Reply to Turnbull et al. and Hulme et al.

Am J Respir Crit Care Med. 2019 Nov 26;:

Authors: Breuer O, Schultz A, Turkovic L, de Klerk N, Keil AD, Brennan S, Harrison J, Robertson C, Robinson PJ, Sly PD, Ranganathan S, Stick SM, Caudri D, AREST CF

PMID: 31769999 [PubMed - as supplied by publisher]

Lower Airway Infection in Preschool Children with Cystic Fibrosis - An International Comparison.

Am J Respir Crit Care Med. 2019 Nov 26;:

Authors: Hulme KM, Linnane B, McNally PG

PMID: 31769996 [PubMed - as supplied by publisher]

Intracellular Survival and Innate Immune Evasion of Burkholderia cepacia: Improved Understanding of Quorum Sensing-Controlled Virulence Factors, Biofilm and Inhibitors.

Microbiol Immunol. 2019 Nov 26;:

Authors: Ganesh PS, Vishnupriya S, Vadivelu J, Mariappan V, Vellasamy KM, Shankar EM

Abstract
B. cepacia complex (Bcc) are opportunistic pathogens implicated with nosocomial infections, and high rates of morbidity and mortality, especially in individuals with cystic fibrosis (CF). B.cepacia are naturally resistant to different classes of antibiotics, and can subvert the host innate immune responses by producing quorum sensing (QS) controlled virulence factors and biofilms. It still remains a conundrum as to how exactly the bacterium survives the intracellular environment within the host cells of CF patients and the immunocompromised although the bacterium can invade human lung epithelial cells, neutrophils and murine macrophages. The mechanisms associated with intracellular survival in the airway epithelial cells and the role of QS and virulence factors in B. cepacia infections in CF largely remain unclear. The current review focuses to understand the role of QS-controlled virulence factors and biofilms, and provides additional impetus to understanding the potentials of QS-inhibitory strategies against B. cepacia. This article is protected by copyright. All rights reserved.

PMID: 31769530 [PubMed - as supplied by publisher]

The extracellular DNA lattice of bacterial biofilms is structurally related to Holliday junction recombination intermediates.

Proc Natl Acad Sci U S A. 2019 Nov 25;:

Authors: Devaraj A, Buzzo JR, Mashburn-Warren L, Gloag ES, Novotny LA, Stoodley P, Bakaletz LO, Goodman SD

Abstract
Extracellular DNA (eDNA) is a critical component of the extracellular matrix of bacterial biofilms that protects the resident bacteria from environmental hazards, which includes imparting significantly greater resistance to antibiotics and host immune effectors. eDNA is organized into a lattice-like structure, stabilized by the DNABII family of proteins, known to have high affinity and specificity for Holliday junctions (HJs). Accordingly, we demonstrated that the branched eDNA structures present within the biofilms formed by NTHI in the middle ear of the chinchilla in an experimental otitis media model, and in sputum samples recovered from cystic fibrosis patients that contain multiple mixed bacterial species, possess an HJ-like configuration. Next, we showed that the prototypic Escherichia coli HJ-specific DNA-binding protein RuvA could be functionally exchanged for DNABII proteins in the stabilization of biofilms formed by 3 diverse human pathogens, uropathogenic E. coli, nontypeable Haemophilus influenzae, and Staphylococcus epidermidis Importantly, while replacement of DNABII proteins within the NTHI biofilm matrix with RuvA was shown to retain similar mechanical properties when compared to the control NTHI biofilm structure, we also demonstrated that biofilm eDNA matrices stabilized by RuvA could be subsequently undermined upon addition of the HJ resolvase complex, RuvABC, which resulted in significant biofilm disruption. Collectively, our data suggested that nature has recapitulated a functional equivalent of the HJ recombination intermediate to maintain the structural integrity of bacterial biofilms.

PMID: 31767757 [PubMed - as supplied by publisher]

Susceptibility of Pseudomonas aeruginosa recovered from cystic fibrosis patients to murepavadin and thirteen comparator antibiotics.

Antimicrob Agents Chemother. 2019 Nov 25;:

Authors: Ekkelenkamp MB, Cantón R, Díez-Aguilar M, Tunney MM, Gilpin DF, Bernardini F, Dale GE, Elborn JS, Bayjanov JR, Fluit A

Abstract
Objectives: To determine the in vitro antimicrobial susceptibility of Pseudomonas aeruginosa isolates cultured from cystic fibrosis (CF) patients and explore associations between strain sequence type and susceptibility.Patients and Methods: Fourteen antibiotics and antibiotic combinations, including the novel antibacterial peptide murepavadin, were tested for activity against 414 Pseudomonas aeruginosa isolates cultured from respiratory samples of CF patients. The complete genomes of the isolates were sequenced and minimum spanning trees were constructed based on the sequence types (STs).Results: Percentage resistance (R) according to CLSI-2019 breakpoints were as follows: cefepime 14%, ceftazidime 11%, ceftazidime-avibactam 7%, ceftolozane-tazobactam 3%, piperacillin-tazobactam 12%, meropenem 18%, imipenem 32%, aztreonam 23%, ciprofloxacin 30%, gentamicin 30%, tobramycin 12%, amikacin 18%, and colistin 4%. Murepavadin MIC50 and MIC90 were 0.12 mg/L and 2 mg/L, respectively. There were no apparent clonal clusters associated with resistance, but higher MICs did appear to occur more often in STs with multiple isolates than in single ST isolates. In general the CF isolates showed a wide genetic distribution.Conclusions: P. aeruginosa CF isolates exhibited the lowest resistance rates against ceftolozane-tazobactam, ceftazidime-avibactam and colistin. Murepavadin demonstrated the highest activity on a per weight basis and may therefore become a valuable addition to the currently available antibiotics for treatment of respiratory infection in people with CF.

PMID: 31767727 [PubMed - as supplied by publisher]

Renal involvement and metabolic alterations in adults patients affected by cystic fibrosis.

J Transl Med. 2019 Nov 25;17(1):388

Authors: Lai S, Mazzaferro S, Mitterhofer AP, Bonci E, Marotta PG, Pelligra F, Murciano M, Celani C, Troiani P, Cimino G, Palange P

Abstract
BACKGROUND: Cystic fibrosis (CF) is one of the most frequent genetic diseases and the median survival of these patients has improved in the last few decades, therefore it becomes necessary to evaluate the long-term complications as renal and cardiovascular risk factors.
AIM OF THE STUDY: To evaluate the incidence, the manifestations of renal disease and the possible association with metabolic and endothelial dysfunction markers in the CF population.
MATERIALS AND METHODS: We performed a cross-sectional, observational study on 226 CF patients. Clinical and laboratory instrumental parameters (metabolic, inflammatory and endothelial dysfunction markers) were evaluated.
RESULTS: We showed 65 patients with chronic kidney disease (CKD) and 158 patients with a reduced value of forced expiratory volume in 1 s (FEV1), of which 58 patients with a severe reduction of FEV1. Moreover 28 patients had undergone lung transplantation and them had a significant lower estimated Glomerular Filtration Rate (eGFR) with respect to the non-transplanted patients (p < 0.001). We reported also a significant association between lower eGFR value and serum triglycerides, total cholesterol and low-density lipoproteins (LDL) (p = 0.005, p < 0.001, p = 0.040; respectively), with a significant negative correlation between eGFR and serum triglycerides (r = - 0.28; p < 0.01). Moreover we found a significant association between lower eGFR value and serum uric acid (SUA) (p = 0.005), while we did not found an association with 25-hydroxy-vitamin-D value, serum glucose and hemoglobin A1c levels.
CONCLUSIONS: Our study showed a high prevalence of CKD in CF patients. Moreover we showed an increase of endothelial dysfunction and metabolic indexes in patients with reduced renal function, as SUA, serum triglycerides and LDL, suggesting the need for an early and complete screening of the main metabolic indexes to reduce cardiovascular risk and progression of renal damage, in particular in patients with lung transplant.

PMID: 31767021 [PubMed - in process]

Mycobacterium abscessus, an Emerging and Worrisome Pathogen among Cystic Fibrosis Patients.

Int J Mol Sci. 2019 Nov 22;20(23):

Authors: Degiacomi G, Sammartino JC, Chiarelli LR, Riabova O, Makarov V, Pasca MR

Abstract
Nontuberculous mycobacteria (NTM) have recently emerged as important pathogens among cystic fibrosis (CF) patients worldwide. Mycobacterium abscessus is becoming the most worrisome NTM in this cohort of patients and recent findings clarified why this pathogen is so prone to this disease. M. abscessus drug therapy takes up to 2 years and its failure causes an accelerated lung function decline. The M. abscessus colonization of lung alveoli begins with smooth strains producing glycopeptidolipids and biofilm, whilst in the invasive infection, "rough" mutants are responsible for the production of trehalose dimycolate, and consequently, cording formation. Human-to-human M. abscessus transmission was demonstrated among geographically separated CF patients by whole-genome sequencing of clinical isolates worldwide. Using a M. abscessus infected CF zebrafish model, it was demonstrated that CFTR (cystic fibrosis transmembrane conductance regulator) dysfunction seems to have a specific role in the immune control of M. abscessus infections only. This pathogen is also intrinsically resistant to many drugs, thanks to its physiology and to the acquisition of new mechanisms of drug resistance. Few new compounds or drug formulations active against M. abscessus are present in preclinical and clinical development, but recently alternative strategies have been investigated, such as phage therapy and the use of β-lactamase inhibitors.

PMID: 31766758 [PubMed - in process]

Back to the source - Modern insights into pulmonary exacerbations and lung function decline from CF registry data.

J Cyst Fibros. 2018 07;17(4):425-427

Authors: Rayment JH, Quon BS

PMID: 29859835 [PubMed - indexed for MEDLINE]

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Am J Respir Crit Care Med. 2019 Nov 25;:

Authors: Ramsey KA, Chen ACH, Radicioni G, Lourie R, Martin M, Broomfield A, Sheng YH, Hasnain SZ, Radford-Smith G, Simms LA, Burr L, Thornton DJ, Bowler SD, Livengood S, Ceppe A, Knowles MR, Donaldson SH, Hill DB, Ehre C, Button B, Alexis NE, Kesimer M, Boucher RC, McGuckin MA

Abstract
RATIONALE: Non-cystic fibrosis bronchiectasis (NCFB) is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.
OBJECTIVES: This study was designed to: (a) measure mucus concentration and biophysical properties of bronchiectasis mucus; (b) identify the secreted mucins contained in bronchiectasis sputum; (c) relate mucus properties to airway epithelial mucin RNA/protein expression; and (d) explore relationships between mucus hyperconcentration and disease severity.
METHODS: Sputum samples were collected from bronchiectasis subjects, with and without chronic erythromycin administration, and healthy controls. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B polymorphisms were identified by qPCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline induced sputa were collected and mucus/mucin concentrations measured.
MEASUREMENTS AND MAIN RESULTS: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within bronchiectasis subjects, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computerized tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced NCFB mucus concentration by 25%.
CONCLUSIONS: Hyper-concentrated airway mucus is characteristic of bronchiectasis subjects, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

PMID: 31765597 [PubMed - as supplied by publisher]

The effects of high-frequency chest compression on end-tidal CO2.

Pediatr Pulmonol. 2019 Nov 25;:

Authors: Weiner GA, Forno E, Weiner DJ

Abstract
INTRODUCTION: High-frequency chest compression (HFCC) is used for airway clearance, but may have other effects. We sought to determine if HFCC provides augmented ventilation.
METHODS: During treatment, capnometry was measured with the HFCC vest set to 6-20 Hz. End-tidal CO2 (etCO2 ) was compared using generalized estimating equations.
RESULTS: Twenty-four measurements were obtained from 15 subjects with mean age 15.2 ± 2.5 years and forced expiratory volume in one second (FEV1 ) % predicted 70 ± 23. EtCO2 decreased with HFCC at 6 Hz when compared with baseline (P < .001), with small changes with increasing oscillation frequency. Change in etCO2 was not predicted by FEV1 , body mass index, age, or sex.
CONCLUSIONS: While HFCC has been shown to be a suitable method of airway clearance, investigators have failed to demonstrate differences between techniques. Assessment of these methodologies will become important as new airway clearance devices are proposed. Other outcome measures (besides FEV1 ) may be needed to assess effects of airway clearance, and we propose that physiologic measures might be one such measure which deserves further exploration.

PMID: 31765524 [PubMed - as supplied by publisher]

Discovery of ubonodin, an antimicrobial lasso peptide active against members of the Burkholderia cepacia complex.

Chembiochem. 2019 Nov 25;:

Authors: Cheung-Lee WL, Parry M, Zong C, Jaramillo Cartagena A, Darst S, Connell N, Russo R, Link AJ

Abstract
We report the heterologous expression, structure, and antimicrobial activity of a lasso peptide, ubonodin, encoded in the genome of Burkholderia ubonensis . The topology of ubonodin is unprecedented amongst lasso peptides with 18 of its 28 amino acids found in the mechanically-bonded loop segment. Ubonodin inhibits RNA polymerase in vitro and has potent antimicrobial activity against several pathogenic members of the Burkholderia genus, most notably B. cepacia and B. multivorans , causative agents of lung infections in cystic fibrosis patients.

PMID: 31765515 [PubMed - as supplied by publisher]

Assessing the feasibility of hyperpolarized 129 Xe multiple-breath washout MRI in pediatric cystic fibrosis.

Magn Reson Med. 2019 Nov 25;:

Authors: Couch MJ, Morgado F, Kanhere N, Kowalik K, Rayment JH, Ratjen F, Santyr G

Abstract
PURPOSE: To assess the feasibility of hyperpolarized 129 Xe multiple-breath washout MRI in pediatric cystic fibrosis (CF) participants with preserved lung function. Fractional ventilation (r), defined as the fractional gas replacement per breath, was mapped using 2 signal models: (1) constant T1 and (2) variable T1 as a function of the hyperpolarized gas washout.
METHODS: A total of 17 pediatric participants were recruited (mean age 11.7 ± 2.8 years), including 7 children with clinically stable CF and 10 aged-matched healthy controls. Pulmonary function tests were performed, including spirometry, to measure the forced expiratory volume in 1 second and nitrogen multiple-breath washout to measure the lung clearance index. Hyperpolarized 129 Xe MRI was performed during consecutive breaths of air following a single 129 Xe inhalation, and fractional ventilation maps were calculated.
RESULTS: The forced expiratory volume in 1 second was similar in both groups (P = .32), but there was a statistically significant difference in lung clearance index between healthy and CF participants (P = .001). With variable T1 modeling, CF participants had a mean r of 0.44 ± 0.08 and healthy participants had a mean r of 0.37 ± 0.12 (P = .20). With constant T1 modeling, CF participants had a mean r' of 0.48 ± 0.08, and healthy participants had a mean r' of 0.43 ± 0.12 (P = .32). Therefore, assuming a constant T1 leads to a relative bias in r of 15.1% ± 6.4% and 20.8% ± 7.4% for CF and healthy participants, respectively (P = .12).
CONCLUSION: This study demonstrates that hyperpolarized 129 Xe multiple-breath washout imaging is feasible in pediatric participants with CF, and inclusion of variable T1 modeling reduces bias in the fractional ventilation measurements.

PMID: 31765507 [PubMed - as supplied by publisher]

What She Leaves Behind.

Am J Nurs. 2019 Dec;119(12):65

Authors: Brown T

Abstract
Cystic fibrosis and an unfinished life.

PMID: 31764059 [PubMed - in process]

The lived experience of adults with cystic fibrosis: what they would tell their younger selves about the gut.

J Hum Nutr Diet. 2019 Nov 25;:

Authors: Cave L, Milnes LJ

Abstract
BACKGROUND: Little is known about adults' experience of living with cystic fibrosis (CF) specifically in relation to the gut. However, their unique perspectives may be meaningful to children with CF and inform the understanding and practice of dietitians. The present study aimed to explore adults' lived experience of the CF gut and how they learnt to manage the gut as they were growing up.
METHODS: Semi-structured interviews were conducted with adult inpatients (n = 10). Interviews were audio-recorded, transcribed verbatim and accounts analysed using interpretative phenomenological analysis.
RESULTS: Three super-ordinate themes were identified: taking Creon, the learning process and this much I (now) know. Participants accounts of how CF affects the gut predominantly focused on taking Creon (pancreatin, Mylan). Various strategies were employed for coping with peer responses to taking Creon at school. Several participants reached adulthood before they understood and/or accepted that taking Creon consistently needed to be normal for them. Knowledge and understanding developed over time, with 'CF experience' and was shaped by family, CF care teams and other children with CF. All had unmet information needs when growing up. Having key explanations earlier, to make connections between eating, taking Creon, gaining weight and growth, did or would have helped most participants. Participants urged children to be assertive, ask questions and not only be involved in managing their diet and gut, but also begin to take control of this aspect of their CF.
CONCLUSIONS: Supporting development of knowledge, skills and confidence to manage diet and the gut needs to be integral to care throughout childhood.

PMID: 31763740 [PubMed - as supplied by publisher]

Whole genome analysis of Pandoraea species strains from cystic fibrosis patients.

Future Microbiol. 2019 Nov 25;:

Authors: Bayjanov JR, Ekkelenkamp MB, Rogers MR, Cantón R, Benaissa-Trouw BJ, Díez-Aguilar M, Tunney M, Fluit AC

Abstract
Aim: Genetic characterization of Pandoraea strains recovered from cystic fibrosis patients. Materials & methods: The whole genome sequence of 12 Pandoraea strains was determined using Illumina technology. The position of the strains within the genus Pandoraea was analyzed using selected partial gene sequences, core genome multi-locus sequence typing and average nucleotide identity analysis. Furthermore, the sequences were annotated. Results: The results show that some strains previously identified as Pandoraea pnomenusa, Pandoraea sputorum, Pandoraea oxalativorans and Pandoraea pulmonicola belong to novel species. The strains did not harbor acquired antibiotic resistance genes but encoded an OXA-type ß-lactamase. Conclusion: The taxonomy of the genus Pandoraea needs to be revised.

PMID: 31762328 [PubMed - as supplied by publisher]

A Rare Case of Myonecrosis with Soft-Tissue Emphysema in a Diabetic Foot Caused by Streptococcus anginosus Isolated in Pure Culture: A Case Study.

J Am Podiatr Med Assoc. 2019 Jul;109(4):305-307

Authors: Route J, Anain J

Abstract
Streptococcus anginosus (SAG) is a known human pathogen and member of the Streptococcus milleri group. SAG is a known bacterial cause of soft-tissue abscesses and bacteremia and is an increasingly prevalent pathogen in infections in patients with cystic fibrosis. We describe a rare case of SAG as an infectious agent in a case of nonclostridial myonecrosis with soft-tissue emphysema. This is the only case found in the literature of SAG cultured as a pure isolate in this type of infection and was associated with a prolonged course of treatment in an otherwise healthy patient.

PMID: 31762305 [PubMed - in process]

Answering the call to address cystic fibrosis treatment burden in the era of highly effective CFTR modulator therapy.

J Cyst Fibros. 2019 Nov 21;:

Authors: Gifford AH, Mayer-Hamblett N, Pearson K, Nichols DP

Abstract
BACKGROUND: We recognize an unprecedented opportunity to study the effects of withdrawing one or more chronic treatments in people with CF (PwCF) who benefit greatly from CFTR modulator therapy, but feasibility and acceptance of such a study within the community is unknown.
METHODS: We surveyed PwCF, their families, and their acquaintances between November 16, 2018, and December 2, 2018, and CF clinicians between December 19, 2018, and January 2, 2019, about treatment withdrawal research. We sought feedback from these groups about their level of interest in this research, the consistency with which they were taking modulator and non-modulator treatments, the ways in which they conceptualized health changes, and what chronic non-modulator treatments they were most interested in stopping. We also asked for stakeholder perspectives on the design of a treatment withdrawal trial, but we intend to report these perspectives elsewhere.
RESULTS: Eighty percent (541/675) of CF community respondents and 95% (206/218) of CF clinicians said that a trial of treatment simplification should be performed in the context of highly effective modulator therapy. Most current CFTR modulator users (292/359, 81%) have not stopped another chronic treatment. Worsening lung function by spirometry or increased daily symptoms were important health indicators. PwCF, their families, and/or their acquaintances ranked airway clearance techniques and inhaled antibiotics as the most burdensome treatments.
CONCLUSIONS: There is considerable support among the CF community and CF clinicians in the U.S. for controlled trials to assess the safety and impact of treatment simplification in patients taking highly effective modulator therapy.

PMID: 31761739 [PubMed - as supplied by publisher]

Caregiver Burden Due to Pulmonary Exacerbations in Patients with Cystic Fibrosis.

J Pediatr. 2019 Dec;215:164-171.e2

Authors: Suthoff E, Mainz JG, Cox DW, Thorat T, Grossoehme DH, Fridman M, Sawicki GS, Rosenfeld M

Abstract
OBJECTIVE: To describe the poorly understood burden of pulmonary exacerbations experienced by primary caregivers of children (aged 2-17 years) with cystic fibrosis (CF), who frequently require prolonged hospitalizations for treatment of pulmonary exacerbations with intravenous (IV) antibiotics.
STUDY DESIGN: In this prospective observational study, 88 caregivers in Germany, Ireland, the United Kingdom, and the US completed a survey during pulmonary exacerbation-related hospitalizations (T1) and after return to a "well state" of health (T2). The impact of pulmonary exacerbations on caregiver-reported productivity, mental/physical health, and social/family/emotional functioning was quantified.
RESULTS: Primary caregivers of children with CF reported significantly increased burden during pulmonary exacerbations, as measured by the 12-item Short-Form Health Survey mental health component and the Work Productivity and Activity Impairment: Specific Health Problem absenteeism, presenteeism, work productivity loss, and activity impairment component scores. Compared to the "well state," during pulmonary exacerbations-related hospitalization caregivers reported lower physical health scores on the Child Health Questionnaire-Parent Form 28. Quality-of-life scores on the Caregiver Quality of Life Cystic Fibrosis scale and total support score on the Multidimensional Scale of Perceived Social Support did not differ significantly between T1 and T2. More caregivers reported a negative impact on family/social/emotional functioning during pulmonary exacerbations than during the "well state."
CONCLUSIONS: Pulmonary exacerbations necessitating hospitalization impose a significant burden on primary caregivers of children with CF. Preventing pulmonary exacerbations may substantially reduce this burden.

PMID: 31761140 [PubMed - in process]

The clinical and genetic relationships of cystic fibrosis to immotile cilia syndrome.

J Pediatr. 2019 Dec;215:1-3

Authors: Wilmott RW

PMID: 31761129 [PubMed - in process]

Streptococcus pseudopneumoniae, an opportunistic pathogen in patients with cystic fibrosis.

J Cyst Fibros. 2019 Nov 20;:

Authors: Dupont C, Michon AL, Normandin M, Salom G, Latypov M, Chiron R, Marchandin H

Abstract
The pathogenic power of Streptococcus pseudopneumoniae has been specified over years, particularly in case of chronic respiratory diseases; S. pseudopneumoniae isolation has however not been characterized before in CF patients. Identification of S. pseudopneumoniae remains challenging due to the high simila-rity level between species of the Streptococcus mitis group. Twenty CF patients with S. pseudopneumoniae were included. Isolates initially identified by phenotypic routine methods were subjected to both recA sequencing and amplification of S. pseudopneumoniae specific markers. Microbiological and clinical data were reviewed for patients with confirmed S. pseudopneumoniae. Thirteen isolates actually belong to S. pseudopneumoniae. S. pseudopneumoniae was associated with pulmonary exacerbation in 46% of the patients, either as the sole pathogen or as part of a polymicrobial infectious process. S. pseudopneumoniae has to be considered as an additional opportunistic pathogen in CF and additional studies are needed to increase knowledge of its epidemiology and clinical significance in CF.

PMID: 31759908 [PubMed - as supplied by publisher]