoints included further lung function parameters (FEV1 (absolute), functional vital capacity percent predicted, forced expiratory flow percent predicted, pulse oximetry), quality of life assessment, pulmonary exacerbations, hospitalization due to pulmonary exacerbations, time to first pulmonary exacerbation, duration of anti-inflammatory, mucolytic or antibiotic treatment, and safety.
RESULTS: There was no significant difference in the change in FEV1 percent predicted, quality of life, other lung function parameters, pulmonary exacerbations or requirement of additional treatment between groups. Overall, the inhalation of lancovutide was safe although a higher rate of adverse events, especially related to the respiratory system, occurred as compared to placebo.
CONCLUSIONS: Lancovutide did not improve FEV1 percent predicted when compared to placebo (NCT00671736).

PMID: 32888826 [PubMed - as supplied by publisher]

Light at the End of Tunnel-Managing Allergic Bronchopulmonary Aspergillosis in Cystic Fibrosis.

J Allergy Clin Immunol Pract. 2020 Sep;8(8):2615-2616

Authors: Singh H

PMID: 32888528 [PubMed - as supplied by publisher]

Pseudomonas aeruginosa - Candida interplay: Effect on in vitro antibiotic susceptibility of Pseudomonas aeruginosa when grown in the presence Candida culture.

Br J Biomed Sci. 2020 Sep 04;

Authors: McIlroy R, Millar BC, Nelson DW, Murphy A, Rao JR, Downey DG, Moore JE

PMID: 32887537 [PubMed - as supplied by publisher]

Airway Inflammation and Host Responses in the Era of CFTR Modulators.

Int J Mol Sci. 2020 Sep 02;21(17):

Authors: Keown K, Brown R, Doherty DF, Houston C, McKelvey MC, Creane S, Linden D, McAuley DF, Kidney JC, Weldon S, Downey DG, Taggart CC

Abstract
The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

PMID: 32887484 [PubMed - as supplied by publisher]

Upper Respiratory Tract Microbiome and Otitis Media Intertalk: Lessons from the Literature.

J Clin Med. 2020 Sep 02;9(9):

Authors: Folino F, Ruggiero L, Capaccio P, Coro I, Aliberti S, Drago L, Marchisio P, Torretta S

Abstract
Otitis media (OM) is one of the most common diseases occurring during childhood. Microbiological investigations concerning this topic have been primarily focused on the four classical otopathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes) mainly because most of the studies have been conducted with culture-dependent methods. In recent years, the introduction of culture-independent techniques has allowed high-throughput investigation of entire bacterial communities, leading to a better comprehension of the role of resident flora in health and disease. The upper respiratory tract (URT) is a region of major interest in otitis media pathogenesis, as it could serve as a source of pathogens for the middle ear (ME). Studies conducted with culture-independent methods in the URT and ME have provided novel insights on the pathogenesis of middle ear diseases through the identification of both possible new causative agents and of potential protective bacteria, showing that imbalances in bacterial communities could influence the natural history of otitis media in children. The aim of this review is to examine available evidence in microbiome research and otitis media in the pediatric age, with a focus on its different phenotypes: acute otitis media, otitis media with effusion and chronic suppurative otitis media.

PMID: 32887458 [PubMed - as supplied by publisher]

Patterns of Health Insurance Coverage and Lung Disease Progression in Adolescents and Young Adults with Cystic Fibrosis.

Ann Am Thorac Soc. 2020 Sep 04;:

Authors: Tumin D, Crowley EM, Li SS, Wooten W, Ren CL, Hayes D

Abstract
RATIONALE: Health insurance coverage has been implicated as a socioeconomic factor affecting clinical outcomes in patients with cystic fibrosis (CF), but evidence for this is mixed and varies by age.
OBJECTIVE: Focusing on adolescents and young adults with CF, we examined how multi-year patterns of health insurance coverage were associated with lung function decline and related outcomes.
METHODS: We used data from the 2000-2015 Cystic Fibrosis Foundation Patient Registry to classify patients in 3 cohorts (ages 12-17, adolescents; 18-23, transitioning to adulthood; and 24-29, young adults) according to health insurance coverage: continuous private, continuous public, intermittent public, and coverage gaps. The primary outcome was the forced expiratory volume in 1 second, percent predicted (FEV1pp), modeled using mixed-effects regression. Additional outcomes included outpatient visits, hospital days for pulmonary exacerbation treatment, bacterial colonization, and body mass index. Outcomes were assessed over a 6-year period (e.g., ages 12-17) while exposures were assessed over the prior 6 years (e.g., ages 6-11).
RESULTS: The 3 cohorts included 3,365, 2,800, and 1,807 patients, respectively. The highest rate of FEV1pp decline was found in the middle cohort, with the annual decline being steeper among patients with continuous public (-3.1/year; 95% confidence interval [CI]: -3.3, -2.8) or intermittent public (-2.4/year; 95% CI: -2.6, -2.2) coverage, compared to patients with continuous private coverage (-2.1/year; 95% CI: -2.2, -2.0). These differences were not explained by differences in outpatient care utilization.
CONCLUSION: During the transition to adulthood, use of public insurance was associated with accelerated lung function decline among patients with CF. The role of insurance as causal factor in this decline, or proxy for other socioeconomic characteristics, should be explored in further studies.

PMID: 32885982 [PubMed - as supplied by publisher]

Cystic Fibrosis and COVID-19.

South Med J. 2020 Sep;113(9):422

Authors: Chapman KD, Moffett KS

PMID: 32885259 [PubMed - in process]

Duodenal Duplication Cysts in Children: Clinical Features and Current Treatment Choices.

Biomed Hub. 2020 May-Aug;5(2):152-164

Authors: Dipasquale V, Barraco P, Faraci S, Balassone V, De Angelis P, Di Matteo FM, Dall'Oglio L, Romano C

Abstract
Background: Duodenal duplication cysts are rare gastrointestinal tract malformations. Most patients experience symptom onset in the first decade of life. This review aims to examine clinical presentation, management strategies and outcomes of duodenal duplication cysts in childhood.
Methods: A Pubmed/Medline (http://www.ncbi.nlm.nih.gov/pubmed/) search in October 2019 for articles published since 1999 using the keywords "duodenal duplication cyst," "child" and "newborn" was carried out. Clinical symptoms, complications, diagnostic examinations, treatment options and outcomes were analyzed and tabulated.
Results: There were 41 citations in the literature providing adequate descriptions of 45 cases of duodenal duplication cysts. The age of presentation ranged from newborn to 18 years. The median interval between initial presentation and definitive diagnosis and treatment was 17 months (range: 2 months to 12 years). Overall, 67% of cases presented with abdominal pain, and 43% were complicated with pancreatitis. Different surgical and endoscopic therapeutic strategies were reported.
Conclusions: Duodenal duplication cysts may be associated with life-threatening complications and/or recurrent symptoms, impairing quality of life. Early recognition of patients who demonstrate suggestive signs and symptoms is important to ensure success of treatment. This review may be useful to highlight the main diagnostic aspects and limit the risk of a delayed diagnosis.

PMID: 32884929 [PubMed]

Lung-targeting lentiviral vector for passive immunisation against influenza.

Thorax. 2020 Sep 03;:

Authors: Tan TK, Gamlen TPE, Rijal P, Townsend AR, Gill DR, Hyde SC

Abstract
When recombinant simian immunodeficiency virus (SIV) is pseudotyped with the F and HN glycoproteins from murine respiratory Sendai virus (rSIV.F/HN), it provides efficient lung cell targeting and lifelong transgene expression in the murine airways. We have shown that a single dose of rSIV.F/HN can direct stable expression of neutralising antibody against influenza in the murine airways and systemic circulation, and protects mice against two different influenza strains in lethal challenge experiments. These data suggest that rSIV.F/HN could be used as a vector for passive immunisation against influenza and other respiratory pathogens.

PMID: 32883885 [PubMed - as supplied by publisher]

Blood eosinophils do not predict inhaled budesonide response in bronchiectasis.

Eur Respir J. 2020 Sep;56(3):

Authors: Aliberti S, Sotgiu G, Martinez Garcia MA

PMID: 32883760 [PubMed - in process]

Factors Associated with Low Lung Function in Different Age Bins in the General Population.

Am J Respir Crit Care Med. 2020 07 15;202(2):292-296

Authors: Breyer-Kohansal R, Faner R, Breyer MK, Ofenheimer A, Schrott A, Studnicka M, Wouters EFM, Burghuber OC, Hartl S, Agusti A

PMID: 32255673 [PubMed - indexed for MEDLINE]

A Phylogeny-Informed Proteomics Approach for Species Identification within the Burkholderia cepacia complex.

J Clin Microbiol. 2020 Sep 02;:

Authors: Wang H, Cissé OH, Bolig T, Drake SK, Chen Y, Strich JR, Youn JH, Okoro U, Rosenberg AZ, Sun J, LiPuma JJ, Suffredini AF, Dekker JP

Abstract
Ancestral genetic exchange between members of many important bacterial pathogen groups has resulted in phylogenetic relationships better described as networks than as bifurcating trees. In certain cases, these reticulated phylogenies have resulted in phenotypic and molecular overlap that challenges the construction of practical approaches for species identification in the clinical microbiology laboratory. Burkholderia cepacia complex (Bcc), a β-proteobacteria species group responsible for significant morbidity in persons with cystic fibrosis and chronic granulomatous disease, represents one such group where network-structured phylogeny has hampered the development of diagnostic methods for species-level discrimination. Here, we present a phylogeny-informed proteomics approach to facilitate diagnostic classification of pathogen groups with reticulated phylogenies, using Bcc as an example. Starting with a set of more than 800 Bcc and Burkholderia gladioli whole genome assemblies, we constructed phylogenies with explicit representation of inferred interspecies recombination. Sixteen highly discriminatory peptides were chosen to distinguish B. cepacia, Burkholderia cenocepacia, Burkholderia multivorans, and B. gladioli and multiplexed into a single rapid liquid chromatography tandem mass spectrometry multiple reaction monitoring (LC-MS/MS MRM) assay. Testing of a blinded set of isolates containing these four Burkholderia species demonstrated 50/50 correct automatic negative calls (100% accuracy with 95% CI of 92.9-100%), and 70/70 correct automatic species-level positive identifications (100% accuracy with 95% CI 94.9-100%) after accounting for a single initial incorrect identification due to a pre-analytic error, correctly identified on re-testing. The approach to analysis described here is applicable to other pathogen groups for which development of diagnostic classification methods is complicated by interspecies recombination.

PMID: 32878952 [PubMed - as supplied by publisher]

Recommended shielding against COVID-19 impacts physical activity levels in adults with cystic fibrosis.

J Cyst Fibros. 2020 Aug 28;:

Authors: Radtke T, Haile SR, Dressel H, Benden C

Abstract
BACKGROUND: Severe acute respiratory syndrome - coronavirus-2 (SARS-CoV-2) has caused a pandemic threatening the life of people with chronic respiratory diseases including cystic fibrosis (CF). This study was designed to investigate health-related aspects of individuals with CF, with and without lung transplantation (LTX), their communication with their specialist healthcare providers during the pandemic, potential changes in peoples' individual therapy regimes and daily physical activity levels.
METHODS: A web-based survey was conducted among Swiss adults with CF with and without LTX, study period from March 16th, 2020 - the day the "extraordinary situation" was officially declared in Switzerland introducing stringent measures protecting the public - until May 16th, 2020.
RESULTS: 327 individuals (25% LTX recipients) were included, 45 individuals reported coronavirus-2019 disease (COVID-19) like symptoms. Of 28 subjects tested, only three subjects were tested positive, all with mild symptoms, no hospitalization required. Almost half of the survey respondents (45%) reported undertaking less physical activity during the lockdown, while 79% and 91% of participants reported no change in traditional airway clearance and inhalation therapies, respectively. Distress regarding a potential SARS-CoV-2 infection or worsening of lung disease were no major concerns for subjects.
CONCLUSIONS: Our study reveals that the direct impact of SARS-CoV-2 on clinical outcomes of individuals with CF was mild although people with chronic lung diseases like CF are considered a high-risk population; overall, this is reassuring. However, strict lockdown measures substantially affected peoples' physical activity levels, a vital cornerstone of CF therapy; and this is worrisome.

PMID: 32878732 [PubMed - as supplied by publisher]

Allergic Bronchopulmonary Aspergillosis in Children with Cystic Fibrosis: An Update on the Newest Diagnostic Tools and Therapeutic Approaches.

Pathogens. 2020 Aug 31;9(9):

Authors: Lattanzi C, Messina G, Fainardi V, Tripodi MC, Pisi G, Esposito S

Abstract
Cystic fibrosis (CF), the most common autosomal-recessive genetic disease in the Caucasian population, is characterized by frequent respiratory infections and progressive lung disease. Fungal species are commonly found in patients with CF, and among them, Aspergillus fumigatus is the most frequently isolated. While bacteria, particularly Pseudomonas aeruginosa, have a well-established negative effect on CF lung disease, the impact of fungal infections remains unclear. In patients with CF, inhalation of Aspergillus conidia can cause allergic bronchopulmonary aspergillosis (ABPA), a Th2-mediated lung disease that can contribute to disease progression. Clinical features, diagnostic criteria and treatment of ABPA are still a matter of debate. Given the consequences of a late ABPA diagnosis or the risk of ABPA overdiagnosis, it is imperative that the diagnostic criteria guidelines are reviewed and standardized. Along with traditional criteria, radiological features are emerging as tools for further classification as well as novel immunological tests. Corticosteroids, itraconazole and voriconazole continue to be the bedrock of ABPA therapy, but other molecules, such as posaconazole, vitamin D, recombinant INF-γ and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulators, have been showing positive results. However, few studies have been conducted recruiting CF patients, and more research is needed to improve the prevention and the classification of clinical manifestations as well as to personalize treatment. Early recognition and early treatment of fungal infections may be fundamental to prevent progression of CF disease. The aim of this narrative review is to give an update on ABPA in children with CF.

PMID: 32878014 [PubMed]

G551D Mutation Impairs Protein Kinase A (PKA)-dependent Activation of CFTR Channel that can be Restored by Novel Gain-Of-Function (GOF) Mutations.

Am J Physiol Lung Cell Mol Physiol. 2020 Sep 02;:

Authors: Wang W, Fu L, Liu Z, Wen H, Rab A, Hong JS, Kirk KL, Rowe SM

Abstract
G551D is a major disease-associated gating mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP- and phosphorylation-dependent chloride channel. G551D causes severe CF disease by disrupting ATP-dependent channel opening, however, whether G551D affects phosphorylation-dependent channel activation is unclear. Here, we use macro patch recording and Ussing chamber approaches to demonstrate that G551D impacts on phosphorylation-dependent activation of CFTR and PKA-mediated phosphorylation regulates the interaction between x-loop in NBD2 and cytosolic loop (CL) 1. We show that G551D not only disrupts ATP-dependent channel opening, but also impairs phosphorylation-dependent channel activation by largely reducing PKA sensitivity consistent with the reciprocal relationship between channel opening/gating, ligand binding, and phosphorylation. Furthermore, we identified two novel GOF mutations: D1341R in the x-loop near the ABC signature motif in NBD2 and D173R in CL1, each of which strongly increased PKA sensitivity both in the WT background and when introduced into G551D-CFTR. When D1341R was combined with a second GOF mutation (e.g., K978C in CL3), we find that the double GOF mutation maximally increased G551D channel activity such that VX-770 had no further effect. We further show that a double charge-reversal mutation of D1341R/D173R-CFTR exhibited similar PKA sensitivity when compared to WT-CFTR. Together, our results suggest that charge repulsion between D173 and D1341 of WT-CFTR normally inhibits channel activation at low PKA activity by reducing PKA sensitivity and negative allostery by the G551D is coupled to reduced PKA sensitivity of CFTR that can be restored by second GOF mutations.

PMID: 32877225 [PubMed - as supplied by publisher]

Do Pulmonary and Extrapulmonary Features Differ Among Cystic Fibrosis, Primary Ciliary Dyskinesia and Healthy Children?

Pediatr Pulmonol. 2020 Sep 02;:

Authors: Kulli HD, Gurses HN, Zeren M, Ucgun H, Cakir E

Abstract
BACKGROUND: PCD is generally likened to CF due to similarities in impaired mucociliary clearance and some other symptoms. The aim of our study was to investigate pulmonary and extrapulmonary characteristics of children with CF and PCD since no studies have addressed respiratory muscle strength in children with PCD, and to compare the results to those obtained from healthy age-matched controls.
METHODS: Pulmonary and extrapulmonary characteristics were assessed by 6-min walk test (6MWT), spirometry, maximum inspiratory (MIP) and expiratory (MEP) pressure measurements and knee extensor strength test in the children with CF, PCD and healthy controls.
RESULTS: Children with PCD and CF had similar PFT results, except FEF25-75 which was lower in PCD (p=0.04). MIP value was lower in the children with CF compared to the healthy controls (p= 0.016), MEP value of the children with PCD was worse than those with CF and healthy controls (p=0.013; p=0.013; respectively). 6MWT distance of the children with CF was lower than their healthy counterparts (p=0.003). Knee extensor muscle strength differed among the children with PCD, CF and healthy control groups, but post hoc test failed to show statistically significance (p=0.010).
CONCLUSION: Children with CF and PCD had some impairments in pulmonary functions, respiratory muscle strength, functional capacity and peripheral muscle strength compared to healthy children. However, the unique characteristics of each disease should be considered during physiotherapy assessment and treatment. The clinicians may especially focus on the respiratory and peripheral muscle strength of the children with PCD. This article is protected by copyright. All rights reserved.

PMID: 32877003 [PubMed - as supplied by publisher]

Sleep Screening for Cystic Fibrosis Patients: A Survey of Cystic Fibrosis Programs.

Pediatr Pulmonol. 2020 Sep 02;:

Authors: Thomas CS, Brown RF

Abstract
OBJECTIVE: The prevalence of sleep disorders in cystic fibrosis (CF) patients is unknown, and no standardized screening or treatment guidelines exist to address sleep disorders in CF. Our study objective was to characterize current sleep screening practices in adult, pediatric, combined, and affiliate CF programs.
METHODS: A survey was developed in REDCap (Research Electronic Data Capture) and distributed to program directors of accredited CF programs in the United States.
RESULTS: Eighty-eight program directors responded (36% adult, 43% pediatric, 16% combined, 3% affiliate, 1% unidentified). Of the respondents, 68% were part of an academic institution, 24% were associated with an academic institution, and 8% were part of a community or private program. Program sizes ranged from <50 to >500 patients. Routine or informal sleep screening was not performed in 44% of adult, 29% of pediatric, and 35% of combined and affiliate programs. Most programs (> 80%) have access to otolaryngology and sleep medicine although not all of these programs refer patients for evaluation of sleep disorders. Most program directors (77%) perceive sleep disorders as a problem in CF and would recommend routine sleep screening. Possible barriers to sleep screening included clinic flow, screening fatigue, and lack of recommendations for sleep screening.
CONCLUSIONS: Formal sleep screening is inconsistent among CF care centers although most survey respondents would recommend the inclusion of screening in routine CF care. Future work is needed to further evaluate the impact of sleep disorders in CF and determine best practices for standardization of sleep screening and treatment. This article is protected by copyright. All rights reserved.

PMID: 32877001 [PubMed - as supplied by publisher]

Impact of Pharmacy Technicians as part of an Integrated Health-System Pharmacy Team on Improvement of Medication Access in the Care of Cystic Fibrosis Patients.

Pediatr Pulmonol. 2020 Sep 02;:

Authors: Zobell JT, Moss J, Heuser SM, Asfour F

Abstract
BACKGROUND: Cystic Fibrosis (CF) is a genetic disease requiring patients to take multiple medications per day. Multiple barriers exist affecting access and adherence. Studies have demonstrated the positive outcomes of pharmacist involvement in CF care. The purpose of this study is to characterize the impact of pharmacy technicians on medication access in the care of CF patients.
METHODS: A retrospective review and analysis of patient medication profiles for patients followed by the integrated pharmacy care process model was performed. Two electronic prescription pathways with pharmacy technician involvement were analyzed. One pathway using a specialty pharmacy CF pharmacy technician (SP technician) examined CF specialty medication delivery times. The other pathway examined the impact of the clinic-based CF pharmacy technician (CB technician) on the number of filling pharmacies for patients.
RESULTS: One-hundred and fifty-three patients met inclusion criteria in the CF specialty medication delivery analysis, and 56 patients met inclusion criteria filling pharmacy analysis. The median delivery time for dornase alfa decreased from 8 days to 3 days, p<0.00001. The number of patients utilizing 1 filling pharmacy increased from 8 (14%) to 21 (38%), (p=0.005); and utilizing 3 filling pharmacies decreased from 14 (25%) to 1 (2%), (p=0.003).
CONCLUSION: The study demonstrated that pharmacy technicians as part of an integrated health-system pharmacy care process model improve medication access in the care of CF patients. This article is protected by copyright. All rights reserved.

PMID: 32876997 [PubMed - as supplied by publisher]

[Cystic fibrosis : A systemic problem].

Radiologe. 2020 Sep;60(9):771-773

Authors: Wielpütz MO, Puderbach MU, Delorme S

PMID: 32876728 [PubMed - as supplied by publisher]