Genomics of antibiotic-resistance prediction in Pseudomonas aeruginosa.

Ann N Y Acad Sci. 2019 01;1435(1):5-17

Authors: Jeukens J, Freschi L, Kukavica-Ibrulj I, Emond-Rheault JG, Tucker NP, Levesque RC

Abstract
Antibiotic resistance is a worldwide health issue spreading quickly among human and animal pathogens, as well as environmental bacteria. Misuse of antibiotics has an impact on the selection of resistant bacteria, thus contributing to an increase in the occurrence of resistant genotypes that emerge via spontaneous mutation or are acquired by horizontal gene transfer. There is a specific and urgent need not only to detect antimicrobial resistance but also to predict antibiotic resistance in silico. We now have the capability to sequence hundreds of bacterial genomes per week, including assembly and annotation. Novel and forthcoming bioinformatics tools can predict the resistome and the mobilome with a level of sophistication not previously possible. Coupled with bacterial strain collections and databases containing strain metadata, prediction of antibiotic resistance and the potential for virulence are moving rapidly toward a novel approach in molecular epidemiology. Here, we present a model system in antibiotic-resistance prediction, along with its promises and limitations. As it is commonly multidrug resistant, Pseudomonas aeruginosa causes infections that are often difficult to eradicate. We review novel approaches for genotype prediction of antibiotic resistance. We discuss the generation of microbial sequence data for real-time patient management and the prediction of antimicrobial resistance.

PMID: 28574575 [PubMed - indexed for MEDLINE]

Pancreatic Enzyme Replacement Therapy: A Concise Review.

JOP. 2019;20(5):121-125

Authors: Brennan GT, Saif MW

Abstract
Pancreatic enzyme replacement therapy is safe and effective at treating pancreatic exocrine insufficiency. There are multiple causes of pancreatic exocrine insufficiency including chronic pancreatitis, cystic fibrosis and pancreatic cancer. Testing fecal elastase-1 level is useful for the diagnosis of pancreatic exocrine insufficiency. Starting doses of pancreatic enzyme replacement therapy should be at least 30-40,000 IU with each meal and 15-20,000 IU with snacks. pancreatic enzyme replacement therapy should be taken in divided doses throughout meals. Patients who do not respond to initial dosages should be evaluated for alternative etiologies and pancreatic enzyme replacement therapy optimized. Despite ease of use and benefit of pancreatic enzyme replacement therapy, challenges still remain clinically and this review hopes to provide a concise guide for clinicians.

PMID: 31736680 [PubMed]

Evaluation of Copeptin during Pulmonary Exacerbation in Cystic Fibrosis.

Mediators Inflamm. 2019;2019:1939740

Authors: Wojsyk-Banaszak I, Sobkowiak P, Jończyk-Potoczna K, Narożna B, Langwiński W, Szczepanik M, Kycler Z, Bręborowicz A, Szczepankiewicz A

Abstract
Copeptin was found to be a stable biomarker of inflammation and stress response in cardiac, renal, metabolic, and respiratory conditions such as pneumonia. The aim of this study was to investigate the copeptin levels in biological fluids (serum and sputum supernatant) of cystic fibrosis pediatric patients during pulmonary exacerbation and remission and to investigate the possible influence of copeptin levels on disease severity and quality of life. Copeptin serum concentrations were measured in 28 pediatric cystic fibrosis (CF) patients: 13 in stable condition and 15 during pulmonary exacerbation. In 10 CF patients, copeptin was also measured in the sputum. In all the patients, we assessed complete blood count, BMI, sputum culture, lung function, and chest imaging (with Brasfield score). The severity of symptoms was assessed using the Shwachman-Kulczycki (SK) score, and the quality of life was assessed with the Cystic Fibrosis Quality of Life Questionnaire-Revised (CFQ-R). Copeptin concentrations in serum and sputum supernatant was measured using an ELISA kit. Statistical analysis was done in Statistica v.12. Serum and sputum copeptin levels were higher in CF patients during pulmonary exacerbation than in a stable period, but the differences were not significant (p = 0.58 and p = 0.13, respectively). Copeptin did not correlate significantly with any clinical, laboratory, or spirometry markers of exacerbation. There was, however, a significant inverse correlation between the serum copeptin level and symptoms severity (r = -0.77, p = 0.008) and radiological changes (r = -0.5626, p = 0.036) during pulmonary exacerbation in pediatric CF patients. Copeptin also inversely correlated with the quality of life domains in CF patients: vitality and eating habits, mostly loss of appetite (p = 0.031 and p = 0.016, respectively). Copeptin may be useful to identify patients with a higher risk of deterioration to improve their outcomes.

PMID: 31736654 [PubMed - in process]

Forskolin-induced swelling of intestinal organoids correlates with disease severity in adults with cystic fibrosis and homozygous F508del mutations.

J Cyst Fibros. 2019 Nov 14;:

Authors: de Winter-de Groot KM, Berkers G, Marck-van der Wilt REP, van der Meer R, Vonk A, Dekkers JF, Geerdink M, Michel S, Kruisselbrink E, Vries R, Clevers H, Vleggaar FP, Elias SG, Heijerman HGM, van der Ent CK, Beekman JM

Abstract
BACKGROUND: CFTR function measurements in intestinal organoids may help to better characterise individual disease expression in F508del homozygous people. Our objective was to study correlations between CFTR function as measured with forskolin-induced swelling in rectal organoids with clinical parameters in adult patients with homozygous F508del mutations.
METHODS: Multicentre observational study. Thirty-four adults underwent rectal biopsy, pulmonary function tests (FEV1 and FVC), chest X-ray and chest CT. Body-mass index (BMI) was assessed at study visit and exacerbation rate was determined during five years prior to study visit. Organoids were cultured and measured after stimulation with 5 µm forskolin for three hours to quantitate CFTR residual function.
FINDINGS: FIS was positively correlated with FEV1 (r = 0.36, 95% CI 0.02-0.62, p = 0.04) and BMI (r = 0.42, 95% CI 0.09-0.66, p = 0.015). FIS was negatively correlated with PRAGMA-CF CT score for% of disease (r = -0.37, 95% CI -0.62- -0.03, p = 0.049). We found no significant correlation between FIS and chest radiography score for CF (r = -0.16, 95% CI -0.48-0.20, p = 0.44). We observed a trend between higher FIS and a lower mean number of exacerbations over the last 5 years of observation, but this was not statistically significant (Poisson regression, p = 0.089).
INTERPRETATION: FIS of intestinal organoids varied between subjects with homozygous F508del and correlated with pulmonary and nutritional parameters. These findings suggest that differences at low CFTR residual function may contribute to clinical heterogeneity in F508del homozygous patients and small changes in CFTR residual function might impact long-term disease expression.

PMID: 31735562 [PubMed - as supplied by publisher]

Characterising burden of treatment in cystic fibrosis to identify priority areas for clinical trials.

J Cyst Fibros. 2019 Nov 14;:

Authors: Davies G, Rowbotham NJ, Smith S, Elliot ZC, Gathercole K, Rayner O, Leighton PA, Herbert S, Duff AJ, Chandran S, Daniels T, Nash EF, Smyth AR

Abstract
In a recent James Lind Alliance Priority Setting Partnership in cystic fibrosis (CF) the top priority clinical research question was: "What are effective ways of simplifying the treatment burden of people with CF?" We aimed to summarise the lived experience of treatment burden and suggest research themes aimed at reducing it. An online questionnaire was co-produced and responses subjected to quantitative and thematic analysis. 941 survey responses were received (641 from lay community). People with CF reported a median of 10 (interquartile range: 6-15) current treatments. Seven main themes relating to simplifying treatment burden were identified. Treatment burden is high, extending beyond time taken to perform routine daily treatments, with impact varying according to person-specific factors. Approaches to communication, support, evaluation of current treatments, service set-up, and treatment logistics (obtaining/administration) contribute to burden, offering scope for evaluation in clinical trials or service improvement.

PMID: 31735561 [PubMed - as supplied by publisher]

Chronische Lungenerkrankungen im Kindesalter.

Rofo. 2019 Sep;191(S 02):S115-S116

Authors: Kurzidim L

PMID: 31430777 [PubMed - indexed for MEDLINE]

Chloride Conductance, Nasal Potential Difference and Cystic Fibrosis Pathophysiology.

Lung. 2019 Nov 16;:

Authors: Procianoy EDFA, de Abreu E Silva FA, Maróstica PJC, Quinton PM

Abstract
PURPOSE: Cystic fibrosis (CF) is a multisystem genetic disease caused by dysfunction of the epithelial anionic channel Cystic Fibrosis Transmembrane conductance Regulator (CFTR). Decreased mucociliary clearance because of thickened mucus is part of the pulmonary disease pathophysiology. It is controversial if the thickened airway surface liquid (ASL) is caused by the deficient chloride secretion and excessive sodium (through ENaC) and water hyperabsorption from the periciliar fluid or by the lack of bicarbonate secretion with relative acidification of the ASL. Correlations between the magnitude of in vivo chloride conductance with phenotypic characteristics and CF genotype can help to elucidate these mechanisms and direct to new treatments.
METHODS: Nasal potential difference was measured in 28 CF patients (age from 0.3 to 28 year) and correlated with pulmonary function, pancreatic phenotype, pulmonary colonization and genotype severity.
RESULTS: The CFTR-chloride conductance was better in older patients (r = 0.40; P = 0.03), in patients with better pulmonary function (r = 0.48; P = 0.01), and was associated with genotype severity. Higher chloride diffusion in the presence of a favorable chemical gradient was associated with Pseudomonas aeruginosa negativity (P < 0.05). More negative NPDmax was associated with pancreatic insufficiency (P < 0.01) as well with genotype severity, but not with the pulmonary function.
CONCLUSIONS: The anion permeability through CFTR, mainly chloride, but bicarbonate as well, is the most critical factor in CF airway pathophysiology. Treatments primarily directed to correct CFTR function and/or airway acidity are clearly a priority.

PMID: 31734731 [PubMed - as supplied by publisher]

Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity.

J Cyst Fibros. 2019 Nov 13;:

Authors: Paranjapye A, Ruffin M, Harris A, Corvol H

Abstract
In patients with cystic fibrosis (CF), genetic variants within and outside the CFTR locus contribute to the variability of the disease severity. CFTR transcription is tightly regulated by cis-regulatory elements (CREs) that control the three-dimensional structure of the locus, chromatin accessibility and transcription factor recruitment. Variants within these CREs may contribute to the pathophysiology and to the phenotypic heterogeneity by altering CFTR transcript abundance. In addition to the CREs, variants outside the CFTR locus, namely "modifiers genes", may also be associated with the clinical variability. This review addresses variants at the CFTR locus itself and CFTR CREs, together with the outcomes of the latest modifier gene studies with respect to the different CF phenotypes.

PMID: 31734115 [PubMed - as supplied by publisher]

Efficient Delivery of MicroRNA and AntimiRNA Molecules Using an Argininocalix[4]arene Macrocycle.

Mol Ther Nucleic Acids. 2019 Oct 11;18:748-763

Authors: Gasparello J, Lomazzi M, Papi C, D'Aversa E, Sansone F, Casnati A, Donofrio G, Gambari R, Finotti A

Abstract
MicroRNAs (miRNAs) are short non-coding RNA molecules acting as gene regulators by repressing translation or by inducing degradation of the target RNA transcripts. Altered expression of miRNAs may be involved in the pathogenesis of many severe human diseases, opening new avenues in the field of therapeutic strategies, i.e., miRNA targeting or miRNA mimicking. In this context, the efficient and non-toxic delivery of premiRNA and antimiRNA molecules might be of great interest. The aim of the present paper is to determine whether an argininocalix[4]arene is able to efficiently deliver miRNA, premiRNA, and antimiRNA molecules to target cells, preserving their biological activity. This study points out that (1) the toxicity of argininocalix[4]arene 1 is low, and it can be proposed for long-term treatment of target cells, being that this feature is a pre-requisite for the development of therapeutic protocols; (2) the delivery of premiRNA and antimiRNA molecules is efficient, being higher when compared with reference gold standards available; and (3) the biological activity of the premiRNAs and antimiRNAs is maintained. This was demonstrated using the argininocalix[4]arene 1 in miRNA therapeutic approaches performed on three well-described experimental model systems: (1) the induction of apoptosis by antimiR-221 in glioma U251 cells; (2) the induction of apoptosis by premiR-124 in U251 cells; and (3) the inhibition of pro-inflammatory IL-8 and IL-6 genes in cystic fibrosis IB3-1 cells. Our results demonstrate that the argininocalix[4]arene 1 should be considered a very useful delivery system for efficient transfer to target cells of both premiRNA and antimiRNA molecules, preserving their biological activity.

PMID: 31733592 [PubMed - as supplied by publisher]

Biological characterization of F508delCFTR protein processing by the CFTR Corrector ABBV-2222/GLPG2222.

J Pharmacol Exp Ther. 2019 Nov 15;:

Authors: Singh AK, Fan Y, Balut C, Alani S, Manelli A, Swensen AM, Jia Y, Neelands TR, Vortherms TA, Liu B, Searle XB, Wang X, Gao W, Hwang TC, Ren H, Cyr D, Kym PR, Conrath K, Tse C

Abstract
Cystic Fibrosis (CF) is the most common monogenic autosomal recessive disease in Caucasians caused by pathogenic mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Significant small molecule therapeutic advances over the past two decades have been made to target the defective CFTR protein and enhance its function. To address the most prevalent defect of the defective CFTR protein (i.e. F508del mutation) in CF, two biomolecular activities are required, namely correctors to increase the "amount" of properly folded F508delCFTR levels at the cell surface, and potentiators to allow the effective opening, i.e. "function" of the F508delCFTR channel. Combined, these activities enhance chloride ion transport yielding improved hydration of the lung surface and subsequent restoration of mucociliary clearance. To enhance clinical benefits to CF patients, a complementary "triple combination" therapy consisting of two corrector molecules, type 1 (C1) and type 2 (C2) with additive mechanisms along with a potentiator (P) are being investigated in the clinic for maximum restoration of mutated CFTR function (Hongyu et al., 2017). We report the identification and in vitro biological characterization of ABBV-2222/GLPG2222, a novel, potent and orally bioavailable C1 corrector developed by Abbvie-Galapagos, and currently in clinical trials that exhibits substantial improvements over the existing C1 correctors. This includes improvements in potency and drug-drug-interaction (DDI) compared to VX-809 (herein reported as Lumacaftor) and improvements in potency and efficacy compared to VX-661 (herein reported as Tezacaftor). ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR with an EC50 <10 nM. SIGNIFICANCE STATEMENT: To address the most prevalent defect of the defective CFTR protein (i.e. F508del mutation) in Cystic Fibrosis, Abbvie-Galapagos has developed ABBV-2222/GLPG2222, a novel, potent and orally bioavailable C1 corrector of this protein. ABBV-2222/GLPG2222 exhibits potent in vitro functional activity in primary patient cells harboring F508del/F508del CFTR and is currently in clinical trials that exhibits substantial improvements over the existing C1 correctors.

PMID: 31732698 [PubMed - as supplied by publisher]

TMEM16A chloride channel does not drive mucus production.

Life Sci Alliance. 2019 Dec;2(6):

Authors: Simões FB, Quaresma MC, Clarke LA, Silva IA, Pankonien I, Railean V, Kmit A, Amaral MD

Abstract
Airway mucus obstruction is the main cause of morbidity in cystic fibrosis, a disease caused by mutations in the CFTR Cl- channel. Activation of non-CFTR Cl- channels such as TMEM16A can likely compensate for defective CFTR. However, TMEM16A was recently described as a key driver in mucus production/secretion. Here, we have examined whether indeed there is a causal relationship between TMEM16A and MUC5AC production, the main component of respiratory mucus. Our data show that TMEM16A and MUC5AC are inversely correlated during differentiation of human airway cells. Furthermore, we show for the first time that the IL-4-induced TMEM16A up-regulation is proliferation-dependent, which is supported by the correlation found between TMEM16A and Ki-67 proliferation marker during wound healing. Consistently, the notch signaling activator DLL4 increases MUC5AC levels without inducing changes neither in TMEM16A nor in Ki-67 expression. Moreover, TMEM16A inhibition decreased airway surface liquid height. Altogether, our findings demonstrate that up-regulation of TMEM16A and MUC5AC is only circumstantial under cell proliferation, but with no causal relationship between them. Thus, although essential for airway hydration, TMEM16A is not required for MUC5AC production.

PMID: 31732694 [PubMed - in process]

Burkholderia cenocepacia ET12 transmission in adults with cystic fibrosis.

Thorax. 2019 Nov 15;:

Authors: Blanchard AC, Tang L, Tadros M, Muller M, Spilker T, Waters VJ, LiPuma JJ, Tullis E

Abstract
This report describes transmission of a Burkholderia cenocepacia ET12 strain (ET12-Bc) at the Toronto Adult Cystic Fibrosis (CF) Centre occurring from 2008 to 2017. Epidemiological and genomic data from 11 patients with CF were evaluated. Isolates were analysed using whole genome sequencing (WGS). Epidemiological investigation and WGS analysis suggested nosocomial transmission, despite enhanced infection control precautions. This was associated with subsequent deaths in 10 patients. ET12-Bc positive patients are no longer cared for on the same unit as ET12-Bc negative patients.

PMID: 31732688 [PubMed - as supplied by publisher]

Acute kidney injury as the presenting complaint of ceftazidime-induced immune-mediated haemolysis.

BMJ Case Rep. 2019 Nov 14;12(11):

Authors: Ferro A, Griffiths M, Smith R, Fry A

Abstract
We present the case of ceftazidime-induced immune-mediated haemolysis with associated acute kidney injury in a 43-year-old woman. The patient initially presented to the regional cystic fibrosis centre for treatment of an infective exacerbation of cystic fibrosis. After initiation of ceftazidime (a third-generation cephalosporin), renal function rapidly deteriorated and a fall in haemoglobin was noted. On transfer to our care, a haemolysis screen identified immune-mediated haemolysis, and renal biopsy confirmed the finding of acute tubular necrosis secondary to haem pigment. The patient's renal function deteriorated such that she required haemodialysis, although she subsequently recovered and is now dialysis-independent. Although acute haemolytic reactions are recognised with third-generation cephalosporins, this is the first reported case of ceftazidime-induced immune-mediated haemolysis with acute kidney injury. Given the increased frequency of cephalosporin usage, it is important for both nephrologists and general physicians to be aware of this rare but very serious complication.

PMID: 31732539 [PubMed - in process]

The Sixty-five Roses of Cystic Fibrosis: A Report of Two Autopsy Cases with Kidney Involvement.

Cureus. 2019 Sep 13;11(9):e5641

Authors: Stoyanov GS, Popov H, Petkova L, Dzhenkov DL

Abstract
Cystic fibrosis (CF), also commonly referred to as mucoviscidosis, is a multigene related disorder, involving a defect in the CF transmembrane conductance regulator protein, with over 1,500 genes, being identified with the condition. The most commonly affected organs, often described in the literature, are the lungs, pancreas, intestines, and skin, which is one of the sites for early diagnostic testing. Herein we report two autopsy cases of CF, with multiorgan involvement and some rarely observed and reported changes. Two pediatric cases of clinically confirmed CF were referred for autopsy at the Department of General and Clinical Pathology, St. Marina University Hospital, Varna, Bulgaria. The first case was of a one-year-old female and the second of a six-month-old female. Both cases had classical CF-associated changes in the lungs, liver, pancreas, and small intestine. The kidneys although normal on gross inspection also had severe changes on histology with a compacted matter in the lumen of the distal tubules, some of which had undergone calcification. These histological renal changes are under-reported in literature, thus unlike the classical reported cystic changes we highlight lumen compaction and calcification as the primary histological hallmark in kidneys of patients with CF.

PMID: 31728230 [PubMed]

Multi-Target CFTR Modulators Endowed with Multiple Beneficial Side Effects for Cystic Fibrosis Patients: Toward a Simplified Therapeutic Approach.

J Med Chem. 2019 Nov 15;:

Authors: Tassini S, Langron E, Delang L, Mirabelli C, Lanko K, Crespan E, Kissova M, Tagliavini G, Fontò G, Bertoni S, Palese S, Giorgio C, Ravanetti F, Ragionieri L, Zamperini C, Mancini A, Dreassi E, Maga G, Vergani P, Neyts J, Radi M

Abstract
Cystic fibrosis (CF) is a multi-organ disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR). In addition to respiratory impairment due to mucus accumulation, viruses and bacteria triggers acute pulmonary exacerbations, accelerating disease progression and mortality rate. Treatment complexity increases with patients' age and simplifying the therapeutic regimen represents one of the key priorities in CF. We have recently reported the discovery of multi-target compounds able to "kill two birds with one stone" by targeting F508del-CFTR and PI4KIIIβ and thus acting simultaneously as correctors and broad-spectrum enterovirus (EV) inhibitors. Starting from these preliminary results, we report herein a hit-to-lead optimization and multi-dimensional SAR study that led to compound 23a. This compound showed good antiviral and F508del-CFTR correction potency, additivity/synergy with lumacaftor and a promising in vitro ADME profile. It was well tolerated in vivo with no sign of acute toxicity and histological alterations in key biodistribution organs.

PMID: 31729878 [PubMed - as supplied by publisher]

Role play for genetic counseling learning: Value and students perceptions.

Tunis Med. 2019 Mar;97(3):426-431

Authors: Ben Abdelaziz R, Boudabous H, Hajji H, Ben Messaoud S, Azzouz H, Ben Chehida A, Tebib N

Abstract
BACKGROUND: Performing genetic counseling is one of the tasks of every paediatrician. This assumes prior training during the residency.
AIM: To assess the impact of role-play (RP) for training of paediatric residents in genetic counseling and participants' perception.
METHODS: Repetitive cross-sectional evaluation study. During two RP sessions, two residents played the role of the parents of a patient with cystic fibrosis, and another the role of the doctor. Residents had an evaluation by standardized patient exercises immediately before and after the session. Test scores were compared by the Wilcoxon rank test for associated samples. A satisfaction questionnaire was completed by the participants anonymously.
RESULTS: Post-test scores were better than pre-test scores overall (p = 0.002) and for items in the cognitive domain (p = 0.002). Of the 12 participants, only one had had previous training in genetic counseling. All participants were satisfied with the learning and felt that it would change the way they practice. All participants thought they could do genetic counseling autonomously, but nine of them wanted to have other RP sessions on the same theme. Only one participant found the session stressful and all wanted to multiply this type of sessions for other learning.
CONCLUSION: RP is an effective and well-accepted means for genetic counseling training. It should be integrated with paediatric resident training.

PMID: 31729716 [PubMed - in process]

Accuracy of Body Size Estimation in Youth with Cystic Fibrosis and Association with Health-Related Quality of Life.

J Clin Psychol Med Settings. 2019 Nov 14;:

Authors: Simon SL, Ferris KA, Durkin K, Riekert K, Duncan C

Abstract
Accuracy of body size estimation may impact motivation to adhere to treatment recommendations and health-related quality of life (HRQOL) in youth with cystic fibrosis (CF), but this has not yet been investigated. Thus, the goal of the current study was to examine accuracy of body size estimation in youth with CF, and associations with HRQOL, lung functioning, and dietary intake. Fifty-four youth diagnosed with CF (M = 13.61 years) completed the Figure Rating Scale, the Cystic Fibrosis Questionnaire-Revised, and a 24-h diet recall interview. Cohen's Weighted Kappa Coefficient evaluated agreement between body size estimation and BMI percentile. Binary logistic regression analyses examined associations between body size accuracy and HRQOL, lung functioning, and dietary intake. A less than adequate agreement was found between youth body size estimation and BMI percentile. Most participants overestimated body size (69.8%). Body Image HRQOL, but neither lung functioning nor dietary intake, was significantly associated with body size estimation accuracy. Working with patients to improve perceptions of body size may also improve HRQOL scores and allow for discussion about treatment goals related to body size.

PMID: 31728881 [PubMed - as supplied by publisher]

New severity assessment in cystic fibrosis: signal intensity and lung volume compared to LCI and FEV1: preliminary results.

Eur Radiol. 2019 Nov 14;:

Authors: Fleischer S, Kraus MS, Gatidis S, Baden W, Hector A, Hartl D, Tsiflikas I, Schaefer JF

Abstract
OBJECTIVES: Magnetic resonance imaging (MRI) aids diagnosis in cystic fibrosis (CF) but its use in quantitative severity assessment is under research. This study aims to assess changes in signal intensity (SI) and lung volumes (Vol) during functional MRI and their use as a severity assessment tool in CF patients.
METHODS: The CF intra-hospital standard chest 1.5 T MRI protocol comprises of very short echo-time sequences in submaximal in- and expiration for functional information. Quantitative measurements (Vol/SI at in- and expiration, relative differences (Vol_delta/SI_delta), and cumulative histograms for normalized SI values across the expiratory lung volume) were assessed for correlation to pulmonary function: lung clearance index (LCI) and forced expiratory volume in 1 s (FEV1).
RESULTS: In 49 patients (26 male, mean age 17 ± 7 years) significant correlation of Vol_delta and SI_delta (R = 0.86; p < 0.0001) during respiration was observed. Individual cumulated histograms enabled severity disease differentiation (mild, severe) to be visualized (defined by functional parameter: LCI > 10). The expiratory volume at a relative SI of 100% correlated significantly to LCI (R = 0.676 and 0.627; p < 0.0001) and FEV1 (R = - 0.847 and - 0.807; p < 0.0001). Clustering patients according to Vol_SI_100 showed that an amount of ≤ 4% was related to normal, while an amount of > 4% was associated with pathological pulmonary function values.
CONCLUSION: Functional pulmonary MRI provides a radiation-free severity assessment tool and can contribute to early detection of lung impairment in CF. Lung volume with SI below 100% of the inspiratory volume represents overinflated tissue; an amount of 4% of the expiratory lung volume was a relevant turning point.
KEY POINTS: • Signal intensity and lung volumes are used as potential metric parameters for lung impairment. • Quantification of trapped air impacts on therapy management. • Functional pulmonary MRI can contribute to early detection of lung impairment.

PMID: 31728685 [PubMed - as supplied by publisher]

Microbiological outliers in cystic fibrosis: resolving uncertainty.

Lancet Respir Med. 2019 Nov 11;:

Authors: Cunningham S

PMID: 31727594 [PubMed - as supplied by publisher]

Prevalence and clinical associations of Staphylococcus aureus small-colony variant respiratory infection in children with cystic fibrosis (SCVSA): a multicentre, observational study.

Lancet Respir Med. 2019 Nov 11;:

Authors: Wolter DJ, Onchiri FM, Emerson J, Precit MR, Lee M, McNamara S, Nay L, Blackledge M, Uluer A, Orenstein DM, Mann M, Hoover W, Gibson RL, Burns JL, Hoffman LR, SCVSA study group

Abstract
BACKGROUND: Staphylococcus aureus is the bacterium cultured most often from respiratory secretions of people with cystic fibrosis. Both meticillin-susceptible S aureus and meticillin-resistant S aureus (MRSA) can adapt to form slow-growing, antibiotic-resistant isolates known as small-colony variants that are not routinely identified by clinical laboratories. We aimed to determine the prevalence and clinical significance of S aureus small-colony variants and their subtypes among children with cystic fibrosis.
METHODS: The Small Colony Variant Staphylococcus aureus (SCVSA) study was a 2-year longitudinal study of children aged 6-16 years at five US cystic fibrosis centres, using culture methods sensitive for small-colony variants. Children were eligible if they had a documented diagnosis of cystic fibrosis and a minimum of two cystic fibrosis clinic visits and two respiratory cultures in the previous 12 months at enrolment. Participants attended clinic visits quarterly, at which respiratory tract samples were taken and measures of lung function (percentage of predicted forced expiratory volume in 1 s [FEV1] and frequency of respiratory exacerbations) were recorded. We determined the prevalence of small-colony variants and their subtypes, and assessed their independent associations with lung function and respiratory exacerbations using linear mixed-effects and generalised estimating equation logistic regression models. Analyses included both univariate models (unadjusted) and multivariate models that adjusted for potential confounders, including age, sex, race, baseline microbiology, treatment with CFTR modulator, and CTFR genotype.
FINDINGS: Between July 1, 2014, and May 26, 2015, we enrolled 230 children. Participants were followed-up for 2 years, with a mean of 6·4 visits (SD 1·14) per participant (range 2-9 visits) and a mean interval between visits of 3·94 months (SD 1·77). Across the 2-year period, S aureus small-colony variants were detected in 64 (28%) participants. Most (103 [56%] of 185) of the small-colony variants detected in these participants were thymidine dependent. Children with small-colony variants had significantly lower mean percentage of predicted FEV1 at baseline than did children without small-colony variants (85·5 [SD 19] vs 92·4 [SD 18·6]; p=0·0145). Small-colony variants were associated with significantly lower percentage of predicted FEV1 throughout the study in regression models, both in univariate analyses (regression coefficient -7·07, 95% CI -12·20 to -1·95; p=0·0068) and in multivariate analyses adjusting for potential confounders (-5·50, -10·51 to -0·48; p=0·0316). Small colony variants of the thymidine-dependent subtype had the strongest association with lung function in multivariate regression models (regression coefficient -10·49, -17·25 to -3·73; p=0·0024). Compared with children without small-colony variants, those with small-colony variants had significantly increased odds of respiratory exacerbations in univariate analyses (odds ratio 1·73, 95% CI 1·19 to 2·52; p=0·0045). Children with thymidine-dependent small-colony variants had significantly increased odds of respiratory exacerbations (2·81, 1·69-4·67; p=0·0001), even after adjusting for age, sex, race, genotype, CFTR modulator, P aeruginosa culture status, and baseline percentage of predicted FEV1 (2·17, 1·33-3·57; p=0·0021), whereas those with non-thymidine-dependent small-colony variants did not. In multivariate models including small-colony variants and MRSA status, P aeruginosa was not independently associated with lung function (regression coefficient -4·77, 95% CI -10·36 to 0·83; p=0·10) and was associated with reduced odds of exacerbations (0·54, 0·36 to 0·81; p=0·0028). Only the small-colony variant form of MRSA was associated with reduced lung function (-8·44, -16·15 to -0·72; p=0·0318) and increased odds of exacerbations (2·15, 1·24 to 3·71; p=0·0061).
INTERPRETATION: Infection with small-colony variants, and particularly thymidine-dependent small-colony variants, was common in a multicentre paediatric population with cystic fibrosis and associated with reduced lung function and increased risk of respiratory exacerbations. The adoption of small-colony variant identification and subtyping methods by clinical laboratories, and the inclusion of small-colony variant prevalence data in cystic fibrosis registries, should be considered for ongoing surveillance and study.
FUNDING: The Cystic Fibrosis Foundation and the National Institutes of Health.

PMID: 31727592 [PubMed - as supplied by publisher]