Polyclonality, Shared Strains, and Convergent Evolution in Chronic CF S. aureus Airway Infection.

Am J Respir Crit Care Med. 2020 Dec 09;:

Authors: Long DR, Wolter DJ, Lee M, Precit M, McLean K, Holmes E, Penewit K, Waalkes A, Hoffman LR, Salipante SJ

Abstract
RATIONALE: S. aureus is the most common respiratory pathogen isolated from patients with cystic fibrosis (CF) in the US. While modes of acquisition and genetic adaptation have been described for Pseudomonas aeruginosa, resulting in improved diagnosis and treatment, these features remain more poorly defined for S. aureus.
OBJECTIVES: To characterize the molecular epidemiology and genetic adaptation of S. aureus during chronic CF airway infection and in response to antibiotic therapy.
METHODS: We performed whole genome sequencing of 1,382 S. aureus isolates collected longitudinally over a mean 2.2 years from 246 children with CF at five US centers between 2008-2017. Results were integrated with clinical and demographic data to characterize bacterial population dynamics and identify common genetic targets of in vivo adaptation.
MEASUREMENTS AND MAIN RESULTS: 45.5% of patients carried multiple, coexisting S. aureus lineages, often having different antibiotic susceptibility profiles. Adaptation during the course of infection commonly occurred in a set of genes related to persistence and antimicrobial resistance. Individual sequence types demonstrated wide geographic distribution, and we identified limited strain sharing among children linked by common household or clinical exposures. Unlike P. aeruginosa, S. aureus genetic diversity was unconstrained, with ongoing flow of new genetic elements into the population of isolates from children with CF.
CONCLUSIONS: CF airways are frequently co-infected by multiple, genetically distinct S. aureus lineages, indicating that current clinical procedures for sampling isolates and selecting antibiotics are likely inadequate. Strains can be shared by patients in close domestic or clinical contact and undergo convergent evolution in key persistence and antimicrobial resistance genes, suggesting novel diagnostic and therapeutic approaches for future study.

PMID: 33296290 [PubMed - as supplied by publisher]

Clinical and molecular characterisation of the R751L-CFTR mutation.

Am J Physiol Lung Cell Mol Physiol. 2020 Dec 09;:

Authors: Haq IJ, Althaus M, Gardner AI, Yeoh HY, Joshi U, Saint-Criq V, Verdon B, Townshend J, O'Brien C, Ben-Hamida M, Thomas M, Bourke S, van der Sluijs P, Braakman I, Ward C, Gray MA, Brodlie M

Abstract
Cystic fibrosis (CF) arises from mutations in the CF transmembrane conductance regulator (CFTR) gene, resulting in progressive and life-limiting respiratory disease. R751L is a rare CFTR mutation that is poorly characterised. Our aims were to describe the clinical and molecular phenotypes associated with R751L. Relevant clinical data were collected from three heterozygote individuals harbouring R751L (2 patients with G551D/R751L and 1 with F508del/R751L). Assessment of R751L-CFTR function was made in primary human bronchial epithelial cultures (HBEs) and Xenopus oocytes. Molecular properties of R751L-CFTR were investigated in the presence of known CFTR modulators. Although sweat chloride was elevated in all three patients, the clinical phenotype associated with R751L was mild. Chloride secretion in F508del/R751L HBEs was reduced compared to non-CF HBEs and associated with a reduction in sodium absorption by the epithelial sodium channel (ENaC). However, R751L-CFTR function in Xenopus oocytes together with folding and cell surface transport of R751L-CFTR were not different to wild-type CFTR. Overall, R751L-CFTR was associated with reduced sodium chloride absorption but had similar functional properties to wild-type CFTR. This is the first report of R751L-CFTR that combines clinical phenotype with characterisation of functional and biological properties of the mutant channel. Our work will build upon existing knowledge of mutations within this region of CFTR and importantly inform approaches for clinical management. Elevated sweat chloride and reduced chloride secretion in HBEs may be due to alternative non-CFTR factors, which require further investigation.

PMID: 33296276 [PubMed - as supplied by publisher]

carP, encoding a Ca2+-regulated putative phytase, is evolutionarily conserved in Pseudomonas aeruginosa and has potential as a biomarker.

Microbiology (Reading). 2020 Dec 09;:

Authors: Mares SE, King MM, Kubo A, Khanov AA, Lutter EI, Youssef N, Patrauchan MA

Abstract
Pseudomonas aeruginosa infects patients with cystic fibrosis, burns, wounds and implants. Previously, our group showed that elevated Ca2+ positively regulates the production of several virulence factors in P. aeruginosa, such as biofilm formation, production of pyocyanin and secreted proteases. We have identified a Ca2+-regulated β-propeller putative phytase, CarP, which is required for Ca2+ tolerance, regulation of the intracellular Ca2+ levels, and plays a role in Ca2+ regulation of P. aeruginosa virulence. Here, we studied the conservation of carP sequence and its occurrence in diverse phylogenetic groups of bacteria. In silico analysis revealed that carP and its two paralogues PA2017 and PA0319 are primarily present in P. aeruginosa and belong to the core genome of the species. We identified 155 single nucleotide alterations within carP, 42 of which lead to missense mutations with only three that affected the predicted 3D structure of the protein. PCR analyses with carP-specific primers detected P. aeruginosa specifically in 70 clinical and environmental samples. Sequence comparison demonstrated that carP is overall highly conserved in P. aeruginosa isolated from diverse environments. Such evolutionary preservation of carP illustrates its importance for P. aeruginosa adaptations to diverse environments and demonstrates its potential as a biomarker.

PMID: 33295862 [PubMed - as supplied by publisher]

Mental Health History and Social Barriers Impacting Caregivers of Infants with Cystic Fibrosis.

Pediatr Pulmonol. 2020 Dec 09;:

Authors: Gillespie ML, Nemastil CJ, Moore-Clingenpeel M, Gilmore D, Dell ML, Krivchenia K

Abstract
OBJECTIVES: Caregivers of infants with cystic fibrosis (CF) carry a heavy treatment burden for their child along with the inherent difficulties of raising an infant. This study investigated the impact of self-reported caregiver mental health diagnoses and social barriers during the first year of life on clinical outcomes.
METHODS: A retrospective chart review was conducted for infants seen in a large tertiary hospital CF clinic over a 5-year period. Baseline characteristics were collected, and documentation from physician and social work notes were reviewed. Demographics and clinical characteristics were compared by presence or absence of self-reported mental health diagnoses, social barriers, and "emotional concern".
RESULTS: Analyses were conducted on 71 patients. Thirty-five percent of caregivers disclosed mental health diagnoses, 52% identified social barriers to care, and 55% reported feeling upset or fatigued. Having a caregiver with a self-reported mental health diagnosis was associated with tobacco smoke exposure (p<0.001) and increased odds of hospitalizations (odds ratio [OR] 3.01, 95% confidence interval [CI] 1.49-6.06), emergency department/urgent care visits (OR 3.17, 95% CI 1.32-7.64), and longer lengths of stay (OR 1.93, 95% CI 1.69-2.20). Caregivers who expressed emotional concern had infants with significantly lower weight-for-length percentiles (p=0.012).
DISCUSSION: Caregiver mental health and social barriers to care are important determinants to address as they may impact clinical outcomes in infants with CF. Identifying barriers and struggles early increases the likelihood that clinical teams can intervene and provide support. Further research into mental health and socioeconomic barriers faced by caregivers of infants with CF is crucial. This article is protected by copyright. All rights reserved.

PMID: 33295695 [PubMed - as supplied by publisher]

Effectiveness of Hypertonic Saline Nebulization in Airway Clearance in Children with Non-Cystic Fibrosis Bronchiectasis: A randomized control trial.

Pediatr Pulmonol. 2020 Dec 09;:

Authors: Anuradha KWDA, Gunathilaka PKG, Wickramasinghe VP

Abstract
INTRODUCTION: Failure to expectorate mucus resulting in progressive airway damage is the hallmark of bronchiectasis. Therefore effective Airway Clearance Techniques (ACT) is the key step in its management. The aim of this study was to evaluate the efficacy of 3% Hypertonic Saline (HS) pre-medication in ACT in children with non CysticFibrosis (non-CF) bronchiectasis.
METHODS: In this randomized crossover control trial five to 15 year old children, diagnosed with non-CFbronchiectasiswere randomized either to receive 200µg of inhaled salbutamol followed by hypertonic saline nebulization (test) or only 200µg of inhaled salbutamol, prior to chest physiotherapy which is the conventional ACT (controls) for 8 weeks. Inhaled salbutamol was administered via a pressurized Metered Dosed Inhaler (pMDI) with a valved holding chamber (VHC). After completion of first phase both groups went throughone month washout period, before being crossed over to the opposite arms in the second phase.Spirometric parameters and number of exacerbations were recorded at the end of phase I, washout period and phase II.
RESULTS: Fifty two out of 63 enrolled completed the study. Baseline characteristics of the two groups were similar. A significantly higher mean improvement was seen in predicted Forced Expiratory Volume in one second(FEV1) in the HS arm during phase 1 [HS=14.15±5.50 vs. conventional =5.04±5.55, p=0.001] and phase II [HS =10.81±5.51 vs. conventional =3.54 ±5.13, p=0.001] compared to conventional ACT arm.HS group showed a significantly higher mean improvement in predicted Forced Vital Capacity (FVC) in phase I [HS=13.77±5.73 vs. conventional= 7.54±4.90, p=0.001] and phase II, [HS=9.42±7.00 vs. conventional =4.42±4.00, p=0.003). Mean number of exacerbations experienced by a single child during phase I (2 months) were significantly less (p=0,001) in HS arm (0.42 ±0.64) compared to that of conventional arm (1.30 ± 1.05) butthis difference was not significant in phase II (HS=0.65 ±0.74 and conventional =1.03 ±0.77, p= 0.074) CONCLUSIONS: Incorporating HS nebulization into ACT is an effective strategy to improve dynamic lung volumes and morbidity in children with non-CF bronchiectasis. This article is protected by copyright. All rights reserved.

PMID: 33295693 [PubMed - as supplied by publisher]

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251).

J Cyst Fibros. 2020 Dec 05;:

Authors: Kazani S, Rowlands DJ, Bottoli I, Milojevic J, Alcantara J, Jones I, Kulmatycki K, Machineni S, Mostovy L, Nicholls I, Nick JA, Rowe SM, Simmonds NJ, Vegesna R, Verheijen J, Danahay H, Gosling M, Ayalavajjala PS, Salman M, Strieter R

Abstract
BACKGROUND: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.
METHODS: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.
RESULTS: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.
CONCLUSIONS: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.

PMID: 33293212 [PubMed - as supplied by publisher]

Exogenous Nitric Oxide Improves Antibiotic Susceptibility in Resistant Bacteria.

ACS Infect Dis. 2020 Dec 08;:

Authors: Rouillard KR, Novak OP, Pistiolis AM, Yang L, Ahonen MJR, McDonald RA, Schoenfisch MH

Abstract
Antibiotic resistance in bacteria is a major global threat and a leading cause for healthcare-related morbidity and mortality. Resistant biofilm infections are particularly difficult to treat owing to the protective biofilm matrix, which decreases both antibiotic efficacy and clearance by the host. Novel antimicrobial agents that are capable of eradicating resistant infections are greatly needed to combat the rise of antibiotic-resistant bacteria, particularly in patients with cystic fibrosis who are frequently colonized by multidrug-resistant species. Our research group has developed nitric oxide-releasing biopolymers as alternatives to conventional antibiotics. Here, we show that nitric oxide acts as a broad-spectrum antibacterial agent while also improving the efficacy of conventional antibiotics when delivered sequentially. Alone, nitric oxide kills a broad range of bacteria in planktonic and biofilm form without engendering resistance. In combination with conventional antibiotics, nitric oxide increases bacterial susceptibility to multiple classes of antibiotics and slows the development of antibiotic resistance. We anticipate that the use of nitric oxide in combination with antibiotics may improve the outcome of patients with refractory infections, particularly those that are multidrug-resistant.

PMID: 33291868 [PubMed - as supplied by publisher]

Essential Oils Biofilm Modulation Activity, Chemical and Machine Learning Analysis. Application on Staphylococcus aureus Isolates from Cystic Fibrosis Patients.

Int J Mol Sci. 2020 Dec 04;21(23):

Authors: Papa R, Garzoli S, Vrenna G, Sabatino M, Sapienza F, Relucenti M, Donfrancesco O, Fiscarelli EV, Artini M, Selan L, Ragno R

Abstract
Bacterial biofilm plays a pivotal role in chronic Staphylococcus aureus (S. aureus) infection and its inhibition may represent an important strategy to develop novel therapeutic agents. The scientific community is continuously searching for natural and "green alternatives" to chemotherapeutic drugs, including essential oils (EOs), assuming the latter not able to select resistant strains, likely due to their multicomponent nature and, hence, multitarget action. Here it is reported the biofilm production modulation exerted by 61 EOs, also investigated for their antibacterial activity on S. aureus strains, including reference and cystic fibrosis patients' isolated strains. The EOs biofilm modulation was assessed by Christensen method on five S. aureus strains. Chemical composition, investigated by GC/MS analysis, of the tested EOs allowed a correlation between biofilm modulation potency and putative active components by means of machine learning algorithms application. Some EOs inhibited biofilm growth at 1.00% concentration, although lower concentrations revealed different biological profile. Experimental data led to select antibiofilm EOs based on their ability to inhibit S. aureus biofilm growth, which were characterized for their ability to alter the biofilm organization by means of SEM studies.

PMID: 33291608 [PubMed - in process]

Understanding Pseudomonas aeruginosa-Host Interactions: The Ongoing Quest for an Efficacious Vaccine.

Cells. 2020 Dec 05;9(12):

Authors: Sainz-Mejías M, Jurado-Martín I, McClean S

Abstract
Pseudomonas aeruginosa is a leading cause of chronic respiratory infections in people with cystic fibrosis (CF), bronchiectasis or chronic obstructive pulmonary disease (COPD), and acute infections in immunocompromised individuals. The adaptability of this opportunistic pathogen has hampered the development of antimicrobial therapies, and consequently, it remains a major threat to public health. Due to its antimicrobial resistance, vaccines represent an alternative strategy to tackle the pathogen, yet despite over 50 years of research on anti-Pseudomonas vaccines, no vaccine has been licensed. Nevertheless, there have been many advances in this field, including a better understanding of the host immune response and the biology of P. aeruginosa. Multiple antigens and adjuvants have been investigated with varying results. Although the most effective protective response remains to be established, it is clear that a polarised Th2 response is sub-optimal, and a mixed Th1/Th2 or Th1/Th17 response appears beneficial. This comprehensive review collates the current understanding of the complexities of P. aeruginosa-host interactions and its implication in vaccine design, with a view to understanding the current state of Pseudomonal vaccine development and the direction of future efforts. It highlights the importance of the incorporation of appropriate adjuvants to the protective antigen to yield optimal protection.

PMID: 33291484 [PubMed - in process]

Evaluation of Rescue Oral Glucocorticoid Therapy during Inpatient Cystic Fibrosis Exacerbations.

Pediatr Pulmonol. 2020 Dec 07;:

Authors: Muirhead CA, Lanocha N, Markwardt S, MacDonald KD

Abstract
An acute pulmonary exacerbation (APE) in Cystic Fibrosis (CF) is characterized by increased pulmonary symptoms attributed to bacterial colonization, neutrophil recruitment and inflammation. Antimicrobials, airway clearance and nutrition are the mainstay of therapy. However, when patients fail to improve, corticosteroids have been added to therapy. We retrospectively examined the use of rescue steroids in a children's hospital from 2013 - 2017 during CF APE treatment following at least one week of inpatient therapy without expected clinical improvement. 106 encounters, of 53 unique patients: aged 6-20 years; who had FEV1 percent predicted (FEV1pp) data at baseline, admission, midpoint, and discharge; and had admission duration of at least 12 days were studied. Encounters treated with steroids had less improvement at midpoint percent change from admission in FEV1pp (4.9, ±11.3) than non-steroid group change in FEV1pp (20.1, ±24.6; p-value<0.001). Failure to improve as expected was the rationale for steroid use. At discharge, there was no difference in mean FEV1pp (p=0.76). Delays in steroid therapy by waiting until the end of the second week increased the total length of stay. Propensity matching comparing outcomes in patients without midpoint improvement in FEV1pp was also evaluated. There was no difference in admission or discharge FEV1pp between groups. Equally, no difference in FEV1pp at follow-up visit or in time until next APE was detected. Secondary analysis for associations including gender, genotype, fungal colonization, or inhaled antimicrobials were non-significant. These data suggest rescue use of corticosteroids during APE does not predictably impact important outcome measures during CF APE treatment. This article is protected by copyright. All rights reserved.

PMID: 33289316 [PubMed - as supplied by publisher]

Development of a penem antibiotic against Mycobacteroides abscessus.

Commun Biol. 2020 Dec 07;3(1):741

Authors: Batchelder HR, Story-Roller E, Lloyd EP, Kaushik A, Bigelow KM, Maggioncalda EC, Nuermberger EL, Lamichhane G, Townsend CA

Abstract
β-lactams are the most widely used antibiotic class to treat bacterial infections in humans. Mycobacteroides abscessus is an emerging pulmonary pathogen resistant to most antibiotics, including penicillins and cephalosporins. With no current FDA-approved treatment and cure rates <50%, there is a pressing need for effective therapies. Here we report T405, a new β-lactam of the penem subclass that exhibits potent activity against M. abscessus and a panel of drug-resistant strains isolated from cystic fibrosis patients. Additionally, in combination with the β-lactamase inhibitor avibactam, the rate of spontaneous resistance of M. abscessus to T405 approached the limit of detection. Lastly, we show the favorable pharmacokinetic profile of T405 in mice and the absence of toxicity at elevated dosage, which support the clinical potential of this compound.

PMID: 33288821 [PubMed - in process]

Alpha-1 antitrypsin for cystic fibrosis complicated by severe cytokinemic COVID-19.

J Cyst Fibros. 2020 Nov 20;:

Authors: McElvaney OJ, O'Connor E, McEvoy NL, Fraughan DD, Clarke J, McElvaney OF, Gunaratnam C, O'Rourke J, Curley GF, McElvaney NG

Abstract
BACKGROUND: The clinical course of severe COVID-19 in cystic fibrosis (CF) is incompletely understood. We describe the use of alpha-1 antitrypsin (AAT) as a salvage therapy in a critically unwell patient with CF (PWCF) who developed COVID-19 while awaiting lung transplantation.
METHODS: IV AAT was administered at 120 mg/kg/week for 4 consecutive weeks. Levels of interleukin (IL)-1β, IL-6, IL-8, and soluble TNF receptor 1 (sTNFR1) were assessed at regular intervals in plasma, with IL-1β, IL-6, IL-8 and neutrophil elastase (NE) activity measured in airway secretions. Levels were compared to baseline and historic severe exacerbation measurements.
RESULTS: Systemic and airway inflammatory markers were increased compared to both prior exacerbation and baseline levels, in particular IL-6, IL-1β and NE activity. Following each AAT dose, rapid decreases in each inflammatory parameter were observed. These were matched by marked clinical and radiographic improvement.
CONCLUSIONS: The results support further investigation of AAT as a COVID-19 therapeutic, and re-exploration of its use in CF.

PMID: 33288475 [PubMed - as supplied by publisher]

Sensitive structural and functional measurements and 1-year pulmonary outcomes in pediatric cystic fibrosis.

J Cyst Fibros. 2020 Dec 04;:

Authors: Willmering MM, Roach DJ, Kramer EL, Walkup LL, Cleveland ZI, Woods JC

Abstract
BACKGROUND: Two functional measurements (multiple breath washout [MBW] and hyperpolarized 129Xe ventilation magnetic resonance imaging [129Xe MRI]) have been shown to be more sensitive to cystic fibrosis (CF) lung obstruction than traditional spirometry. However, functional techniques may be sensitive to different underlying structural abnormalities. The purpose of this study was to determine relationships between these functional markers, their pathophysiology, and 1-year clinical outcomes.
METHODS: Spirometry, MBW, 129Xe MRI, and ultrashort echo-time (UTE) MRI were obtained in a same-day assessment of 27 pediatric CF patients (ages 11.5±5.0) who had not begun CFTR modulator therapies. UTE MRI was scored for structural abnormalities and functional metrics obtained via spirometry, MBW and 129Xe MRI. 1-year outcomes (ΔFEV1 and pulmonary exacerbations), during which ≈50% initiated modulator therapy, were obtained from the electronic medical record.
RESULTS: MBW, 129Xe MRI, and UTE MRI detected clinically significant disease in more subjects (>78%) compared to spirometry (<30%). UTE MRI suggests increased odds of bronchial changes when mucus plugging is present in the same lobe. MBW and 129Xe MRI correlated best with mucus plugging, while spirometry correlated best with consolidations. Bronchial abnormalities were associated with future pulmonary exacerbations.
CONCLUSIONS: MBW, 129Xe MRI, and UTE MRI are more sensitive for detection of pediatric CF lung disease when compared to spirometry. MBW and 129Xe MRI correlated with structural abnormalities which occur in early CF disease, suggesting MBW and 129Xe MRI are valuable tools in mild CF lung disease that can guide clinical decision making.

PMID: 33288474 [PubMed - as supplied by publisher]

siRNA delivery to macrophages using aspherical, nanostructured microparticles as delivery system for pulmonary administration.

Eur J Pharm Biopharm. 2020 Dec 04;:

Authors: Fischer T, Tschernig T, Drews F, Brix K, Meier C, Simon M, Kautenburger R, Schneider M

Abstract
The delivery of oligonucleotides such as siRNA to the lung is a major challenge, as this group of drugs has difficulties to overcome biological barriers due to its polyanionic character and the associated hydrophilic properties, resulting in inefficient delivery. Especially in diseases such as asthma, chronic obstructive pulmonary disease and cystic fibrosis, where increased proinflammation is present, a targeted RNA therapy is desirable due to the high potency of these oligonucleotides. To address these problems and to ensure efficient uptake of siRNA in macrophages, a microparticulate, cylindrical delivery system was developed. In the first step, this particle system was tested for its aerodynamic characteristics to evaluate the aerodynamic properties to optimize lung deposition. The mass median aerodynamic diameter of 2.52 ± 0.23µm, indicates that the desired target should be reached. The inhibition of TNF-α release, as one of the main mediators of proinflammatory reactions, was investigated. We could show that our carrier system can be loaded with siRNA against TNF-α. Gel electrophoreses allowed to demonstrate that the load can be incorporated and released without being degraded. The delivery system was found to transport a mass fraction of 0.371% [%w/w] as determined by inductively coupled plasma mass spectroscopy. When investigating the release kinetics, the results showed that several days are necessary to release a major amount of the siRNA indicating a sustained release. The cylindrical microparticles with an aspect ratio of 3.3 (ratio of length divided by width) were then tested in vitro successfully reducing TNF-α release from human macrophages significantly by more than 30%. The developed formulation presents a possible oligonucleotide delivery system allowing due to its internal structure to load and protect siRNA.

PMID: 33285246 [PubMed - as supplied by publisher]

A current review of the safety of cystic fibrosis transmembrane conductance regulator modulators.

J Clin Pharm Ther. 2020 Dec 07;:

Authors: Gavioli EM, Guardado N, Haniff F, Deiab N, Vider E

Abstract
WHAT IS KNOWN AND OBJECTIVE: Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators has led to improved clinical outcomes and an increase in lifespans of cystic fibrosis (CF) patients. As CF patients continue to live longer, they are at risk for developing adverse drug reactions associated with polypharmacy and CFTR modulators.
COMMENT: The authors aim to describe safety concerns of the current combination CFTR modulators, based upon a literature review, including notable safety concerns and recommendations for drug-drug interactions.
WHAT IS NEW AND CONCLUSION: Cystic fibrosis transmembrane conductance regulator agents are generally well tolerated with low discontinuation rates when compared to placebo. Elevations in liver enzymes and drug-drug interactions are the most notable safety concerns. Additionally, lumacaftor/ivacaftor has shown more respiratory-related adverse events and drug-drug interactions compared to elexacaftor/tezacaftor/ivacaftor and tezacaftor/ivacaftor. Postmarketing studies are needed to determine long-term safety concerns.

PMID: 33285018 [PubMed - as supplied by publisher]

Steps Ahead: optimising physical activity and health in people with cystic fibrosis: Study Protocol for a pilot randomised trial.

HRB Open Res. 2020;3:21

Authors: Curran M, Tierney AC, Collins L, Kennedy L, McDonnell C, Jurascheck AJ, Sheikhi A, Walsh C, Button B, Galvin R, Casserly B, Cahalan R

Abstract
Background: Physical activity (PA) and exercise are widely documented as key components in the management of cystic fibrosis (CF). In recent years there have been significant improvements in telehealth, in particular; fitness tracking, smartphone use and remote monitoring, all of which may have potential to impact on positive health outcomes in people with CF. The objective of this pilot randomised trial is to explore the potential efficacy of a fitness tracker, which is remotely monitored, combined with personalised text message feedback and goal setting, on lung function, aerobic capacity and PA in adults with CF. Secondary endpoints include quality of life, body composition and wellbeing. Methods: This is a pilot randomised trial which will be conducted at the University Hospital Limerick, Ireland. Participants will be randomised to the intervention or active comparator after their baseline assessment. The 12-week intervention will consist of a fitness tracker (Fitbit Charge 2) which is linked to an online monitoring system (Fitabase) for data collection purposes that enables the physiotherapist to remotely monitor participant data. The CF physiotherapist will set short- and long-term goals with participants and will send one-way text message feedback on Fitbit data and weekly progress. This message will consist of positive reinforcement and re-assess participant goals. The active comparator group will receive a fitness tracker which is also linked to Fitabase; however, no feedback will be provided to participants in this group. Both groups will be re-assessed at 12 weeks. After this point, both groups will continue with the Fitbit alone for a further 12 weeks. Both groups will be re-assessed at 24 weeks. Discussion: This is a novel concept which utilises modern technology, remote monitoring and personalised feedback to investigate the effect on health outcomes in people with CF.  Trial registration: ClinicalTrials.gov NCT03672058 (14/09/2018).

PMID: 33283151 [PubMed]

Vasculitis in Cystic Fibrosis.

Front Pediatr. 2020;8:585275

Authors: Sposito F, McNamara PS, Hedrich CM

Abstract
Cystic fibrosis (CF) is an autosomal-recessive multi-organ disease characterized by airways obstruction, recurrent infections, and systemic inflammation. Vasculitis is a severe complication of CF that affects 2-3% of CF patients and is generally associated with poor prognosis. Various pathogenic mechanisms may be involved in the development of CF-related vasculitis. Bacterial colonization leads to persistent activation of neutrophilic granulocytes, inflammation and damage, contributing to the production of antineutrophil cytoplasmic autoantibodies (ANCAs). The presence of ANCA may on the other hand predispose to bacterial colonization and infection, likely entertaining a vicious circle amplifying inflammation and damage. As a result, in CF-associated vasculitis, ongoing inflammation, immune cell activation, the presence of pathogens, and the use of numerous medications may lead to immune complex formation and deposition, subsequently causing leukocytoclastic vasculitis. Published individual case reports and small case series suggest that patients with CF-associated vasculitis require immune modulating treatment, including non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, hydroxychloroquine, and/or disease-modifying anti-rheumatic drugs (DMARDs). As immunosuppression increases the risk of infection and/or malignancy, which are both already increased in people with CF, possible alternative medications may involve the blockade of individual cytokine or inflammatory pathways, or the use of novel CFTR modulators. This review summarizes molecular alterations involved in CF-associated vasculitis, clinical presentation, and complications, as well as currently available and future treatment options.

PMID: 33282799 [PubMed]

Barriers and incentives for Italian paediatricians to become smoking cessation promoters: a GARD-Italy Demonstration Project.

J Thorac Dis. 2020 Nov;12(11):6868-6879

Authors: Cilluffo G, Ferrante G, Cutrera R, Piacentini G, Bignamini E, Landi M, Martucci P, Morcaldi L, Midulla F, Viegi G, La Grutta S

Abstract
Background: Paediatricians rarely devote any time to screening and treatment for parental tobacco use. The present project is part of a Global Alliance against Chronic Respiratory Diseases (GARD)-Italy Demonstration Project, aimed to increase the skills of primary care physicians and paediatricians as "promoter of smoking cessation". The aims of this study were: (I) to identify latent classes of barriers and incentives for smoking cessation counseling among paediatricians using latent class analysis (LCA); (II) to investigate risk factors for inclusion into the identified classes.
Methods: In 2018, 1,500 Italian paediatricians were invited to complete an online survey on passive smoke exposure in children. LCA was used to discover underlying response patterns, and to identify respondent groups with similar attitudes toward passive smoke exposure in children. Multinomial logistic regression helped investigate which explanatory variables influenced inclusion into a class. A P value <0.05 was considered significant.
Results: The overall response rate was 71% (n=1,071/1,500). Three classes were identified: Class 1 "passive" (n=226, 21.10%); Class 2 "unmotivated" (n=124, 11.58%); and Class 3 "proactive" (n=721, 67.32%). Assuming Class 3 as reference, ever having been a smoker was borderline associated (P=0.052) with increased probability of inclusion into Class 1 (OR =1.43, 95% CI, 1.00-2.06). Having 6-15 or ≥15 years of work experience versus having less than five years was associated with decreased probability of being in the "passive" class (OR =0.46, 95% CI, 0.22-0.96 and OR =0.49, 95% CI, 0.27-0.87, respectively), as was discussing parents' addiction to alcohol/drugs (OR =0.50, 95% CI, 0.33-0.76).
Conclusions: We identified three profiles among Italian paediatricians related to barriers and incentives for smoking cessation promotion. Tailored educational interventions for paediatricians are required to promote smoking cessation programs.

PMID: 33282389 [PubMed]

Novel therapeutic approaches for the management of cystic fibrosis.

Multidiscip Respir Med. 2020 Jan 28;15(1):690

Authors: Jaques R, Shakeel A, Hoyle C

Abstract
Cystic fibrosis (CF) is a genetic condition characterised by the build-up of thick, sticky mucus that can damage many of the body's organs. It is a life-long disease that results in a shortened life expectancy, often due to the progression of advanced lung disease. Treatment has previously targeted the downstream symptoms such as diminished mucus clearance and recurrent infection. More recently, significant advances have been made in treating the cause of the disease by targeting the faulty gene responsible. Hope for the development of potential therapies lies with ongoing research into new pharmacological agents and gene therapy. This review gives an overview of CF, and summarises the current evidence regarding the disease management and upcoming strategies aimed at treating or potentially curing this condition.

PMID: 33282281 [PubMed]

Development of a Broadly Protective, Self-Adjuvanting Subunit Vaccine to Prevent Infections by Pseudomonas aeruginosa.

Front Immunol. 2020;11:583008

Authors: Das S, Howlader DR, Zheng Q, Ratnakaram SSK, Whittier SK, Lu T, Keith JD, Picking WD, Birket SE, Picking WL

Abstract
Infections caused by the opportunistic pathogen Pseudomonas aeruginosa can be difficult to treat due to innate and acquired antibiotic resistance and this is exacerbated by the emergence of multi-drug resistant strains. Unfortunately, no licensed vaccine yet exists to prevent Pseudomonas infections. Here we describe a novel subunit vaccine that targets the P. aeruginosa type III secretion system (T3SS). This vaccine is based on the novel antigen PaF (Pa Fusion), a fusion of the T3SS needle tip protein, PcrV, and the first of two translocator proteins, PopB. Additionally, PaF is made self-adjuvanting by the N-terminal fusion of the A1 subunit of the mucosal adjuvant double-mutant heat-labile enterotoxin (dmLT). Here we show that this triple fusion, designated L-PaF, can activate dendritic cells in vitro and elicits strong IgG and IgA titers in mice when administered intranasally. This self-adjuvanting vaccine expedites the clearance of P. aeruginosa from the lungs of challenged mice while stimulating host expression of IL-17A, which may be important for generating a protective immune response in humans. L-PaF's protective capacity was recapitulated in a rat pneumonia model, further supporting the efficacy of this novel fusion vaccine.

PMID: 33281815 [PubMed - in process]